IBD Literature Report
Coverage: July 05, 2026 - July 12, 2026
146
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Therapeutics & Mechanisms (21 papers)
Efficacy and safety of ustekinumab in Asian patients with moderately to severely active Crohn’s disease: a small subpopulation analysis of UNITI/IM-UNITI long-term extension through 5 years. Intestinal research | 2026-07-10
This final long-term extension (LTE) analysis assessed the long-term efficacy and safety of ustekinumab (UST) in the Asian patient subpopulation of the UNITI/IM-UNITI study. Patients completing safety and efficacy evaluations at Week 44 of the maintenance study were eligible to participate in the LTE and continued their UST treatment. Unblinding occurred after Week 44 analyses were completed, and patients still receiving placebo were discontinued; no placebo data were reported beyond Week 44 in this report. Efficacy assessments were performed every 12 weeks (q12w) until unblinding and at dosing visits thereafter through Week 252. Safety events (per 100 patient-years [PY]) were assessed through Week 272. Sixty-three Asian patients entered the LTE. At Week 44, clinical response/clinical remission rates in the UST 90 mg subcutaneous (SC) q12w and every 8 weeks (q8w) arms were 75.0%/58.3% and 61.5%/53.8%, respectively. At Week 252, clinical response/clinical remission rates in the UST 90 mg SC q12w and q8w arms were 58.3%/41.7% and 23.1%/15.4%, respectively. Normalized C-reactive protein levels were maintained over 252 weeks of UST treatment. Among patients who entered the LTE, the number of treatment-emergent adverse events and serious infections in the UST 90 mg SC combined group was 267.2/100 PY and 4.5/100 PY, respectively. Maintenance therapy with UST 90 mg SC was well tolerated and efficacious in maintaining clinical remission and response rates through 5 years in Asian patients with Crohn’s disease, consistent with the global population. (ClinicalTrials.gov Identifier: UNITI-1 [NCT01369329], UNITI-2 [NCT01369342], and IM UNITI [NCT01369355]).
Ye BD, Sugimoto K, Cheon JH, Gasink C, Imai Y, Wahking B, Zhuo J, Kawamura S, Hibi T
Efficacy and safety of ozanimod in Japanese patients with moderately to severely active ulcerative colitis naive to immunomodulators or advanced therapies: post hoc analysis of the phase 2/3 J-True North study. Intestinal research | 2026-07-10
There is limited evidence for ozanimod, an oral sphingosine 1-phosphate receptor modulator, in patients with ulcerative colitis (UC) before treatment is escalated to an immunomodulator (IM) or advanced therapy (AT), including biologics and Janus kinase inhibitors. We performed post hoc analyses to examine the efficacy and safety of ozanimod 0.92 mg versus placebo in a subgroup of Japanese IM-/AT-naive patients with moderately to severely active UC, without concomitant corticosteroids (CS), enrolled in the randomized J-True North study. The analyses comprised 29 and 30 patients treated with ozanimod 0.92 mg and placebo, respectively. The clinical response rate was significantly greater in the ozanimod group at Week 12 (75.9% vs. 40.0%; P=0.0103) and Week 52 (62.1% vs. 16.7%; P=0.0010). Clinical remission, endoscopic improvement, and histologic remission rates at Weeks 12 and 52 were significantly better in the ozanimod group. Changes in the rectal bleeding subscore, stool frequency subscore, symptomatic response, and symptomatic remission were apparent by Week 2 in both groups, and tended to be better in the ozanimod group from Week 5 onward. Treatment-emergent adverse events occurred in 79.3% and 63.3% of patients in the ozanimod and placebo groups, respectively; the most frequent were nasopharyngitis (ozanimod vs. placebo: 17.2% vs. 13.3%) and pyrexia (13.8% vs. 10.0%, respectively). This subgroup analysis demonstrated that ozanimod 0.92 mg was significantly more effective than placebo in Japanese IM-/AT-naive UC patients without concomitant CS therapy, consistent with the results of global trials. The safety profile of ozanimod 0.92 mg was consistent with prior studies. ClinicalTrials.gov (NCT03915769) and the Japan Registry of Clinical Trials (jRCT2080224654).
Hisamatsu T, Fujii T, Nakase H, Matsuoka K, Saruta M, Kobayashi T, Inoue S, Toriyama K, Wang D, Uchikawa Y
Efficacy of Ustekinumab on Skin Reactions Induced by Tumor Necrosis Factor-Alpha Inhibitors in Patients with Inflammatory Bowel Disease. Inflammatory intestinal diseases | 2026-07-09
Tumor necrosis factor-alpha (TNF-α) inhibitors sometimes induce skin reactions in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Ustekinumab (UST) has been reported to be effective in treating TNF-α inhibitor-induced skin reactions. Here, we aimed to investigate the efficacy of UST on skin reactions and its long-term efficacy in the treatment of CD and UC. CD and UC patients who switched to UST due to skin reactions (skin reaction group) or secondary failure of TNF-α inhibitors (non-skin reaction group) in our hospital between June 2017 and September 2023 were included. The primary outcome was the efficacy of UST for skin reactions, classified as complete remission, partial remission, or no response. The secondary outcome was cumulative UST continuation, assessed using Kaplan-Meier analysis and Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was performed after adjusting for age, clinical remission status, and type of inflammatory bowel disease (CD or UC). Eighty-two patients (CD, 68; UC, 14) were included; 20 developed skin reactions, most commonly psoriasiform dermatitis (30%). After switching to UST, 15 patients achieved complete remission of the skin reaction, and four achieved partial remission. After IPTW adjustment, the UST continuation rate did not differ significantly between groups (p = 0.205), and skin reactions were not associated with UST continuation (hazard ratio 0.55; 95% CI: 0.24-1.26; p = 0.159). UST was effective for 95% of TNF-α inhibitor-induced skin reactions without affecting long-term UST continuation, supporting its clinical utility.
Fujimoto K, Hosomi S, Kobayashi Y, Nakata R, Nishida Y, Maruyama H, Ominami M, Nadatani Y, Fukunaga S, Otani K
Real-World Effectiveness, Safety and Quality of Life With Ustekinumab for the Treatment of Crohn’s Disease: Results of the UK Ustekinumab Real World Evidence Study (UndieS) Study Group.★ Alimentary pharmacology & therapeutics | 2026-07-09
While randomised controlled trials have demonstrated the efficacy of ustekinumab for treating Crohn’s disease (CD), real-world effectiveness and patient experience in heterogeneous clinical populations remain less well characterised. We aimed to assess the effectiveness and safety of ustekinumab in routine clinical care incorporating patient-reported outcomes. This prospective multicentre study recruited adult patients initiating ustekinumab for CD as part of routine clinical care across 22 UK hospitals. Study visits were conducted at baseline and at Weeks 8, 16/20, 56, 80 and 104. Data collected included participant demographics, disease phenotype, previous treatment history, disease activity scores, laboratory measures, dosing regimens, patient-reported outcomes (patient experience, quality of life [QoL] and treatment satisfaction) and adverse events. The primary outcome was corticosteroid-free clinical remission (defined as mHBI < 5) at Week 56. Six hundred one participants were recruited between October 2019 and August 2023, with 20% naïve to advanced therapies. At baseline, 43% of participants were assessed as being in clinical remission according to mHBI, whereas only 12% had quiescent disease per the IBD-Control questionnaire. The primary endpoint was achieved by 33% of participants (95% CI, 30%-37%). Cumulative probabilities of ustekinumab persistence were 78% at 1 year and 63% at 2 years. The IBD-Control-8 score showed improvement from baseline to Week 8, increasing from a median of 5 (IQR: 2-10) to 12 (IQR: 8-14), though QoL impairment remained evident in many participants. Most adverse events were mild and consistent with the established safety profile of ustekinumab. In this large real-world cohort, ustekinumab treatment was associated with sustained improvements in both clinical outcomes and QoL measures. Our data suggest that patients treated in clinical practice differ markedly from Phase 3 trial participants. QoL, and not only disease activity as assessed using a conventional disease activity score, may play a significant role in the decision to initiate ustekinumab. Systematic integration of QoL measures into routine care may improve patient care and treatment outcomes.
Young D, Booker C, Samaan M, Kok K, Donovan F, Hart A, Batchelor J, Limdi J, Bodger K, Cummings JRF
Clinical characteristics, treatment and prognosis of ixekizumab-induced inflammatory bowel disease. Immunopharmacology and immunotoxicology | 2026-07-09
Background： To explore the clinical characteristics of ixekizumab-induced inflammatory bowel disease (IBD) and provide references for prevention, diagnosis and treatment.Methods： Clinical reports of ixekizumab-induced IBD published on December 31, 2025 were collected for retrospective analysis.Results： A total of 30 patients were enrolled, with a median age of 47.5 years (range 21, 81). The median time of IBD onset was 4 months (range 0.25, 24). Abdominal pain (80.0%), diarrhea (56.7%), hematochezia (30.0%), bloody diarrhea (26.7%), weight loss (26.7%), and fever (23.3%) were the main symptoms. Colonoscopy can reveal ulcers (80.0%), loss of vascular pattern (26.7%), erythema (26.7%), friability (26.7%), colitis (23.3%), and bleeding (20.0%). After discontinuing ixekizumab and receiving systemic steroids (70.0%), anti-TNF therapy (53.3%), and mesalazine treatment, most patients experienced symptom improvement.Conclusion： Ixekizumab was associated with exacerbation or new-onset IBD within the first six months. Gastrointestinal symptoms and a family history of IBD should be ruled out before ixekizumab is administered. During the treatment with ixekizumab, the patient’s gastrointestinal symptoms should be closely monitored.
Pan Y, Sun W, Wang C
Phage intervention improves colitis and response to corticosteroids by attenuating virulence of Crohn’s disease-associated bacteria. Science translational medicine | 2026-07-08
Adherent-invasive Escherichia coli (AIEC) exhibits proinflammatory properties and has been implicated in the pathogenesis of Crohn’s disease (CD), a form of inflammatory bowel disease (IBD). Antibiotic use in CD lacks specificity and may worsen microbiome disruption, prompting interest in bacteriophages (phages) for targeted microbiome editing. Here, we identified HER259, a phage active against clinical AIEC isolates. HER259 ameliorated colitis in gnotobiotic models and attenuated the virulence of AIEC strain NRG857c, including suppression of the FimH adhesin through inversion of the fimS promoter to its “off” orientation. The effects were confirmed in CD-microbiota colitis models. Withdrawal of HER259 treatment led to reversion of the fimS promoter and reactivated colitis. The HER259 phage also enhanced the therapeutic effect of subtherapeutic budesonide independent of microbial drug metabolism. These findings support targeted phage therapy as an adjunct treatment approach in IBD, demonstrating modulation of bacterial virulence and improved response to conventional treatments that may reduce drug-related side effects.
Jackson K, Galipeau HJ, Hann A, Constante M, Zangara MT, Bording-Jorgensen M, Fuentes A, Ho H, Wang J, Shimbori C
Early real-world effectiveness of mirikizumab in a difficult-to-treat ulcerative colitis cohort.Case report Gastroenterologia y hepatologia | 2026-07-07
Abstract not available.
Elosua A, Zabalza L, Vicuña M, Rubio S, Nantes Ó, Arrondo A, Rodríguez C
Effectiveness and safety of Ustekinumab in older patients with Crohn´s disease with high comorbidity burden: a real-world study. Gastroenterologia y hepatologia | 2026-07-07
Elderly patients are an increasingly relevant group in inflammatory bowel disease, yet clinical trials often exclude them. Ustekinumab might be a suitable treatment due to its adequate clinical and excellent safety outcomes. Our primary aim was to evaluate 1- and 2-year clinical remission rates. Secondary aims included steroid-free clinical and biochemical remission rates and treatment persistence. A bi-center retrospective observational study was performed, including patients aged ≥50 years with CD and an age-adjusted Charlson comorbidity index ≥3 starting ustekinumab between January 2017 and October 2023. Clinical remission was defined as a Harvey-Bradshaw Index <5 and biochemical remission as fecal calprotectin <250 mg/kg together with C-reactive protein <5mg/L. Severe infections were those requiring hospitalization, and incident malignancies were defined as new diagnoses following the first ustekinumab dose. Eighty-two patients were included, with a median age of 70.1 (IQR: 62.3-76) years and a median Charlson index of 4 (3-5). Ustekinumab achieved 1- and 2-year clinical remission rates of 88.1% and 77.6%, respectively, with a 2-year biochemical remission rate of 35.4%. Steroid free clinical remission at 1- and 2-years were 88.1% and 75.5%, respectively. Prior exposure to biologics was associated with lower remission rates. The 2-year treatment persistence rate was 94% (84.6%-97.8%). Overall, 54 (65.9%) patients underwent dose intensification. Severe infections and new malignancies occurred in 4.9% of patients during follow-up. Ustekinumab attained high 2-year clinical remission and treatment persistence rates, although with a 35.4% biochemical remission rate. Besides, the incidence of severe infections was low and within the expected range for this age group.
Martínez-Cuevas C, Morera-Sauca L, Madrigal RE, Barrio J, Asenjo CB, Utrilla SU, Perez-Miranda M, Ramos CL, Mata L, García-Alonso FJ
Cancer risk with methotrexate-TNF antagonist combination therapy compared to TNF-antagonist monotherapy in IBD.★ Inflammatory bowel diseases | 2026-07-07
In patients with inflammatory bowel diseases (IBD), tumor necrosis factor antagonists (anti-TNFs) are frequently used alongside immunomodulators to improve treatment efficacy. While an increased risk of cancers with thiopurines is well established, there is sparse data on cancer risk with methotrexate. We conducted a retrospective cohort study of patients with Crohn’s disease (CD) or ulcerative colitis (UC) at a large, integrated healthcare system. Eligible patients received either anti-TNF monotherapy or combination (anti-TNF + methotrexate) between 1999 and 2025. The primary outcome was incident cancer confirmed by chart review. Cox-proportional hazards models were used to identify the independent effect of combination therapy on cancer risk, adjusting for relevant covariates. Our study included 2332 patients with IBD (80.9%) on anti-TNF monotherapy and 549 (19.1%) on combination therapy. Mean age at inclusion was 35 years, and 75.8% had CD. Mean follow-up duration was 3.3 years. Over 1353 and 8031 person-years of follow-up, incidence rates of all cancers were 7.4 and 6.4 per 1000 person-years in the combination and monotherapy groups, respectively (P = .64). We observed no increased risk of cancer between groups for all cancers (adjusted HR 0.94, 95% CI, 0.47-1.89), skin cancer (adjusted HR 0.57, 95% CI, 0.07-4.51) or non-skin cancers (adjusted HR 1.00, 95% CI, 0.48-2.11). Age ≥ 60 years and prior thiopurine exposure were associated with an increased risk of cancer. Combination anti-TNF and methotrexate therapy was not associated with an increased cancer risk compared to anti-TNF monotherapy in patients with IBD in our cohort.
Anvari S, Wanchaitanawong W, Xiong X, Cai T, Ananthakrishnan AN
Assessing trial eligibility and real-world response to vedolizumab and ustekinumab in patients with ulcerative colitis. Scandinavian journal of gastroenterology | 2026-07-06
Biologic therapies for patients with inflammatory bowel disease (IBD) were approved via large randomized controlled trials (RCTs) with strict criteria for patient enrollment. As newer IBD medications are approved, ongoing assessment is necessary to determine whether RCT eligibility criteria are too restrictive or adequately reflect real-world practice. Here, we investigate the trial-eligibility and clinical outcomes of patients with ulcerative colitis (UC) started on vedolizumab (VDZ) and ustekinumab (UST) therapy. This single-center retrospective cohort study at a large academic IBD referral center included patients with UC who received a new prescription for UST or VDZ between January 2020 and June 2023. The primary outcome assessed whether patients met trial eligibility using the inclusion and exclusion criteria from the UNIFI and GEMINI-1 RCTs. We also assessed treatment failure between the trial-eligible and ineligible groups. Only 19/168 (11.3%) of patients with UC (n = 85 receiving VDZ; n = 83 receiving UST) were trial-eligible. The most common reasons for ineligibility were prior biologics and inadequate wash-out periods, the use of topical therapy, medical comorbidities and ongoing treatment with high doses of prednisone. Treatment failure was numerically higher in trial-ineligible compared to trial-eligible patients, though this difference was not statistically significant. Most patients initiated on UST or VDZ would not have qualified for inclusion in their respective RCTs, largely due to current treatments. Revising trial eligibility criteria may be warranted to improve external validity and enable recruitment of a more diverse study population representative of real-world patients.
Le Breton S, Mithal A, Ahmed T, Huh J, Papamichael K, Cheifetz AS
Long-term clinical and endoscopic efficacy of vedolizumab and therapeutic persistence in patients with ulcerative colitis in China: a multicenter observational study. Intestinal research | 2026-07-06
Limited data are available on the long-term efficacy of vedolizumab (VDZ) in Asian patients with ulcerative colitis (UC), particularly regarding endoscopic outcomes. In this multicenter, retrospective, real-world study, UC patients treated with VDZ were evaluated for steroid-free remission, endoscopic remission (Mayo endoscopic score ≤ 1), and mucosal healing (Mayo endoscopic score = 0) at weeks 52, 104, and 156. Treatment persistence was analyzed using Kaplan-Meier curves. Among 239 patients, steroid-free remission was achieved in 59.4%, 52.9%, and 40.3% at weeks 52, 104, and 156, respectively. Endoscopic remission and mucosal healing rates were 53.3% and 32.2% at week 52, 39.8% and 27.5% at week 104, and 34.8% and 26.2% at week 156. The probability of treatment persistence was 76.8%, 63.3%, and 56.4% at these time points. Anti-tumor necrosis factor (anti-TNF) exposure was independently associated with a higher risk of failing to achieve long-term VDZ persistence (hazard ratio [HR], 2.754; 95% confidence interval [CI], 1.478-5.135; P= 0.001), whereas achieving early steroid-free remission after induction was an independent protective factor (HR, 0.480; 95% CI, 0.235-0.978; P= 0.043). VDZ-related adverse events occurred in 7.1% of patients, with no serious events reported. VDZ demonstrated long-term clinical and endoscopic efficacy with a high safety profile in Chinese UC patients. Notably, anti-TNF-naive patients with early steroid-free remission were more likely to maintain long-term treatment persistence.
Huang Z, Yao L, Qiu Y, Chao K, Li Q, Lin L, Liu J, Mao R, Cao Q, Chen M
Effectiveness and safety of mirikizumab in multirefractory ulcerative colitis: analysis from a real-world cohort. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver | 2026-07-04
Mirikizumab is a selective anti-IL-23 monoclonal antibody approved for moderate-to-severe ulcerative colitis (UC). Evidence regarding its efficacy mostly derives from registration trials, as real-world data in multi-refractory populations remain limited. We conducted an observational study including UC patients treated with mirikizumab. Clinical activity was assessed using the partial Mayo (pMayo) score at baseline, Week12 (W12), and Week24 (W24). Urgency, biomarkers, endoscopic activity and safety were evaluated. Steroid-free clinical remission (SFCR) was defined as pMayo≤1 without corticosteroids; clinical response as ≥3-point or ≥30% reduction. Changes over time were analyzed using paired non-parametric tests; logistic regression identified predictors of remission. One-hundred-twenty-three highly treatment-expierenced patients were included (median 3 prior advanced therapies, IQR 2-4). Most patients (89.0%) continued extended IV induction after W12. SFCR was achieved in 25.2% (31/123) at W12 and 31.3% (30/96) at W24, while clinical response occurred in 70.7% and 67.7%, respectively. Bowel urgency improved at W12 and W24 (p<0.001). Adverse events occurred in 20.3% of patients; the colectomy rate was 4.9%. Higher baseline pMayo and prior JAKi exposure were associated with lower remission. Mirikizumab showed encouraging effectiveness and safety in multirefractory UC. Prior JAKi exposure emerged as a potential negative predictor of remission; this hypothesis-generating signal warrants validation.
Melotti L, Monicelli O, Dussias NK, Pardi V, Jairath V, Hupé M, Salice M, Privitera Hrustemovic H, Gionchetti P, Rizzello F
Randomized trial comparing 5-year follow-up of first-line infliximab to conventional therapy in paediatric Crohn’s disease.★ Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2026-07-04
The TISKids study previously demonstrated that first-line infliximab (FL-IFX) was more effective than conventional treatment in achieving clinical remission without treatment escalation at 52 weeks in children with moderate-to-severe Crohn’s disease (CD). We investigated 5-year outcomes. The TISKids is a multicentre, open-label randomised controlled trial in newly diagnosed, untreated CD patients aged 3-17 years (wPCDAI>40). Patients were randomised to FL-IFX (five IFX infusions, then stopped) or conventional treatment (exclusive enteral nutrition or prednisolone). Both groups received azathioprine maintenance. The primary outcome was sustained clinical remission (wPCDAI<12.5, CDAI<150 or PGA remission) without additional CD-related therapy at 5 years. Secondary outcomes included time to (re)start IFX or another biological. One-hundred patients were randomised; six were lost to follow-up. At 5 years, sustained clinical remission without additional CD-related therapy was observed in 3/48 (6%) FL-IFX patients versus 1/46 (2%) of conventionally treated patients(p=0.617), whilst 42/48 (88%) in FL-IFX and 44/46 conventionally treated patients required additional CD-related treatment (p=0.271). Median time to (re)start of biologic therapy was 65 weeks [95%CI 53-122] for FL-IFX versus 31 weeks [95%CI 22-57] for conventional treatment (p=0.037). After 5-years follow-up in the TISKids trial, we found that almost all patients required additional CD-related treatment, irrespective of induction therapy with five infusion of FL-IFX or conventional treatment. FL-IFX delayed the need for additional biological treatment, indicating its potential as preferred treatment option for patients with moderate-to-severe CD at diagnosis. These findings underscore that patients with moderate-to-severe CD require early and maintained treatment with infliximab.
Vuijk SA, Jongsma MME, Cozijnsen MA, van Pieterson M, de Meij TGJ, Groeneweg M, Wolters VM, van Wering H, Hojsak I, Kolho KL
Cytotoxic T-Lymphocyte-Associated Protein 4 Deficiency Colitis Masked by Recurrent Cytomegalovirus Colitis Successfully Treated With Vedolizumab.Case report ACG case reports journal | 2026-07-03
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) deficiency is a primary immunodeficiency syndrome caused by mutations in the CTLA-4 gene. Its heterogeneous presentation, often with multisystem involvement, can result in delayed diagnosis and treatment. CTLA-4 deficiency colitis (CDC) is endoscopically and histologically indistinguishable from inflammatory bowel disease and may be masked by a secondary process, underscoring the importance of genetic testing. We present a case of corticosteroid-refractory CDC in a frail, comorbid woman that was masked by recurrent cytomegalovirus colitis. Vedolizumab was commenced and steroid-free clinical remission was achieved after 5 months. There was no recurrence of colitis until vedolizumab was self-ceased after 12 months. CDC flared 7 months post vedolizumab cessation but due to patient preference, it was not recommenced.
Shibu R, Soosaipillai G, Rajendran Pillai S, Mohsen W
Comments on “Prevalence, patient characteristics and outcomes of high-dose upadacitinib in inflammatory bowel disease”.Letter Therapeutic advances in gastroenterology | 2026-07-02
Risk of Infections With Infliximab vs Adalimumab Among Children With Inflammatory Bowel Disease.★ JAMA network open | 2026-07-01
Infliximab and adalimumab are the only biologics approved by the US Food and Drug Administration for use in children with inflammatory bowel disease (IBD). The comparative infection risks between infliximab and adalimumab have not been evaluated in clinical settings. To compare the risk of infections with infliximab vs adalimumab among pediatric patients with IBD using nationwide claims data. This cohort study used data from 2 nationwide health care claims databases from January 1, 2016, to February 28, 2025. The study included children and adolescents aged 6 to 17 years with a diagnosis of Crohn disease or ulcerative colitis who newly initiated infliximab or adalimumab and had 180 days or more of prior continuous enrollment. Initiation of adalimumab vs infliximab. Serious infections were defined as infections requiring hospitalization, using a validated algorithm. Outpatient infections were defined as an outpatient infection diagnosis with a targeted antimicrobial dispensed within 1 day. Baseline covariates within each dataset were balanced with 1:1 propensity score matching and results were pooled using fixed effects meta-analysis. Incidence rates and hazard ratios (HRs) were estimated over a 180-day follow-up. After applying exclusion criteria, 4239 children with IBD initiating infliximab (2467; mean [SD] age, 13.3 [2.9] years; 1462 boys [59.3%]; 1502 with Crohn disease [60.9%]) or adalimumab (1772; mean [SD] age, 14.0 [2.7] years; 1047 boys [59.1%]; 1068 with Crohn disease [60.3%]) were identified. After matching, each exposure group included 1533 patients. The incidence of serious infections was 29 per 1000 person-years for infliximab (reference) and 34 per 1000 person-years for adalimumab (pooled HR, 1.15; 95% CI, 0.63-2.11). Outpatient infections were more common, with rates of 358 per 1000 person-years for infliximab and 386 per 1000 person-years for adalimumab (pooled HR, 1.08; 95% CI, 0.90-1.29). Results of sensitivity analyses, including restriction to monotherapy, originator-only use, first-line users only, exclusion of gastrointestinal infections from the outcome, and extending follow-up to 365 days, were all consistent with the primary findings. No mycobacterial infections were observed in the overall cohort. In this cohort study of children and adolescents with IBD, serious infections were rare. No evidence of differences in infection risk were observed between infliximab and adalimumab. These findings suggest that the 2 agents may have comparable infection risk profiles in pediatric IBD, although meaningful differences cannot be ruled out.
Lyu N, Tracy M, Schneeweiss S, Savage TJ
Correction to: P0562 Comparative Efficacy and Safety of Upadacitinib Versus Oral Prednisolone for the Induction of Remission in Ulcerative Colitis: A Prospective, Multicenter, Open-label, Randomized Controlled Trial (PREDUPA Trial) Protocol and P0563 Mirikizumab Demonstrated Sustained and Durable Long-Term Efficacy and Favorable Safety in Week 52 Endoscopic Responders with Crohn’s disease: 3-year VIVID-2 Open-Label Extension Interim Results.★ Journal of Crohn’s & colitis | 2026-07
Comparative efficacy of advanced therapies in biological-exposed ulcerative colitis - a network meta-analysis of randomized trials. European journal of gastroenterology & hepatology | 2026-06-29
Patients with ulcerative colitis who fail biological therapy represent a challenging population with limited comparative evidence to guide the sequencing of advanced treatments. The present network meta-analysis aimed to compare the efficacy of biologics and small molecules for the induction and maintenance of remission in biological-exposed ulcerative colitis. We conducted a systematic review of randomized controlled trials (RCTs) from MEDLINE, Embase, and Scopus enrolling adults with moderate-to-severe ulcerative colitis and prior exposure or failure to biologicals from inception to March 2025. Outcomes included induction and maintenance of clinical remission. Frequentist and Bayesian random-effects models were applied, and comparative efficacy was ranked using surface under the cumulative ranking curve (SUCRA) values. Twenty-one RCTs (n = 5417 induction; n = 3076 maintenance) were included. For induction, most advanced therapies outperformed placebo, though adalimumab, vedolizumab, ozanimod, and mirikizumab did not reach statistical significance. Upadacitinib ranked highest for induction (SUCRA: 89.3), followed by tofacitinib (88.5) and ustekinumab (77.5). For maintenance, all evaluated agents were superior to placebo. Upadacitinib ranked highest (SUCRA: 85.9), followed by vedolizumab (73.6) and etrasimod (71.8). Subgroup analysis of re-randomized studies confirmed the superiority of upadacitinib and vedolizumab. Certainty of evidence was generally low due to imprecision and publication bias. In biologic-experienced ulcerative colitis, upadacitinib demonstrated the highest efficacy for both induction and maintenance of remission, with tofacitinib and ustekinumab effective alternatives for induction, and vedolizumab a strong option for long-term maintenance. Further head-to-head trials in biologic-experienced populations are warranted.
Giri S, Kulkarni A, Harindranath S, Malakar S, Jena A, Joshi H, Nath P
pH-responsive microgels containing multifunctional ginsenoside Rh2-based liposomes remodel intestinal environment to enhance celastrol therapy for ulcerative colitis. Materials today. Bio | 2026-06-29
Ulcerative colitis (UC) is a chronic inflammatory bowel disease closely associated with intestinal mucosal barrier damage, abnormal immune responses, and gut microbiota dysbiosis. Celastrol (Cel), a natural triterpenoid compound, has shown great potential in modulating macrophage polarization and inhibiting inflammation. However, its clinical translation is hampered by poor solubility and nonspecific biodistribution. To address these issues, we developed a novel drug delivery system. Initially, functional liposomes (Rh2-LPs@Cel) were constructed by substituting cholesterol with ginsenoside Rh2. This strategy not only reduced drug leakage and enhanced the formulation stability, but also imparted intrinsic bioactivity to the carrier. Subsequently, these liposomes were coated with chitosan-sodium alginate to form a pH-responsive microgel (M/Rh2-LPs@Cel) for colon-targeted delivery. Experimental results showed that this microgel could precisely deliver drugs to the colon after oral administration. It effectively promoted the polarization of macrophages towards an anti-inflammatory phenotype, reduced the levels of pro-inflammatory factors, reshaped the diversity of the gut microbiota, elevated short-chain fatty acid levels, and repaired the intestinal epithelial barrier, thereby alleviating the colonic pathological damage induced by dextran sulfate sodium in mice. It is worth noting that M/Rh2-LPs@Cel did not show significant toxicity in vitro or in vivo. In conclusion, this work presents a promising approach for UC that combines efficient drug delivery, targeted release, and multiple therapeutic effects. Our findings provide a valuable foundation for the clinical application of natural bioactive compounds in inflammatory bowel disease management.
Lin P, Wang Z, Yang W, Yang X, Yu M, Fang J, Ma Z, Zhou A, Yu W
Synergistic effects of partial enteral nutrition combined with Ustekinumab in induction and maintenance therapy for Crohn’s disease: Real-world experience from a multicentre cohort. Clinical nutrition (Edinburgh, Scotland) | 2026-06-25
Ustekinumab (UST) is effective for Crohn’s disease (CD) but has some limitations. Partial enteral nutrition (PEN) may be helpful for CD remission, yet its ability to augment UST efficacy remains undefined. This study assessed the value of PEN combined with UST as induction and maintenance therapy for CD. Patients with active CD who were treated with UST for over 52 weeks were included from three Inflammatory Bowel Disease centres in China during January 2021 to July 2023. Patients were divided into the UST + PEN group and the UST-alone group according to whether they were combined with PEN (taking enteral nutrition ≥900 kcal/day). Outcomes measured at week 24 (induction phase) and week 52 (maintenance phase) included nutritional/inflammatory markers, CD Activity Index (CDAI), Simple Endoscopic Score for CD (SES-CD), intestinal wall thickness, and blood flow (via intestinal ultrasound or computed tomography enterography). Deep remission, clinical, endoscopic, and radiological response/remission, plus intestinal/perianal complications, were compared using the propensity score weighting method. A total of 229 patients (157 UST-alone and 72 UST + PEN) were enrolled; median PEN intake was 1560 kcal/day (IQR: 900-1800 kcal/day) over a median of 180 days (IQR: 60-309 days). The UST + PEN group achieved a higher rate of clinical remission at week 24 and a superior rate of deep remission, clinical remission, endoscopic response, endoscopic remission, and radiologic response at week 52 (all p < 0.05). The combination therapy group had more benefits in improving intestinal stenosis and perianal disease (both p < 0.05). In addition, the UST + PEN group showed significant improvements in nutritional indicators (hemoglobin and albumin), along with reductions in inflammatory markers. Subgroup analyses further demonstrated the superiority of UST + PEN treatment in TNFi-naïve and TNFi-exposed patients with CD. Notably, a dose- and duration-dependent trend of PEN synergy was observed. Both treatments were well-tolerated with a comparable incidence of adverse events. The combination of PEN and UST significantly enhanced deep remission, and clinical, endoscopic, and radiologic outcomes. It also promoted the improvement of intestinal/perianal complications and improved the levels of inflammatory and nutritional indices in CD. PEN thus served as a valuable adjunct to UST (and potentially other IL-23 inhibitors) for optimizing outcomes, especially in refractory CD with penetrating or stenotic complications.
Wang B, Zeng Y, Han L, Wang Z, Lai Y, Gao X, Guo Q, Chao K, Yang Q
Intestinal subepithelial myofibroblasts in inflammatory bowel disease: fibroblast heterogeneity, fibrosis, and therapeutic targeting.Review Frontiers in medicine | 2026-06-24
Intestinal fibrosis remains one of the most challenging complications of inflammatory bowel disease (IBD), frequently leading to bowel strictures, impaired intestinal function, and surgical intervention. Among the stromal cell populations involved in intestinal remodeling, intestinal subepithelial myofibroblasts (ISEMFs) have emerged as central regulators of epithelial homeostasis, mucosal repair, immune responses, and extracellular matrix remodeling. However, persistent inflammatory and microbial stimuli can drive pathological ISEMF activation, resulting in excessive matrix deposition and progressive fibrosis. This review aims to provide a comprehensive overview of the physiological and pathological roles of ISEMFs in IBD. We first discuss their functions in maintaining epithelial integrity, supporting the intestinal stem-cell niche, and coordinating tissue repair. We then examine the mechanisms underlying ISEMF activation during chronic inflammation, focusing on immune-stromal crosstalk, profibrotic cytokines, mechanotransduction, metabolic reprogramming, and key signaling pathways including TGF-β/Smad, JAK/STAT, and Wnt/β-catenin. Particular attention is given to recent advances in single-cell and spatial transcriptomics that have revealed marked fibroblast heterogeneity and identified pathogenic fibroblast subsets associated with fibrostenotic disease. Finally, we summarize current and emerging therapeutic strategies targeting stromal pathways, including antifibrotic agents, cytokine-directed therapies, fibroblast subset-specific interventions, and biomarker-guided precision approaches. By integrating advances in stromal biology, fibrosis mechanisms, and translational therapeutics, this review highlights ISEMFs as key drivers of intestinal fibrosis and promising targets for future disease-modifying therapies in IBD.
Li F, Xu C, Chen J, Lei T, Tian X, Zhang Y, Chen G
Pathogenesis & Basic Science (18 papers)
Revisiting pharmacological actions of disodium cromoglycate in light of GPR35: New therapeutic contexts for classical drugs.Review Biochemical pharmacology | 2026-07-09
Mast cell stabilizers such as disodium cromoglycate have been used for decades as prophylactic anti-allergic agents, yet their molecular targets remained unknown, and their intracellular mechanisms were long debated. Identification of GPR35 as a receptor engaged by multiple mast cell stabilizers provided a new framework to reinterpret classical pharmacology. Here, historical and recent evidence linking mast cell stabilizers to GPR35 is integrated and pharmacological characteristics of GPR35 are described in the context of species difference and intracellular signaling. GPR35 is expressed in epithelial, myeloid, and sensory neuronal compartments, raising the possibility that some “mast cell stabilizer” phenotypes reflect actions outside mast cells. This perspective becomes particularly relevant in inflammatory bowel disease, where genetic studies support a protective role for GPR35 in mucosal homeostasis, potentially through epithelial barrier integrity and macrophage function. Emerging data also implicate GPR35 in neurogenic inflammation/itch pathways and vascular remodeling, further broadening therapeutic considerations. Accumulating evidence suggests that GPR35 exhibits physiologically relevant constitutive activity, implying that the GPR35-mediated actions may depend not only on ligand engagement but also on expression levels and cellular states. Implications for drug repositioning of mast cell stabilizers and future GPR35-targeted therapeutics are also discussed.
Tanaka S
Discovery of an oral, potent and highly selective immunoproteasome inhibitor for the treatment of rheumatoid arthritis and ulcerative colitis. European journal of medicinal chemistry | 2026-07-09
The immunoproteasome plays a critical role in enhancing antigen presentation, regulating inflammatory responses and modulating T-cell differentiation. Its overexpression can lead to abnormal generation of self-antigen peptides and promote their presentation on MHC class I molecules, thereby breaking immune tolerance, activating CD8+ T cells and driving autoimmune pathological processes. Therefore, as a promising therapeutic target for autoimmune diseases, a variety of immunoproteasome inhibitors have been developed. However, these inhibitors have limitations in terms of selectivity and oral bioavailability, which restricts their development in clinical applications. To address these, we designed a series of novel compounds and then screened compound ent-F10, which is an orally active immunoproteasome inhibitor. Compound ent-F10 exhibits potent and highly selective inhibition against the β5i subunit (IC50: 0.08 μM), with a β5/β5i selectivity ratio of 123.8. In the mouse ulcerative colitis model, ent-F10 demonstrates favorable oral in vivo pharmacodynamics. Furthermore, ent-F10 also showed dose-dependent oral efficacy in a rat rheumatoid arthritis model. Moreover, ent-F10 exhibits lower inhibitory activity against hERG, reducing the potential risk of cardiac toxicity, which further demonstrates its safety. Collectively, ent-F10 can be developed as a potent, selective and orally available drug candidate.
Ye X, Ma Y, Sun P, Wang X, Guo D, Miao H, Wen T, Xie F, Wang S, Jiao R
Ameliorative Effects of Newly Developed Citrus Hybrid “Mubong” Peel Extract on Experimental Colitis and Gut Microbiota Dysbiosis. Food science & nutrition | 2026-07-09
“Mubong,” a newly developed citrus hybrid, is recognized for its unique flavor profile, yet its chemical composition and therapeutic potential remain unexplored. In the present work, we profiled the phytochemical content and antioxidant capacities of “Mubong” flesh and peel, then evaluated the anti-inflammatory effects of the “Mubong” Peel Extract (MPE) using in vitro (LPS-stimulated RAW 264.7 cells) and in vivo (DSS-induced colitis) models, coupled with microbiota analysis. In vitro anti-inflammatory activity was studied by measuring nitric oxide (NO) production and NF-κB signaling in RAW-Blue cells. In vivo, ICR mice were administered MPE (400 mg/kg) orally during DSS-induced colitis. Disease severity was evaluated through the Disease Activity Index (DAI), colon length, and histological analysis. To characterize microbial and metabolic shifts, we integrated 16S rRNA hypervariable region sequencing with targeted quantification of short-chain fatty acids (SCFAs). MPE was found to be rich in naringin (2730.66 ± 93.90 mg/100 g), neohesperidin (1493.85 ± 82.67 mg/100 g), and d-limonene (69.06%). In vitro, MPE (200-400 μg/mL) significantly inhibited NO production and suppressed NF-κB-dependent transcriptional activity. In mice, MPE treatment was associated with the attenuation of weight loss, reduction of DAI scores, and the mitigation of colon shortening. These clinical improvements were also coincided with a reduction in pro-inflammatory cytokines, specifically TNF-α (~80 to ~52 pg/mL) and IL-6 (~30 to ~3 pg/mL), and restoration of the SCFAs, propionic acid (~35% to ~80%) and butyric acid (~30% to ~50%). Microbiota analysis revealed that MPE treatment correlated with alterations in the gut landscape, specifically the enrichment of obligate anaerobes such as Lachnoclostridium and Acetatifactor. Furthermore, these microbial changes paralleled a recovery trend in short-chain fatty acids (butyrate and propionate) otherwise depleted by DSS. Our findings suggest that MPE exerts anti-inflammatory activity, likely through the modulation of NF-κB/AP-1-dependent transcriptional activity and preservation of gut microbial homeostasis. These preclinical findings suggest that “Mubong” warrants further investigation as a potential functional food candidate for the management of ulcerative colitis and related inflammatory disorders.
Assefa AD, Kim SS, Han SG, Park Y, Park JS
Orientin alleviates ulcerative colitis by regulating ferroptosis and glycolysis via the ROS/HIF-1α/GLUT1 signaling axis. Journal of ethnopharmacology | 2026-07-09
Crataegus pinnatifida Bunge, a plant used traditionally in herbal medicine for digestive health, is known for its gut-protective properties. Orientin, a natural flavonoid compound abundant in this species, exhibits anti-inflammatory and gut-protective activities. This study examined the therapeutic potential of orientin against ulcerative colitis (UC) and aimed to elucidate its underlying molecular mechanisms. This study established a DSS-triggered UC mouse model. RNA sequencing was carried out to identify key signaling pathways implicated in orientin’s therapeutic effects. Disease activity, intestinal barrier integrity, inflammatory responses, ferroptosis, were systematically evaluated. To validate the role of GLUT1 in the pathogenesis of UC, GLUT1-knockdown mice were utilized. Additionally, LPS-stimulated primary intestinal epithelial cells (IECs) were employed to further confirm the protective effects of orientin in vitro. RNA sequencing revealed that orientin significantly modulated genes associated with inflammation, ferroptosis, and metabolic pathways. Orientin alleviated DSS-triggered colitis by boosting body weight, preserving colon length, reducing histological damage. GLUT1 deficiency exacerbated intestinal injury, whereas orientin treatment attenuated these effects by regulating the ROS/HIF-1α/GLUT1 signaling axis. Orientin also repressed pro-inflammatory cytokines, neutrophil infiltration, and oxidative stress, while inhibiting the ferroptosis pathway. Moreover, it normalized glycolytic reprogramming by targeting the ROS/HIF-1α/GLUT1 pathway. In vitro studies further confirmed orientin’s protective effects on IECs by enhancing barrier function, reducing inflammation, and restoring metabolic homeostasis. This study underscores the pivotal role of the ROS/HIF-1α/GLUT1 axis and demonstrates the therapeutic potential of orientin in UC.
Guo X, Huang BN, Liu YH, Wang YQ, Che HY, Liu XK
Natural chlorophyll‑sodium alginate oral hydrogel for robust treatment of ulcerative colitis.★ International journal of biological macromolecules | 2026-07-09
Ulcerative colitis (UC) is a chronic and relapsing inflammatory bowel disorder that may lead to debilitating symptoms and serious complications such as toxic megacolon, intestinal perforation, and colon cancer. Conventional oral therapies are often limited by poor bioavailability and significant adverse effects. Herein, we developed an oral hydrogel for treatment of UC by electrostatic and hydrogen-bonding interactions of chlorophyll (Chl) and sodium alginate (SA) for the first time. The as-prepared Chl-SA hydrogel exhibited excellent biocompatibility and pH-responsive properties. In vitro assays showed that it reduced TNF-α (216.5 pg/mL compared with 863.4 pg/mL in the LPS group), increased IL-10 (321.53 pg/mL compared with 91.66 pg/mL in the LPS group), and achieved 70% DPPH radical scavenging, confirming its potent anti-inflammatory and antioxidant activities. It exhibited robust therapeutic effects in a DSS-induced colitis mouse model after seven days of treatment, including ameliorating intestinal inflammation and restoring barrier integrity. These effects were achieved by mitigating oxidative stress, promoting mucosal healing and the expression of ZO-1 and occludin-1, as well as rebalancing the gut microbiota and restoring its richness and diversity. Importantly, given that hydrogels are generally known to offer advantages for patients with dysphagia over traditional oral formulations, the present study suggests that the Chl-SA hydrogel can offer therapeutic potential as a suitable oral dosage form for UC.
Dai L, Zou B, Jiang Y, Wan S, Zhao L, Bai R, Su J, Sun H
Preparation, characterization, and preventive effects of ginseng polysaccharide-stabilized selenium nanoparticles against DSS-induced colitis. Nanomedicine (London, England) | 2026-07-09
To overcome the poor colloidal stability of selenium nanoparticles (SeNPs) and combine ginseng polysaccharide bioactivity with nano selenium advantages for ulcerative colitis prevention. Ginseng polysaccharide functionalized SeNPs (GP-SeNPs) were prepared. Particle size, in vitro antioxidant activity, cellular uptake, and protection against H2O2‑induced oxidative stress were assessed. A DSS‑induced colitis mouse model was used to assess preventive effects. GP-SeNPs showed smaller particle size (101.00 ± 1.22 nm), strong antioxidant activity, enhanced cellular uptake, and protection against oxidative stress in vitro. In DSS mice, GP-SeNPs alleviated colon shortening, weight loss, disease activity index, pro‑inflammatory cytokine mRNA expression, oxidative stress, and colonic histopathological damage. Ginseng polysaccharide functionalization improved the stability and biological performance of SeNPs, supporting their development as functional ingredients for intestinal health protection.
Zhou X, Chen T, Tang X, Chen L, Chen X, Wu D, Hu J
T cell transfer into immunodeficient mice uncovers a paralytic phenotype beyond colitis. Experimental animals | 2026-07-09
Adoptive transfer of CD45RBhigh T cells into immunodeficient mice is a well-established model for inducing colitis. Here, we report for the first time that a subset of these mice unexpectedly developed paralysis, a phenotype resembling experimental autoimmune encephalomyelitis (EAE). Paralytic mice exhibit the hallmark features of central nervous system (CNS) pathology, including spinal cord demyelination and immune cell infiltration, with prominent involvement of ex-Th17 (also called Th1-like) cells. The presence of ex-Th17 cells in the CNS of the affected mice suggests their contributory role in the development of paralysis. Notably, ex-Th17 cells have also been implicated in the pathogenesis of T cell transfer-induced colitis. Given the shared involvement of ex-Th17 cells in both the colitis model and the EAE-like CNS autoimmune model, we conducted comparative single-cell RNA sequencing analyses of ex-Th17 populations from colonic samples of patients with Crohn’s disease and cerebrospinal fluid samples of patients with multiple sclerosis. These analyses revealed a convergent upregulation of the IFN-γ signaling pathway in both disease contexts. Collectively, our findings establish this model as a valuable platform for investigating how identical immune challenges can lead to tissue-specific autoimmune pathology and highlight ex-Th17 cells as a potential mechanistic link between systemic and CNS autoimmunity.
Katsumoto R, Ebihara S
Lactobacilli Mitigate Gut Inflammation by Modulating T-Helper/T-Regulatory Cells and Suppressing Signaling Pathways in Food-Derived Models.Review Probiotics and antimicrobial proteins | 2026-07-08
Intestinal inflammation disrupts epithelial integrity, fuels antibiotic resistance, and underlies disorders such as inflammatory bowel disease. Lactobacillus species, established inhabitants of traditional and contemporary fermented foods, are increasingly viewed as bioactive cultures that shape host immunity and support formulation of next-generation functional foods. This review integrates multidisciplinary evidence from in vitro studies, animal models, human observations, and multi omics datasets to clarify how dietary or probiotic Lactobacillus strains alleviate gut inflammation. Particular attention is given to strain specific effects on T-helper/T-regulatory cell balance, suppression of TLR4-MyD88, NF-κB, MAPK, and NLRP3 signaling cascades, and the influence of food matrices, microencapsulation, dosage, and processing parameters on bacterial viability and efficacy, which are the factors central to food industry application. Across models, Lactobacillus consistently down regulates pro-inflammatory Th1/Th17 responses, while expanding forkhead box protein 3 (Foxp3⁺) T reg, leading to reduced TNF-α, IL-1β, and IL-6 and elevated IL-10 and TGF-β. Short chain fatty acids (SCFAs) and indole metabolites derived from fermentation further dampen NF-κB activity and reinforce epithelial barrier function. Food matrix studies show that dairy and cereal formulations enhance probiotic survival, whereas acidic beverages often require micro encapsulation; a daily intake of ~ 1010 CFU appears both effective and safe. Taken together, these insights position Lactobacillus as a scientifically robust, industry ready tool for developing anti-inflammatory foods, prioritizing future work for well-designed human feeding trials that couple multi-omics read outs and optimizing strain matrix combinations.
Kulyar MF, Naqvi SUAS, Bernotiene E, Akhtar M
Ginseng marc-derived low-molecular-weight neutral glucan SN-GOS ameliorates ulcerative colitis via inhibition of apoptosis and activation of autophagy in human intestinal HT-29 cells and DSS-induced inflammatory colitis mice. Carbohydrate research | 2026-07-08
Although ginseng marc has been routinely discarded as a waste, it still contains considerable amounts of bioactive compounds, including polysaccharides. This study assessed the protective effects of a low-molecular-weight neutral glucan, SN-GOS, obtained by enzymatic degradation of polysaccharides from Panax ginseng marc, against ulcerative colitis (UC) using human intestinal HT-29 cells and dextran sulphate sodium (DSS)-induced inflammatory colitis mice models. Correlation NMR spectroscopy and methylation analysis confirmed that SN-GOS is a starch-like branched glucan consisting mainly of glucose (92.67 mol%) and having a backbone composed of (1 → 4)(1 → 6)-α-d-glucopyranosyl units, with other minor sugars and variable linkages. SN-GOS (25-500 μg/mL) significantly suppressed TNF-α-induced inflammatory apoptotic death of HT-29 cells by downregulating caspase-9 cleavage, DNA fragmentation, disruption of mitochondrial membrane potential (MMP), and upregulating Bcl-2 expression. SN-GOS also attenuated pro-inflammatory cytokine expression (TNF-α and interleukin-6) and ROS generation caused by TNF-α treatment. In addition, SN-GOS increased LC3-II expression with a concomitant reduction in p62/SQSTM1 accumulation, suggesting activation of autophagy-associated responses. Furthermore, SN-GOS attenuated TNF-α-induced phosphorylation of ERK and p38 MAPK, suggesting modulation of inflammatory stress-related MAPK signaling. Oral administration of SN-GOS (200-400 mg/kg) resulted in significant recovery of colon length, body weight, and damaged crypts and ulcerative tissues in DSS-induced colitis mice. These results suggest that SN-GOS alleviates UC-associated inflammatory injury by inhibiting inflammatory apoptotic cell death, promoting autophagy-associated responses, and suppressing inflammatory MAPK signaling, supporting its potential use as a functional food ingredient for UC management.
Lee J, Lim JS, Bleha R, Capek P, Pohl R, Ree J, Shin CY, Choi TG, Synytsya A, Park YI
Circulating PEG-indoleamine 2,3-dioxygenase ameliorates diverse inflammatory diseases without toxicity or compromising immunocompetence. Proceedings of the National Academy of Sciences of the United States of America | 2026-07-08
Indoleamine 2,3-dioxygenase (IDO), the enzyme responsible for tryptophan catabolism, is protective in many autoimmune and inflammatory diseases. We previously developed a localized immunomodulation approach through the fusion of IDO to a carbohydrate binding protein [E. Bracho-Sanchez et al., Nat. Biomed. Eng. 7, 1156-1169 (2023)]. Here we further develop IDO as a protein therapeutic for inflammation, investigating systemic delivery via conjugation of poly(ethylene glycol) (PEG) to IDO. PEGylation extended circulation time and treatment PEG-IDO demonstrated therapeutic efficacy in five autoimmune and inflammatory models. Treatment with a single dose of PEG-IDO resulted in reversal of hind limb paralysis in experimental autoimmune encephalomyelitis as model of multiple sclerosis; protected against hepatic damage in liver ischemia-reperfusion injury; prevention of abdominal aortic aneurysm; and decreased severity of imiquimod-induced psoriasis. Treatment with two doses of PEG-IDO provided maintenance of body weight and colon length in acute ulcerative colitis. PEG-IDO treatment increased regulatory T cell populations and reduced pathogenic Th17 cell populations and inflammatory cytokine production. Systemic delivery of PEG-IDO had little-to-no off-target effects. Mice maintained immunocompetency, clearing the Listeria monocytogenes infection, and had no observed toxicity. Additionally, PEG-IDO increased serum kynurenine, consistent with a kynurenine-mediated mechanism of action. These findings demonstrate systemic immunomodulation via circulating PEG-IDO ameliorates a breadth of disparate autoinflammatory diseases, protecting against inflammation-driven tissue destruction in spinal cord, liver, abdominal aorta, skin, and colon, while presenting a positive safety profile, and expanding the scope of potential applications for this therapeutic approach.
Simonovich JA, Clark RA, Kwiatkowski AJ, Fuchs MJ, Viso ME, Lu C, Macias SL, Pinto I, Shrestha AP, Ngo TB
Harmaline and the gut-brain-immune axis: a novel therapeutic avenue in neuroinflammation and ulcerative colitis.Review Inflammopharmacology | 2026-07-08
Chronic inflammatory disorders like neuroinflammatory disorders and ulcerative colitis (UC) have some common pathogenic mechanisms such as persistent activation of nuclear factor-κB (NF-κB), oxidative and nitrosative stress, mitochondrial dysfunction, immune dysregulation, and disruption of the integrity of the epithelial barrier. The gut-brain-immune axis is a bidirectional communication pathway, with growing evidence that intestinal inflammation impairs central neuroimmune responses and vice versa, underscoring the importance of therapeutic interventions that can address and impact these interconnected axes. Harmaline or β-carboline alkaloid, a naturally occurring compound mainly found in Peganum harmala and Banisteriopsis caapi, has gradually gained a lot of interest due to its wide range of pharmacological properties such as anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory. The review focuses on the reported modulation of the major inflammatory pathways, such as inhibition of NF-κB signalling, attenuation of pro-inflammatory cytokine production, regulation of oxidative stress through the Nrf2-dependent pathway, and reversible inhibition of monoamine oxidase-A (MAO-A), by critically evaluating the inflammopharmacological profile of harmaline. All of these molecular activities indicate that harmaline could affect biological activities related to neuroinflammation, intestinal inflammation, and gut-brain-immune communications. Nevertheless, there is limited direct experimental evidence supporting the efficacy of harmaline in disease-specific models of ulcerative colitis, neuroinflammation, and microbiota-associated diseases. Hence, the indicated therapeutic relevance of harmaline has to be considered as hypothesis-generating and mechanistically plausible but for now not experimentally proven in disease-specific contexts. In general, harmaline is a promising mechanistic lead compound to be investigated in future complex inflammatory diseases which involve brain/gut and neuroimmune interactions. Additional research regarding disease-specific efficacy, pharmacokinetic properties, tissue distribution, microbiota-related aspects, dose-response, and safety aspects is needed to evaluate its translatability.
Giri M, Arya S, Grover M, Yadav D, Chatterjee S, Rath SK
Computational Toxicology Prioritization of CYP3A4 and DPP7 as Candidate Triclosan-Relevant Molecular Targets in Ulcerative Colitis. Toxicology mechanisms and methods | 2026-07-07
Triclosan (TCS), a synthetic broad-spectrum antimicrobial classified as a novel persistent organic pollutant, is detected in over 75% of human urine samples, yet its molecular targets in ulcerative colitis (UC) remain uncharacterized at a systems level. We integrated network toxicology, multi-cohort machine learning, molecular docking, 100-ns all-atom molecular dynamics (MD) simulation, and single-cell transcriptomics to address this gap. Intersection of UC transcriptomic differentially expressed genes with database-derived TCS targets yielded 479 shared candidate targets; because these databases include indirect and probabilistic associations, this set was treated as a hypothesis-generating list for downstream feature compression rather than as evidence of direct molecular interference. KEGG enrichment identified the AGE-RAGE signaling pathway, PPAR signaling, and TNF signaling among the top enriched pathways. LASSO regression and random forest algorithms distilled a 10-gene diagnostic signature that achieved cross-cohort AUC of 0.910-1.000 across six independent GEO datasets, consistent with strong discriminative performance. Molecular docking on ligand-free receptors produced predicted Vina scores of -7.1 kcal/mol (CYP3A4) and -7.0 kcal/mol (DPP7); redocking recovered the co-crystal pose (0.85 Å RMSD for the TCS-sized DPP7 ligand) and small-molecule decoys scored markedly worse, supporting protocol specificity but not biochemical binding or inhibition. Over 100 ns of MD simulation, the docked poses remained stable for both targets. Single-cell RNA sequencing of GSE214695 independently corroborated cell-type-specific CYP3A4 downregulation in intestinal epithelial cells and broad DPP7 upregulation across immune subsets in UC. In silico perturbation via CellOracle predicted that CYP3A4 suppression would impair cytoplasmic translation, while DPP7 suppression would polarize innate inflammation toward an IL-1β-driven phenotype. Together, these analyses computationally prioritize CYP3A4 and DPP7 as candidate TCS-relevant targets in UC and generate testable hypotheses for future experimental validation; they do not by themselves establish direct target engagement, inhibition, or causal contribution to UC.
Wang J, Jiang S, Zhang Y, Gao H, Zhao X, Liu L, Li Z
SLFN11 binds DDX1 to counteract human mesenchymal stem/stromal cell senescence through inhibition of mTOR/eIF4E signaling pathway activation. Life sciences | 2026-07-06
Mesenchymal stem/stromal cells (MSCs) are indispensable for cellular therapy; however, long-term in vitro expansion triggers replicative and stress-induced senescence, which undermines their stemness and therapeutic potential. This study aimed to investigate the protective effect and underlying mechanism of the Schlafen (SLFN) 11 gene against human MSC senescence in vitro and to evaluate the efficacy and safety of SLFN11-overexpressing MSCs. SLFN11 was overexpressed in human MSCs via lentiviral transduction. Protective effects were comprehensively assessed in replicative and stress-induced senescence models by evaluating cell cycle arrest, proliferative and clonogenic capacities, DNA damage, pluripotency, and β-galactosidase activity. Molecular interactions were elucidated through co-immunoprecipitation (Co-IP) and LC-MS/MS, whereas therapeutic efficacy was determined using a DSS-induced ulcerative colitis mouse model. SLFN11 overexpression significantly attenuated senescence by reducing DNA damage accumulation, reversing cell cycle arrest, and enhancing proliferation, clonogenicity, and stemness properties. Mechanistically, SLFN11 bound the RNA helicase DDX1 to attenuate mTOR/eIF4E signaling, thereby resisting senescence. Compared to control MSCs, SLFN11-overexpressing MSCs exhibited superior protection against ulcerative colitis, as evidenced by reduced colonic lesions, maintenance of mucosal integrity, and inhibition of proinflammatory factor secretion. SLFN11-overexpressing MSCs also showed no detectable tumorigenicity or chromosomal aberrations. These findings delineate a non-canonical role for SLFN11 safeguarding MSCs from senescence via the DDX1/mTOR/eIF4E axis. SLFN11-overexpressing MSCs therefore constitute a promising and safe cell therapy source, characterized by preserved pluripotency and augmented therapeutic efficacy.
Zhu XX, Luo Y, Xu JY, Yang X, Liu YS, Xiao JH
IL-7R-Enriched Extracellular Vesicles From the Thymus Drive Colitis via Promoting Neutrophil Extracellular Trap Formation.★ Advanced science (Weinheim, Baden-Wurttemberg, Germany) | 2026-07-06
Mounting evidence highlights the involvement of extra-intestinal organs in inflammatory bowel disease (IBD) progression, yet the mechanisms underlying gut-extraintestinal organ crosstalk remain poorly understood. Extracellular vesicles (EVs) serve as pivotal mediators of inter-organ communication. Here, this study demonstrates that circulating EVs from colitis exacerbate colitis severity by inducing neutrophil extracellular trap (NET) formation. Inhibition of circulating EV secretion or NET formation alleviates colitis severity. Mechanistically, EVs enriched with interleukin-7 receptor (IL-7R) are identified as critical drivers of NET-mediated colitis exacerbation. Downregulation of IL-7R ameliorates colitis symptoms, whereas IL-7R upregulation worsens disease progression. IL-7R is found to induce NETs via the protein-arginine deiminase type 4 (PAD4) pathway to aggravate colitis. Furthermore, this study establishes that thymus-derived EVs are the primary source of IL-7R-enriched circulating EVs. During colitis, elevated circulating lipopolysaccharide (LPS) stimulates the thymus to release IL-7R-enriched EVs, which then migrate via the thymus-gut axis and promote NET formation in colonic tissues. This study reveals a previously unrecognized thymus-gut communication axis mediated by IL-7R-enriched EVs in IBD pathogenesis and provides an explanation for why IBD predominantly affects children and young adults. Targeting this axis may offer novel therapeutic strategies for IBD management.
Liao Y, Liu Y, Yang R, Zhu Z, Wu J, Li D, Su J, He Y, Luo S, Cao F
Comparative analysis of bronchial asthma and ulcerative colitis in a combined mouse model. PeerJ | 2026-06-30
Bronchial asthma (BA) and ulcerative colitis (UC) are chronic immune-mediated inflammatory diseases affecting the airway and intestinal mucosa, respectively. Increasing clinical evidence suggests a close association between BA and UC, with mutual aggravation of disease severity when both conditions coexist. However, the underlying mechanisms and suitable experimental models to investigate BA-UC comorbidity remain limited. This study aimed to establish a reliable murine model of comorbid BA-UC and to evaluate the bidirectional impact of airway and intestinal inflammation. Forty specific-pathogen-free (SPF)-grade female C57BL/6 mice were randomly assigned to four groups: control, BA, UC, and comorbid BA-UC. BA was induced by intraperitoneal sensitization with ovalbumin (OVA) followed by repeated aerosolized OVA challenges, while UC was induced by intermittent administration of dextran sulfate sodium (DSS). The comorbid model was established by synchronously combining both protocols in the same animals. Pulmonary function, airway hyperresponsiveness, Disease Activity Index (DAI), body weight, quality-of-life scores, colon length, and histopathological changes in lung and colon tissues were assessed and compared among groups. Compared with the control group, mice in the BA, UC, and comorbid BA-UC groups exhibited significant abnormalities in pulmonary function parameters. Among all experimental groups, the comorbid BA-UC group showed the most pronounced decline in quality-of-life scores. Line graph analysis revealed significant differences in colon length shortening and body weight changes in the comorbid BA-UC group (P < 0.05), with colon shortening being significantly greater than that observed in the UC group alone (P < 0.05). Inflammatory cell infiltration was significantly increased in the BA and comorbid BA-UC groups compared with the UC group (P < 0.05). Although granuloma scores were higher in the BA and comorbid BA-UC groups than in the control group, these differences did not reach statistical significance. In contrast to controls, all disease groups (BA, UC, and comorbid BA-UC) exhibited significantly increased pathological injury scores. The synchronous induction of BA and UC using OVA and DSS successfully establishes a stable and reproducible murine model of comorbid BA-UC. This model demonstrates that BA and UC mutually exacerbate airway and intestinal inflammation, supporting the existence of a bidirectional gut-lung immune interaction. The comorbid BA-UC model provides a valuable experimental platform for future mechanistic studies and the development of integrated therapeutic strategies targeting coexisting inflammatory diseases.
Tian Y, Chen L, Lian Z, Wu C, Yang X
Procaine hydrochloride improves DSS-induced colitis via inhibition of IL-6/STAT3 and FOXP3 methylation. European cytokine network | 2026-06-30
Disruption of immune barrier function is considered a hallmark feature of inflammatory bowel disease. In the present study, the potential effects of the methyltransferase inhibitor procaine hydrochloride on intestinal barrier integrity, as well as T cell differentiation in the context of inflammatory bowel disease were explored. Using an experimental model of dextran sulfate sodium-induced ulcerative colitis, mice received daily treatment with either sulfasalazine (100 mg/kg) or procaine hydrochloride (45 mg/kg), or saline (10 μL/g) as a negative control, for 7 consecutive days. Subsequent analysis included disease activity index score, histopathology, expression levels of intestinal epithelial tight junctions and apoptotic protein, production of inflammatory cytokines, frequencies of lymphocyte populations in the spleen by flow cytometry and methylation levels of Forkhead box protein 3 (FOXP3). Procaine alleviated dextran sulfate sodium-induced colitis, with a reduced disease activity index (p < 0.05) and histopathological score (p < 0.001). Procaine treatment resulted in a 1.96-fold increase in splenic FOXP3+ CD25+ Tregs (p < 0.001). Administration of procaine significantly enhanced tight junction expression (p < 0.01), decreased the expression of BAX and cleaved caspase-3 protein expression, while increasing that of the anti-apoptotic protein BCL-2. Procaine also significantly suppressed IL-6/signal transducer and activator of transcription factor 3 (STAT3) signaling pathway. In addition, procaine amplified FOXP3+ Tregs by inhibiting FOXP3 methylation. The protective potential of procaine hydrochloride against intestinal barrier injury in colitis may be attributed to increased abundance of Tregs and the augmentation of their anti-inflammatory properties. The potential mechanisms may involve modulation of IL-6/STAT3 signaling pathway and inhibition of FOXP3 methylation.
Xiong A, Tian Y, Liang X, Liu S, Shi C, Cao Y, Su C
GM-CSF promotes pro-inflammatory macrophage activation associated with Akt/mTOR signaling during experimental colitis. Frontiers in immunology | 2026-06-26
Ulcerative colitis (UC) is an intestinal immune disorder of unknown etiology. Mounting evidence reveals a central role of macrophages in the hemostatic balance of gut immunity, and dysfunctional macrophages are associated with UC pathogenesis. Granulocyte macrophage-colony stimulating factor (GM-CSF) is an essential modulator of macrophages and has recently been recognized as a potential target in many autoimmune disorders. However, the action of GM-CSF in gut inflammation remains unspecified. The significance of GM-CSF in UC and its mechanism of action were investigated. GM-CSF expression was examined in colon biopsy tissues from UC patients and healthy controls. A dextran sodium sulfate (DSS)-induced colitis mouse model was used to evaluate the effect of GM-CSF neutralizing antibody (GM-CSF Ab). Macrophage infiltration, CD4+ T helper (Th) cell responses, macrophage polarization, and glycolysis-related genes were assessed using in vivo and in vitro experiments. The involvement of the Akt/mTOR pathway was also examined. GM-CSF expression was significantly elevated in colon biopsy tissues from UC patients compared to controls. Administration of GM-CSF Ab to DSS-treated mice attenuated gut inflammation. Furthermore, GM-CSF Ab inhibited the infiltration of macrophages and inflammatory CD4+ Th cells into the intestine of DSS-colitis mice. In vitro experiments showed that GM-CSF induced M1-type polarization of peritoneal macrophages and subsequently augmented the Th17 response. Further experiments indicated that the proinflammatory phenotype of macrophages induced by GM-CSF was related to glycolytic metabolism, which was influenced by the Akt/mTOR pathway. Collectively, this study suggests that GM-CSF is associated with the regulation of glycolytic metabolism involving the Akt/mTOR pathway, and subsequently alters macrophage function to promote intestinal inflammation.
Shen S, Chen K, Li L, Jiang M, Jia Y, Bai X, Zeng Z, Ma C, Dang Y, Hu K
Holarrhena pubescens (Kutaj) bark extract mitigates SDS-induced IBD-like pathologies in Drosophila melanogaster by preserving barrier integrity and antioxidant defense. Frontiers in pharmacology | 2026-06-24
Inflammatory bowel disease (IBD) is a group of chronic conditions characterized by relapsing inflammation of gastrointestinal tract. Conventional treatments for IBD are confronted with various challenges including treatment failure, a therapeutic ceiling that restricts effectiveness and associated adverse effects. Present study employed Drosophila melanogaster as a model organism to investigate the protective effect of Holarrhena pubescens Wall. ex G. Don (Kutaj) Bark Extract (HpBE) against sodium dodecyl sulfate (SDS)-induced IBD-like etiologies. Ultra-high performance liquid chromatography (UHPLC) identified Epigallocatechin (EGC), Epicatechin (EC) and Protocatechuic acid as key phytometabolites in HpBE. On LCMS/MS-TQ analysis, these phytometabolites were also detected in whole body lysates of Drosophila treated with HpBE, confirming their absorption. HpBE was tolerated well in Drosophila, enhanced survival and mitigated SDS-induced intestinal injury, as demonstrated by smurf and trypan blue dye exclusion assays. Importantly, treatment with HpBE improved feed uptake, restored excretory function and prevented weight loss. Notably, HpBE also prevented the general sickness associated with inflamed gut, as evident from enhanced climbing activity. SDS-exposed flies that received HpBE, exhibited enhanced antioxidant defence and preserved cytoskeletal integrity of gut, as evidenced by increased GSH levels, SOD activity and phalloidin staining. These effects of HpBE were found to be associated with the modulation in gene expression related to Wnt/β-Catenin and JAK-STAT signalling. Overall, present study underlines the protective potential of HpBE against SDS-induced IBD-like etiologies in D. melanogaster model, and lays a foundation for further research to correlate these findings with clinical observations.
Balkrishna A, Kauts S, Kumar S, Sengar GS, Verma S, Dev R, Varshney A
Microbiome & Immunology (16 papers)
Novel SLC10A2 variants induce primary bile acid malabsorption and dysbiosis with IBD-like features.★ Inflammatory bowel diseases | 2026-07-11
We describe biochemically and functionally validated primary bile acid malabsorption caused by novel biallelic SLC10A2 variants in a child initially diagnosed with Crohn’s disease. Pediatric IBD cohort reanalysis identified PBAM-compatible genotypes, supporting selective testing when clinical features are suggestive.
Johnson CR, Gillette L, Qurbonov Q, Plone A, Schmieder SS, Anderson M, Cibelli K, Zhang YJ, Raghunathan K, Field M
Adaptive graph learning of microbial phylogeny enables accurate and interpretable microbiome-based host phenotype prediction. Applied and environmental microbiology | 2026-07-10
The human microbiome is inherently structured by phylogeny, yet most predictive models treat microbial taxa as independent features, thereby underusing evolutionary information that may improve disease classification. While recent deep learning approaches have attempted to incorporate phylogeny, they generally rely on projecting phylogenetic trees into Euclidean spaces, which can distort the intrinsic topology of evolutionary relationships. To address this limitation, we propose PhyloGCNE, a framework that models microbiome samples directly as graphs and employs edge-aware graph convolution to integrate phylogeny. Unlike previous methods that rely on fixed, distance-based aggregation, PhyloGCNE learns how phylogeny-informed edge attributes should influence signal propagation across evolutionary hierarchies. We further introduce a Phylogenetic Saliency Propagation (PSP) framework for model interpretation, which attributes importance scores to microbial taxa by integrating gradient sensitivity with evolutionary context. Benchmarked against one synthetic and eight real-world data sets spanning inflammatory bowel disease, colorectal cancer, type 2 diabetes, oral squamous cell carcinoma, gastric cancer, and dietary fiber intervention, PhyloGCNE consistently outperforms existing state-of-the-art approaches. Together, these results establish PhyloGCNE as an accurate and interpretable phylogeny-aware framework for microbiome-based host phenotype prediction.IMPORTANCEThe human microbiome is a complex ecosystem closely linked to physiological health, yet traditional analysis often treats microbes as isolated features, ignoring their shared evolutionary history. This study introduces PhyloGCNE, a novel framework that integrates the evolutionary tree directly into the analysis of microbiome data. By modeling microbial communities as interconnected networks rather than independent entities, this approach captures shared biological traits across related lineages. We demonstrate that this method significantly improves the accuracy of predicting host phenotypes, such as inflammatory bowel disease and colorectal cancer. Crucially, unlike many “black box” artificial intelligence models, this tool identifies specific, biologically relevant microbial signatures driving these predictions. This advancement provides a powerful, interpretable approach for deciphering the complex links between the human microbiome and host phenotypes.
Dong B, Wang B, Chen J, Xu X, Xu ZZ
Extremophyte-derived exosome-like nanovesicles remodel intestinal barrier dysfunction by multi-dimensional intervention: physical barrier repair with immune homeostasis and microbiome regulation.★ Journal of nanobiotechnology | 2026-07-10
Intestinal barrier is the body’s largest immune structure and essential for nutrient absorption. Its dysfunction allows the translocation of pathogenic substances into circulation, thereby driving the pathogenesis of inflammatory bowel disease (IBD). Plant-derived exosome-like nanovesicles (ELNs), recognized for their biocompatibility and ability to traverse biological barriers, hold considerable potential for managing intestinal inflammation. Specially, plants cultivated under extreme environmental conditions typically adapt to be stress resistant with greater accumulation of associated biologics, which may in-turn confer unique bioactivities to their respective ELNs. This study investigated the protective effects and mechanisms of ELNs derived from the extremophyte Rosa roxburghii (R-ELNs) and Artemisia sphaerocephala Krasch (A-ELNs) against intestinal barrier dysfunction. In vitro and in vivo studies indicated that the ELNs, especially R-ELNs, provided enhanced protection against intestinal barrier dysfunction. Specifically, mucus secretion and tight junction protein expression were promoted, and macrophages were polarized toward M2 anti-inflammatory phenotypes. Furthermore, R-ELNs modulated the composition of the intestinal microbiota, thereby promoting a balanced microecological environment. Importantly, the protective effect of R-ELNs was suggested to be through an inhibitory effect on excessive activation of pro-inflammatory signaling proteins (AKT, p38). Notably, exosomes (Exos) derived from R-ELN-treated M2 macrophages had distinct miRNA profiles that can target inflammatory pathway genes (Tgfbr1, Map3k7, Met), enabling anti-inflammatory roles via intercellular communication. These findings suggested that R-ELNs can restore intestinal barrier dysfunction via multiple synergistic mechanisms, positioning R-ELNs as a novel and promising preventive strategy for inflammatory bowel disease.
Li D, Du L, Yi G, Liang T, Midgley AC, Shu G, He Y, Dong Y, Li G, Yao X
Protein kinase Cη-MARCKS axis associations with epithelial barrier disturbance and inflammatory readouts in ulcerative colitis. Scientific reports | 2026-07-10
Intestinal epithelial barrier disruption is a hallmark of ulcerative colitis (UC). Protein kinase Cη (PKCη) and its substrate myristoylated alanine-rich C-kinase substrate (MARCKS) have been implicated in cytoskeletal organization and barrier regulation, but their roles in UC remain incompletely defined. PKCη expression and its association with disease severity were assessed using Gene Expression Omnibus (GEO) datasets, dextran sodium sulfate (DSS)-induced colitis mouse model, and UC patient colon tissues. Adenoviral shRNA-mediated PKCη knockdown was performed in mice, with outcomes including body weight, colon length, disease activity index (DAI), histological changes, and permeability. PKCη, MARCKS, and tight junction proteins were assessed by RT-qPCR, Western blot, and immunohistochemistry. LPS-stimulated Caco-2 cells with PKCη knockdown/overexpression, with or without MARCKS knockdown, were used for validation. Protein interaction was tested by Co-immunoprecipitation (Co-IP). Cytokines (TNF-α, IL-1β, IL-6) were measured by ELISA. PKCη expression was elevated in UC mucosa and in DSS-induced colitis mice. In mice, PKCη knockdown was associated with reduced disease activity, lower intestinal permeability, decreased pro-inflammatory cytokines, and a more favorable tight-junction profile. Similar directional changes were observed in LPS-stimulated Caco-2 cells, whereas PKCη overexpression showed opposite effects. Co-immunoprecipitation suggested that PKCη and MARCKS occur in the same protein complex, and PKCη modulation was accompanied by changes in MARCKS abundance and phosphorylation. MARCKS knockdown partially attenuated the effects of PKCη overexpression. PKCη may contribute to epithelial barrier dysfunction and inflammation in settings relevant to ulcerative colitis, possibly through modulation of MARCKS expression and phosphorylation. Further studies are required to establish causality and to assess whether the PKCη-MARCKS axis has therapeutic relevance.
Liu Z, Shang Y, Sun D, Han X, Gao F, Chen X
Sialidase inhibitor modulates gut microbiota and enhances mucosal protection in the treatment of ulcerative colitis. mSystems | 2026-07-10
Ulcerative colitis (UC) is characterized by mucosal barrier erosion, a process exacerbated by bacterial sialidases. We investigated the therapeutic efficacy of the sialidase inhibitor (SI) in UC. In a pilot randomized clinical trial, SI intervention significantly improved clinical symptoms and endoscopic outcomes in mild-to-moderate UC patients. This improvement correlated with an enrichment of butyrate-producing taxa and beneficial metabolic pathways. In a dextran sulfate sodium-induced colitis mouse model, SI attenuated inflammation and restored mucus layer integrity, accompanied by increased expression of Muc2 and Tff3. Crucially, unlike broad-spectrum antibiotics, SI preserved microbial community resilience while specifically enriching beneficial mucolytic commensals, Akkermansia muciniphila and Bacteroides acidifaciens. These findings identify SI as a promising therapeutic strategy that targets sialidase activity to reinforce the mucosal barrier and restore gut homeostasis.IMPORTANCEThe gut microbiota plays a pivotal role in maintaining mucosal integrity and intestinal homeostasis; however, dysbiosis-driven mucus layer degradation remains a hallmark of ulcerative colitis (UC). Current interventions like antibiotics often disrupt microbial diversity, exacerbating dysbiosis and failing to address mucosal thinning, which is a critical factor in UC progression. Developing strategies to reinforce the mucus barrier without compromising microbial balance is urgently needed, but such approaches remain underexplored. Our study demonstrates that sialidase inhibitors (SIs) uniquely preserve mucosal thickness by curbing microbial mucin degradation while selectively enriching beneficial taxa and butyrate-producing bacteria. Unlike antibiotics, SIs enhance mucosal protection without destabilizing microbial communities, offering a dual-action therapeutic strategy. This work bridges a critical knowledge gap, providing evidence for microbiota-targeted therapies that synergistically restore mucosal health and microbial ecology in UC.CLINICAL TRIALSThis study was registered with the Chinese Clinial Trial Registry as ChiCTR2000028767.
Zhao Y, Chen L, Li C, Xu Y, Huang J, Chen S, Yu Z, Liu X
Interleukin-8 in health and disease.Review Molecular biomedicine | 2026-07-09
Cytokines are among the main factors involved in indirect cell-to-cell communication in physiological and pathological conditions. In this way, cytokines are soluble and tissue-resident easily detectable biomarkers for the diagnosis and the prediction of clinical outcome, as well as drug targets. Over the years, the pleiotropic IL-8 gained a central role in the pathogenesis of several immunological disorders, spanning from autoimmune pathologies and sepsis to neurological, liver and cardiovascular diseases. In several solid cancers, IL-8 not only serves as a prognostic biomarker but also as predictive tool. Increasing evidence highlighted IL-8 as a prognostic/predictive biomarker even for immunotherapy to stratify eligible patients, to avoid unnecessary toxicity and progression. Today, a comprehensive review covering IL-8 in all these fields has not yet been published. Hence, we aim to provide preclinical and clinical evidence on the biology and functions of IL-8, involved in the pathogenesis of non-malignant diseases, including inflammatory bowel diseases, sepsis, neuroinflammation, liver and cardiovascular pathologies. In oncology area, we will describe the pro-tumorigenic roles, including the characterization of the immunosuppressive microenvironment, also discussing the implications of direct/indirect IL-8 targeting and the involvement of gut microbiota. Unfortunately, the main obstacles to establish IL-8 as a useful non-invasive clinical tool for diagnosis and treatments’ selection are the lack of the standardization of method detection and the source of IL-8 production.
Bazzichetto C, Dell’Aquila E, Veroli M, Belluomini L, Bonato A, Bernardini G, Bevilacqua M, Cattazzo F, Dalbeni A, Tampu TM
Oral Prebiotic Polysaccharide Hydrogels Sustaining Colon Antibody Release Alleviate Inflammatory Bowel Disease.★ Advanced science (Weinheim, Baden-Wurttemberg, Germany) | 2026-07-06
Inflammatory bowel disease (IBD) is a chronic systemic immune disorder with unclear pathogenesis that involves complex interplay between inflammation, gut microbiota, and immune dysregulation. The advance of antibodies targeting tumor necrosis factor-alpha and interleukin-12/23, e.g., infliximab (IFX) and ustekinumab (UTK), has greatly improved the clinical treatments. The current intravenous dosing scheme, however, yields partial responses with potentially severe systemic side effects. Here, we report that oral prebiotic polysaccharide hydrogels based on inulin and alginate-dopamine conjugate (predaGel) mediating efficient and sustained colon antibody delivery and reactive oxygen species (ROS) scavenging effectively alleviate IBD. predaGel with pH and enzyme dual responsiveness is stable in the stomach, adhesive to the intestine, and slowly degrading in the colon, resulting in site-specific and controlled release of IFX. The mucosal retention, ROS scavenging, and gut microbiota remodeling properties endowed by dopamine and inulin in predaGel not only prevent diarrhea and suppress oxidative stress but also prolong drug function and restore immune homeostasis. Intriguingly, oral administration of IFX and/or UTK-encapsulated predaGel cures IBD and restores colon function, offering an effective oral alternative to IFX injection. This oral prebiotic hydrogel strategy, with simplicity and multi-functions, presents a potentially safer and better biologic therapy for IBD.
Dong X, He H, Cao L, Meng F, Zhong Z
Huanglian-Wendan Decoction alleviates DSS-induced colitis by modulating the gut microbiota and protecting against intestinal injury via suppression of colonic apoptosis and endoplasmic reticulum stress. Natural products and bioprospecting | 2026-07-06
Inflammatory bowel disease (IBD) is a chronic disorder characterized by recurrent intestinal inflammation and gut microbiota dysbiosis. Huanglian-Wendan Decoction (HLWDD) has been clinically used for IBD treatment; however, its underlying mechanisms remain unclear. In this study, a dextran sulfate sodium (DSS, 2.25%)-induced IBD mouse model was established to evaluate the therapeutic effects of HLWDD. The protective mechanisms were investigated in colon tissues of DSS-induced mice using ELISA, immunoblotting, histological, and immunohistochemical analyses. In addition, the impact of HLWDD on gut microbiota dysbiosis was analyzed using 16S rRNA sequencing. Antibiotic treatment was applied before DSS administration to deplete gut microbiota and verify the role of microbial modulation. Furthermore, the phytochemical constituents of HLWDD were characterized using liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (LC-QTOF-MS/MS). The results demonstrated that HLWDD markedly alleviated DSS-induced colitis, as evidenced by reduced body weight loss, rectal bleeding, colon shortening, and disease activity index (DAI) scores. Mechanistically, HLWDD suppressed inflammatory responses in colon tissues by inhibiting the TLR4/MyD88/NF-κB and IL-6/JAK2/STAT3 signaling pathways, while enhancing epithelial barrier integrity through upregulation of ZO-1, Occludin, Claudin-1, and Mucin-2. In addition, HLWDD attenuated endoplasmic reticulum stress (ERS) and apoptosis by downregulating CHOP, phospho-eIF2α, cleaved caspase-3, and Bax, while increasing Bcl-2 expression in colonic tissues. Microbiota analysis revealed an increased abundance of beneficial bacterial genera such as Akkermansia and Escherichia-Shigella-related commensals, along with enrichment of beneficial bacterial families including Ruminococcaceae, Lachnospiraceae, and Verrucomicrobiaceae, whereas potentially harmful taxa such as Escherichia and Paraprevotella were reduced. HLWDD also increased the production of short-chain fatty acids (SCFAs), including acetate, butyrate, and isobutyrate, thereby promoting intestinal homeostasis. Importantly, the protective effects of HLWDD were largely abolished following antibiotic-mediated gut microbiota depletion, confirming the essential role of microbial modulation in its therapeutic action. Collectively, these findings suggest that HLWDD ameliorates IBD by regulating gut microbiota composition and function, thereby inhibiting colonic ER stress and apoptosis and restoring intestinal barrier integrity. This study provides mechanistic evidence supporting the potential clinical application of HLWDD as a novel therapeutic strategy for IBD.
Li L, Zhan X, Ullah H, Guo W, Gui P, Peng W, Mei Q, Dai W, Duan Y, Yuan X
Periodontitis as a Model for Inflammatory Uncoupling of Bone Remodeling.Review Journal of periodontal research | 2026-07-06
Periodontitis is traditionally regarded as an oral biofilm-driven inflammatory disease that leads to progressive loss of the tooth-supporting alveolar bone. However, accumulating evidence indicates that periodontal bone loss is more accurately understood as a state of pathological uncoupling of bone remodeling, in which exaggerated bone resorption coexists with inadequate bone formation response. In this review, we reposition periodontitis within the broader context of inflammatory skeletal diseases and synthesize current mechanistic insights from osteoimmunology, bone biology, and mechanobiology. We discuss how excessive osteoclastogenesis in periodontitis is sustained by receptor activator of nuclear factor kappa-B ligand (RANKL) dominance derived from osteocytes, osteoblast-lineage cells, stromal cells, monocytes/macrophages, B and T lymphocytes, and neutrophils within a cytokine-rich microenvironment characterized by tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-17A signaling. Persistent activation of nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways further enhance osteoclast differentiation, survival, and resorptive activity. At the same time, inflammatory mediators actively suppress osteoblast-lineage commitment by inhibiting Runx2 and Osterix, antagonizing canonical Wnt/β-catenin signaling through the upregulation of sclerostin and Dickkopf-1 (DKK1), and impairing bone matrix production and mineralization. We further examine how disruption of key osteoclast-osteoblast coupling mechanisms, including ephrinB2/EphB4 and semaphorin signaling, prevents the effective transition from resorption to formation, while osteocyte dysfunction amplifies the uncoupled phenotype by integrating inflammatory and mechanical signals. Comparisons with rheumatoid arthritis, inflammatory bowel disease-associated bone loss, and peri-implantitis reveal shared immune-driven mechanisms of remodeling imbalance, whereas the unique features of alveolar bone, including high turnover, continuous mechanical loading, and chronic microbial exposure, make it particularly susceptible to inflammatory uncoupling. Together, these concepts support a therapeutic shift toward restoring physiological coupling instead of solely inhibiting resorption and position periodontitis as a clinically accessible model for understanding and targeting inflammatory bone loss across skeletal diseases.
de Molon RS, Tetradis S, Vernal R, Leite FRM, Van Dyke TE
A biocompatible and colon-targeted oral delivery platform based on maize starch and alginate for enhancing probiotic efficacy in ulcerative colitis management.★ International journal of biological macromolecules | 2026-07-06
Probiotics help treat ulcerative colitis (UC) by stabilizing gut microbiota, strengthening the mucosal barrier, and modulating immune responses, yet their viability plummets in the harshly acidic stomach. To overcome this limitation, we engineered a colon-targeted, double-layer oral delivery system in which Lactobacillus plantarum (LP) is first adsorbed onto porous maize starch (PMS) and subsequently coated with calcium-cross-linked alginate to form microgels (LP@aPMS). Scanning electron microscopy and confocal laser scanning microscopy confirmed that the dense alginate shell tightly enveloped PMS, shielding LP from gastric erosion. In dextran sulfate sodium-induced colitis mice, oral administration of LP@aPMS markedly improved clinical outcomes, characterized by reduced disease-activity index and rectal bleeding scores, mitigated colonic shortening and body-weight loss, and increased overall survival rate. Mechanistically, LP@aPMS elevated the anti-inflammatory cytokine IL-10 and significantly suppressed pro-inflammatory mediators (TNF-α, IFN-γ, IL-6, IL-1β), thereby reversing DSS-induced histopathological damage in colonic tissue. These results demonstrate that PMS-based bilayer microgels provide effective gastric protection, targeted intestinal release, and potent therapeutic benefits, laying an experimental and technological foundation for next-generation probiotic microgel preparations.
Cao Y, Li X, Zhang H, Wang T, Feng W, Wang R, Xing J
Cortex Phellodendri total alkaloids ameliorate ulcerative colitis by restoring intestinal barrier integrity via modulation of the ER-mitochondria axis. Journal of ethnopharmacology | 2026-07-04
Cortex Phellodendri (Huangbai), the dried bark of Phellodendron chinense C.K.Schneid. (Rutaceae), represents a classic botanical drug in Traditional Chinese Medicine (TCM) historically prescribed to “clear heat and dry dampness” for treating gastrointestinal inflammatory conditions such as dysentery. However, its multi-component cooperative mechanisms remain largely enigmatic. This study aimed to elucidate the material basis of Cortex Phellodendri total alkaloids (CPA) and investigate its systemic mechanisms and cooperative interactions in ameliorating ulcerative colitis (UC), with a specific focus on the endoplasmic reticulum (ER)-mitochondria axis. The chemical profile of CPA was characterized using UPLC-MS/MS. In vivo efficacy and synergistic effects were evaluated in a dextran sulfate sodium (DSS)-induced colitis mouse model. The underlying molecular mechanisms were explored using DIA-based quantitative proteomics and validated via Western blotting in both colon tissues and a DSS-induced Caco-2 cellular model. CPA effectively ameliorated DSS-induced colitis and restored intestinal barrier integrity. Proteomic and molecular validations revealed that CPA’s efficacy centers on recalibrating the ER-mitochondria axis by blunting the PKR-eIF2α-ATF4 stress cascade and rescuing mitochondrial fitness through SIRT1/3 and OPA1 upregulation. Furthermore, by utilizing its two primary pure alkaloids, berberine (BBR) and phellodendrine (PHE), as mechanistic comparators, we demonstrated that the whole CPA extract exhibits robust cooperative potentiation in silencing IKK/NF-κB signaling and upregulating Claudin-1, along with potent additive effects in suppressing organelle-specific stress. CPA serves as a scientifically validated, multi-target botanical therapeutic for the management of UC. The demonstrated BBR-PHE synergy provides a modern pharmacological blueprint for the traditional “Principal-Adjuvant” theory, highlighting the essential role of the coupled ER-mitochondria network in intestinal barrier restoration.
Xu S, Wu X, Wan J, Gao S, Chen L, Li H, Luo L, Wu J, Sun S, Huang C
Propensity-Matched Case Control Study of Anti-Interleukin-23 Therapies in Clostridioides difficile Infection. Research square | 2026-07-03
Clostridioides difficile infection remains a major cause of infectious morbidity and mortality, largely driven by a dysregulated, toxin-mediated host immune response that current pathogen-targeted therapies fail to address. Interleukin-23-driven Th17 responses and subsequent neutrophil activation play a major role in disease severity and intestinal injury. Observational data suggest that targeting this pathway with anti-IL-23 monoclonal antibodies (therapies already used for inflammatory bowel disease, psoriasis) may significantly reduce mortality in these patients. We conducted a retrospective cohort study of adult patients hospitalized with C. difficile infection using the Epic Cosmos electronic health record database (> 300 million patients across 1,949 healthcare organizations). Propensity score matching (10:1) was used to balance baseline demographic and clinical covariates between patients exposed an available anti-IL-23 monoclonal antibody therapy (ustekinumab, guselkumab, tildrakizumab, risankizumab, mirikizumab) within 90 days prior to diagnosis and unexposed controls. The primary outcome was 30-day all-cause mortality, evaluated using a multivariable Cox proportional hazards regression model, adjusted by ATLAS severity. The propensity-matched cohort included 328 index cases of C. difficile infection exposed to anti-IL-23 within 90-days and 3,155 controls. Anti-IL-23 exposure was associated with a significantly reduced hazard of 30-day mortality (HR 0.341, 95% CI 0.121-0.962, P = 0.042). Heterogeneity of treatment effect analysis revealed a statistically significant positive interaction between baseline ATLAS severity and anti-IL-23 efficacy (P = 0.029). No significant difference was observed in 180-day recurrent infection-free survival between groups (HR 0.808, 95% CI 0.514-1.27, P = 0.355). Antecedent anti-IL-23 therapy is associated with a significant reduction in 30-day mortality following C. difficile infection. These findings support the concept that inhibiting IL-23 mediated inflammation alongside standard anti-C. difficile antibiotics may improve outcomes in C. difficile infection. The significant interaction with baseline severity suggests that the clinical utility of this immunomodulatory therapy may lie in high-risk patient phenotypes. Further prospective studies are warranted to confirm these observations and evaluate the clinical role for IL-23 inhibition in C. difficile infection.
Madden GR, Ma JZ
Oral colon-targeted micro-nano formulation engineered in microfluid for synergistic therapy of inflammatory bowel disease.★ Biomaterials | 2026-07-03
The management of inflammatory bowel disease (IBD) continues to pose a substantial clinical obstacle, owing to the intricate nature of its pathophysiology. Targeted micro/nano drug delivery systems, which can exploit the synergistic effects of multiple components, represent a promising therapeutic strategy. In this study, we developed a colon-targeted co-delivery system based on hydrogel microspheres (CCB@HMs) using droplet microfluidics, serving as a versatile micro/nano platform for IBD therapy. This system enables the targeted delivery of budesonide (BDS) while leveraging curcumin (Cur) and inulin as both drug carriers and antioxidants, thereby compensating for the limited reactive oxygen species (ROS)-scavenging capacity of BDS and achieving synergistic therapeutic effects. In vitro and in vivo evaluations demonstrated that CCB@HMs efficiently deliver drugs to inflamed colonic tissues, providing prolonged retention and sustained release. The microspheres effectively scavenge ROS, alleviate oxidative stress, modulate intestinal immunity, repair the epithelial barrier, and restore gut homeostasis. Collectively, these results confirm the synergistic therapeutic effects of CCB@HMs in a murine colitis model, positioning them as a promising targeted and multifunctional oral delivery strategy for IBD.
Zhou G, Wang X, Cao Y, Yue Z, Zhao X, Ruan X, Hu J, Liu X, Deng D
Orally administered biomimetic nanovesicles engineered with FGF2 orchestrate mucosal healing and microbiome remodeling in inflammatory bowel disease. Materials today. Bio | 2026-07-02
Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation and profound microbial dysbiosis, presenting significant therapeutic challenges. While fibroblast growth factor 2 (FGF2) possesses potent regenerative capabilities, its oral administration is severely hindered by rapid gastrointestinal degradation. To overcome these delivery barriers, this study investigates a novel, targeted therapeutic strategy utilizing nanoscale outer membrane vesicles (OMV/FGF2) naturally secreted during the normal growth of FGF2-engineered Gram-negative bacteria. The isolated OMV/FGF2 (120.1 nm, -13.7 mV) maintained robust structural integrity in simulated gastric fluid and demonstrated highly favorable cytocompatibility. In a dextran sulfate sodium (DSS)-induced murine colitis model, orally administered OMV/FGF2 significantly attenuated disease severity, mitigating weight loss and colon shortening. Mechanistically, OMV/FGF2 actively restored the intestinal physicochemical barrier by upregulating tight junction proteins (Occludin, ZO-1) and promoting mucus hypersecretion. Furthermore, 16S rRNA analysis revealed that OMV/FGF2 reversed microbial dysbiosis, enhancing α-diversity and enriching beneficial commensals (e.g., Bacteroides, Lactobacillus) while suppressing pathogenic populations. Ultimately, OMV/FGF2 ameliorates intestinal inflammation through a synergistic dual mechanism of fortifying the epithelial barrier and remodeling the gut microbiome. This engineered nanoplatform provides a promising, orally bioavailable therapy for IBD.
Yi M, Luo J, Abdo E, Lu Z, Pan X, Han X, Sun X, Xia Y, Dai J, Shi K
Targeting the Gut Microbiota with Herbal Compounds from Traditional Chinese Medicine: A Mechanistic Synthesis of a Novel Therapeutic Approach for Ulcerative Colitis.Review Journal of inflammation research | 2026-06-29
Ulcerative colitis (UC) represents a chronic relapsing inflammatory bowel disease characterized by substantial unmet clinical needs and limited curative modalities. Accumulating evidence implicates gut microbiota dysbiosis as a pivotal pathogenic driver, positioning microbiota-targeted interventions as promising therapeutic strategies. This review systematically delineates the mechanisms by which herbal compounds from Traditional Chinese Medicine ameliorate UC through the restoration of microbial and metabolic homeostasis-including the modulation of beneficial commensals and their bioactive metabolites-thereby reinforcing intestinal barrier integrity and dampening mucosal inflammation. Although translational bottlenecks persist, integrative multi-omics frameworks coupled with advanced pharmaceutical engineering offer viable pathways to bridge preclinical findings and clinical application. Taken together, deciphering the bidirectional crosstalk between herbal compounds and the gut microbiome paves the way for mechanism-based, personalized botanical therapeutics in UC management.
Chen J, Chen J, Wang Z
A standardized fecal microbiota transplantation protocol enables consistent, microbiota-driven colitis in IL-10-deficient mice. Frontiers in microbiology | 2026-06-24
Gut microbiota dysbiosis is a central feature of inflammatory bowel disease (IBD), yet experimental systems that enable controlled investigation of microbiota-driven inflammation remain limited. In interleukin-10-deficient (Il10-/-) mice, intestinal inflammation is strictly dependent on the presence of commensal microbiota; however, disease onset and severity are highly variable, reflecting differences in microbial composition across environments. To overcome this limitation, pharmacologic approaches such as piroxicam administration have been widely used to synchronize disease, but these methods introduce epithelial injury and non-microbiota-dependent inflammatory pathways that confound mechanistic interpretation. Here, we describe a standardized fecal microbiota transplantation (FMT) protocol that enables controlled microbiota-driven induction of colitis in Il10-/- recipient mice without the use of chemical triggers. In this model, recipient mice aged 8-10 weeks receive fecal microbiota via oral gavage from either colitic Il10-/-; Itgb7-/- double knockout (DKO) donor mice or non-colitic young Il10-/- controls. The DKO donors exhibit impaired mucosal immune regulation and reduced IgA responses, features associated with the emergence of a colitogenic microbial community. Repeated FMT administration over 9 weeks promotes uniform disease induction and reduces variability in disease kinetics across experimental cohorts. Importantly, this approach preserves microbiota-driven disease mechanisms while improving experimental consistency compared with conventional spontaneous Il10-/- models and avoids the confounding effects of pharmacologic synchronization. The protocol is compatible with downstream histological, immunological, and microbiome analyses and provides a practical platform for investigating host-microbiota interactions and microbiome-targeted therapeutic strategies in IBD.
Kaur P, Rivera-Nieves J
Biomarkers & Precision Medicine (13 papers)
The NLRP3 inflammasome as a dynamic context-dependent regulator: mechanisms, disease progression, and therapeutic implications.Review Journal of translational medicine | 2026-07-10
The NLRP3 inflammasome is a central regulator of innate immunity and inflammation, but its functions extend beyond a simple pro-inflammatory role. Increasing evidence indicates that the biological consequences of NLRP3 activation are highly context-dependent, with protective or pathogenic effects determined by cellular composition, tissue microenvironment, and disease stage. In this review, we examine NLRP3 biology across three interconnected dimensions: cellular context, including immune and non-immune compartments; microenvironmental context, including infectious versus sterile inflammation and tissue repair versus tissue damage; and disease context, including stage- and time-dependent functional shifts. We further discuss three major determinants of NLRP3 output: cytokine bias between IL-1β and IL-18, cell-fate decisions between pyroptosis and survival, and epigenetic programming of inflammasome-responsive states. Using representative disease settings such as cancer, inflammatory bowel disease, and autoimmune disorders, we illustrate how similar NLRP3 activation can lead to divergent biological outcomes. We also discuss the therapeutic implications of this plasticity, arguing that effective intervention will require context-selective rather than universal inhibition. A more precise understanding of NLRP3 context dependence may support rational trial design, biomarker development, future patient-stratification frameworks, and more biologically informed therapeutic strategies in NLRP3-related diseases.
Liu S, Liu X, Hu J, Chen H, Yang S, Feng J, Sui Y
Traditional Chinese Medicine in the Treatment of Ulcerative Colitis: From Pharmacokinetics to Personalized Therapy. The American journal of Chinese medicine | 2026-07-10
Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by immune dysregulation, intestinal microbiota imbalance, and disruption of the mucosal barrier. Current clinical management is challenged by high relapse rates and significant interindividual variability in drug responses. Traditional Chinese Medicine (TCM) has shown unique therapeutic advantages in UC treatment through multi-targeted interventions such as the modulation of the immune-microbiota axis, restoration of mucosal integrity, and reduction of oxidative stress. However, two major bottlenecks, the complex pharmacokinetic (PK) behaviors of multi-component systems and the lack of personalized dosing strategies, hinder the optimization of its clinical efficacy. This review emphasizes the PK underpinnings of TCM therapy for UC by integrating current knowledge on absorption, distribution, metabolism, and excretion (ADME) characteristics, both PK and pharmacodynamic (PD) and analytical modeling advances, and PK-informed strategies that facilitate individualized clinical use. By integrating PK profiling with patient-specific variables, this review aims both to provide a theoretical and methodological framework for precision TCM in UC management and to ultimately facilitate a paradigm shift from empirical therapy to quantitatively optimized interventions.
Peng X, Zheng S, Tian G, Dai S, Li Y
Integrative metagenomics and structural bioinformatics identify explainable gut microbial variants associated with Crohn’s disease. PloS one | 2026-07-10
Metagenomics has revealed disease-associated shifts in microbial taxa and functions in inflammatory bowel disease (IBD) patients. However, the role of genomic variation in gut commensals remains poorly understood. Here, we integrated metagenomic profiling, variant calling, and structural bioinformatics to identify disease-associated variants in the gut microbes. Crohn’s disease (CD) and ulcerative colitis (UC) showed significant negative associations with Bacteroides uniformis, Bacteroides vulgatus, and Eubacterium rectale. These bacteria exhibited 190,712 single-nucleotide polymorphisms, including 479 CD-specific and 235 UC-specific variants. Variant prioritization identified a CD-specific Val170Leu substitution in the conserved starch-binding domain of the Starch Utilization System D (SusD) protein in B. uniformis. Structural modeling and cyclodextrin docking indicated reduced binding affinity in the mutant, while 200-ns molecular dynamics simulations showed stable ligand retention only in the wild type. These findings suggest that impaired starch metabolism driven by SusD variation may contribute to B. uniformis depletion in CD and demonstrate the value of integrating metagenomics with structural analyses to identify functionally relevant microbial variants.
Khan N, Nasir MM, Aziz U, Manzoor H, Raziq MF, Hussain Z, Jabeen I, Kayani MUR
Aspergillus ruber, a Candidate Beneficial Gut Fungus, Alleviates Colitis by Secreting 3-Methyldioxyindole, a Metabolite Linked to Aryl Hydrocarbon Receptor Signaling. Journal of agricultural and food chemistry | 2026-07-09
Inflammatory bowel disease (IBD) is closely associated with intestinal microecological imbalance, and the role of gut fungi in its pathogenesis has attracted increasing attention. Our previous study showed that polyphenols from foxtail millet bran (BPIS) alleviated experimental colitis while increasing the abundance of Aspergillus ruber. Here, we found that gavage with A. ruber ameliorated dextran sodium sulfate (DSS)-induced colitis, as reflected by reduced body weight loss, disease activity index, colon shortening, and tissue injury. Metabolomics analysis identified 3-methyldioxyindole as a major candidate metabolite, which was further verified in the liquid culture metabolite extract of A. ruber and functionally validated in vivo using the purified compound. Mechanistically, the anti-inflammatory effect of 3-methyldioxyindole was aryl hydrocarbon receptor (AhR)-dependent, blocked by the AhR antagonist CH-223191, and associated with suppressed p65 and IκBα phosphorylation in the NF-κB pathway. These findings support fungal-derived postbiotic strategies for colitis intervention.
Li H, He S, Qiao Q, Li Z, Dong X
TREM1 signaling amplifies neutrophil-mediated inflammation in inflammatory bowel disease.★ Nature communications | 2026-07-08
In inflammatory bowel disease (IBD), complex immune dysregulation induces chronic inflammation. TREM1 is a receptor expressed on myeloid cells and is activated by ligands such as PGLYRP1 to amplify inflammatory responses. Here, we analyze the function of TREM1 signaling in neutrophil-driven inflammation, identifying two positive feedback loops. First, neutrophils activated by phorbol 12-myristate 13-acetate (PMA) or by bacteria release PGLYRP1, which forms a ligand complex with bacterial peptidoglycan and activates TREM1, thereby enhancing neutrophil degranulation, reactive oxygen species production, and NETosis. Second, TREM1 activation on monocytes promotes the secretion of chemokines and cytokines that recruit and activate additional neutrophils, further perpetuating inflammation. In vivo, TREM1 activation exacerbates colitis in mice, with the gut commensal bacterium Blautia faecis potentially contributing to human TREM1 activation in IBD. In biopsy samples from patients with IBD, an elevated TREM1 pathway signature is associated with inflamed tissue and treatment resistance in ulcerative colitis. Our findings thus highlight TREM1 as a regulator of mucosal inflammation, and a potential therapeutic target for IBD.
Andrade W, Xu H, Peng Y, Yao Z, Bevers J, Puno R, Shi Y, Pham V, Choi M, Sun Y
Serum REG3α as a biomarker for clinical and endoscopic activity in ulcerative colitis. Scientific reports | 2026-07-07
Current biomarkers, including serum C-reactive protein (CRP) and fecal calprotectin, have limitations in monitoring disease activity of ulcerative colitis (UC). Regenerating islet-derived protein 3α (REG3α), which is constitutively produced by Paneth cells, is a bactericidal C-type protein against Gram-positive bacteria. Preliminary studies suggest that REG3α may serve as a promising novel blood-based biomarker for assessing disease activity in patients with UC. A total of 128 patients with UC were prospectively enrolled. Blood samples were obtained on the same day as endoscopy. Serological markers including REG3α, CRP, albumin, and serum calprotectin were measured. The clinical and endoscopic activity were assessed using the total Mayo score (remission, mild, or moderate-to-severe) and the Mayo endoscopic subscore (MES), respectively. Serum levels of REG3α, CRP, albumin, and calprotectin were significantly correlated with clinical activity (Mayo score ≥ 6) (Spearman’s ρ = 0.362, P < 0.001; ρ = 0.429, P < 0.001; ρ = -0.312, P < 0.001; and ρ = 0.253, P = 0.004, respectively). Serum levels of REG3α, CRP, and albumin were also significantly correlated with endoscopic activity (MES ≥ 2) (ρ = 0.362, P < 0.001; ρ = 0.420, P < 0.001; and ρ = -0.240, P = 0.006, respectively), whereas serum calprotectin was not (ρ = 0.147, P = 0.098). The combination of serum REG3α and CRP predicted clinical and endoscopic activity with AUC values of 0.847 and 0.783, respectively, showing improved discriminatory performance compared with the individual biomarkers in this cohort. Among 19 patients who underwent serial follow-up of REG3α levels, a significant decrease was observed during periods of clinical improvement (P = 0.005), although this finding should be interpreted as preliminary. REG3α is a promising blood-based biomarker associated with both clinical and endoscopic activity in UC. When interpreted together with CRP, it showed improved discriminatory performance in this cohort. This serum-based approach may be useful as an adjunctive option when stool-based testing is less feasible. However, the combined REG3α-CRP model should be considered exploratory, and the serial monitoring findings should be interpreted as preliminary. Further validation in larger, independent cohorts, including direct comparison with fecal calprotectin, is required before broader clinical application can be considered.
Kim SJ, Lee BI, Cho ML, Park JS, Yang S, Lee HH, Lee KM, Ji JS, Oh EJ, Park SH
Association between hemoglobin-to-red cell distribution width ratio and occurrence of sepsis during ICU stay in inflammatory bowel disease patients who died: a retrospective study using the EICU-CRD database. PloS one | 2026-07-07
The hemoglobin-to-red cell distribution width ratio (HRR) is a biomarker associated with systemic inflammation and outcomes in critical illness. Within clinical databases, there exists an extreme-prognosis subgroup of inflammatory bowel disease (IBD) patients, those who all died within 30 days of ICU admission. Due to limitations in the database, this study can only analyze this specific subgroup. This study aims to explore and describe the association between admission HRR and the occurrence of sepsis during ICU stay in this specific subgroup of IBD patients. A retrospective cohort study was conducted using the eICU Collaborative Research Database (2014-2015), including 229 eligible patients. Multivariable logistic regression was used to assess the independent association, adjusting for confounders. The dose-response relationship was examined using restricted cubic spline (RCS) models. Subgroup and interaction analyses were performed across age, sex, and race. The sepsis group had a significantly lower admission HRR than the non-sepsis group (6.04 ± 1.66 vs. 6.77 ± 2.0, P = 0.008). After full adjustment, each 1-unit increase in HRR was associated with 20.3% lower odds of sepsis (P = 0.007). Compared to the lowest quartile (HRR < 5.1), patients in the highest quartile (HRR ≥ 7.85) had 66.8% lower adjusted odds of sepsis (P = 0.015). RCS analysis indicated a linear, inverse relationship between HRR and sepsis (P for non-linearity = 0.42). Subgroup analysis revealed the negative association was more pronounced in patients aged <65, males, and White patients. However, formal interaction tests were not statistically significant (all P for interaction >0.05), indicating the association did not differ meaningfully across these subgroups. In this specific cohort, a lower admission HRR was associated with the occurrence of sepsis. Due to inherent selection bias, this finding describes an association within this specific subgroup and cannot be generalized. This exploratory study generates the hypothesis that HRR may reflect a unique pathophysiological state in end-stage IBD, a hypothesis that requires validation in prospective, unbiased cohorts.
Li Y, Hua Q, Li Z, Jiang M
Activation of GABABR alleviates colitis by reprogramming macrophage polarization via the IRAK-M/NLRP3/NF-κB pathway. Biochemical pharmacology | 2026-07-07
Although the metabotropic GABA type B receptor (GABABR) has emerged as an immune modulator, its specific role in regulating the dysregulated macrophage polarization that drives inflammatory bowel disease (IBD) pathogenesis remains undefined. Utilizing a dextran sulfate sodium-induced colitis model and lipopolysaccharide-stimulated macrophages, we observed that colonic inflammation significantly downregulates GABABR expression concomitant with a pronounced shift toward M1 polarization. Pharmacological activation of GABABR with baclofen ameliorated clinical and histopathological manifestations, restored mucosal barrier integrity, and suppressed mast cell accumulation. Mechanistically, baclofen upregulated the negative regulator Interleukin-1 receptor-associated kinase M (IRAK-M), which inhibited the NOD-like receptor family pyrin domain containing 3 (NLRP3) / nuclear factor-kappa B (NF-κB) signaling cascade and promoted repolarization toward the protective M2 phenotype. The essential role of IRAK-M was confirmed via genetic knockout; such ablation abolished the protective effects of baclofen, exacerbated colitis, enhanced NLRP3/NF-κB activation, and drove M1 polarization. Transcriptomic analysis of IRAK-M-deficient mice revealed profound alterations in immune-related pathways, validating IRAK-M as a critical downstream effector. Furthermore, inhibition of NLRP3 with CY-09 and genetic deletion recapitulated the M2-promoting effects observed with GABABR activation. Collectively, these findings establish GABABR as a pivotal regulator of intestinal immune homeostasis that controls macrophage polarization through the IRAK-M/NLRP3/NF-κB axis, positioning GABABR as a promising therapeutic target for IBD.
Xie H, Liu H, Xiu Y, Lao R, Yu T, Che Y, Su R, Wu D, Yi W, Cheng X
From polyamine metabolism genes to immunoproteasome subunits: a transcriptome-based screening of candidate biomarkers in Crohn’s disease. Scientific reports | 2026-07-04
This study explored Polyamine metabolism (PM)-related biomarkers and their regulatory processes in Crohn’s disease (CD) using three transcriptome datasets (GSE179285, GSE126124, and GSE102133) and 59 PM-related genes (PMRGs). Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify candidate genes, resulting in four key candidates: PSMB10, PSMB8, PSMB9, and PSME2, selected from 796 differentially expressed genes (DEGs). Machine learning and expression validation confirmed that PSMB9, PSMB10, and PSME2 were overexpressed in the CD group, with ROC curve analysis revealing AUC values above 0.8 in all three datasets, supporting their potential as biomarkers. Functional enrichment analysis showed their involvement in the degradation of valine, leucine, and isoleucine, and cell adhesion molecules. Immune infiltration analysis, inferred from the same transcriptomic data, showed that the expression levels of these genes were positively correlated with the abundance of 27 immune cell types in CD tissues. Additionally, these biomarkers were linked to other digestive diseases, such as colon disease and proctitis. Notably, CARFILZOMIB demonstrated significant binding to these biomarkers, suggesting a potential mechanistic link that warrants further experimental investigation. This research emphasizes the role of PSMB9, PSMB10, and PSME2 as promising biomarkers for CD and provides a foundation for further exploration of the regulatory mechanisms of PM in CD.
Qi H, Ding X, Leng G, Zhang M, Luo S, Zhou Y, Yang Y, Yang H, Wang Q, Jin X
Multi-Omics Framework Integrating Genetics, Microbiome, Metabolism, and Immunity for Deciphering Ulcerative Colitis Pathogenesis and Diagnostic Biomarker Discovery. FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2026-07
Ulcerative colitis (UC) is an inflammatory bowel disease involving complex interactions between genetics, gut microbiota, metabolism, and immunity. This study aimed to systematically evaluate multi-omics factors potentially associated with UC susceptibility and identify reliable diagnostic biomarkers. A two-sample Mendelian randomization (MR) framework assessed potential causal associations between gut microbiome, circulating metabolites, immune cell phenotypes, and UC susceptibility. Significant MR findings were integrated with multiple transcriptomic datasets to identify differentially expressed candidate genes. Immune infiltration analysis, machine learning modeling, and external validation were subsequently performed. Single-cell and spatial transcriptomics were used to localize key genes and to explore their potential cell type-specific functions within the tissue microenvironment, followed by qRT-PCR validation in independent clinical tissues and siRNA-mediated IFITM2 knockdown in THP-1-derived macrophages. MR analyses identified potential causal associations for specific microbiota, sphingomyelin-related metabolites, and immune cell phenotypes with UC susceptibility. Integrative analysis prioritized four core signature genes: SAG, WDR48, IFITM2, and SIRPA. A random forest model achieved an AUC of 0.964 and identified a four-gene signature with strong diagnostic performance. Single-cell and spatial transcriptomics localized IFITM2 upregulation mainly to myeloid cells, particularly Neutrophil_IFITM2. CellChat suggested a potential CD4_Tem_IL7R-ANXA1-FPR1-Neutrophil_IFITM2 axis. qRT-PCR supported the expression directions of the four genes, and IFITM2 knockdown in THP-1-derived macrophages reduced TNF-α, IL-6, and IL-1β mRNA expression. This multi-omics framework supports the potential roles of specific microbiota, sphingolipid metabolism, and immune phenotypes in UC pathogenesis. The four-gene signature and characterization of Neutrophil_IFITM2, supported by independent qRT-PCR validation and preliminary IFITM2 knockdown experiments, may provide a framework for precision diagnosis and future mechanistic studies in UC.
Wang Y, Tian Y, Cui H, Chang S, Tang T, Chang Y
Dietary emulsifiers and host inflammation synergistically drive genomic evolution of Crohn’s disease-associated Escherichia coli toward enhanced pathogenicity.★ Journal of Crohn’s & colitis | 2026-07
The rising incidence of Crohn’s disease (CD) in Westernized countries has been linked to changes in diet and increased consumption of food additives, yet the mechanisms by which these factors fuel intestinal inflammation remain unclear. Adherent-invasive Escherichia coli (AIEC), a pathobiont involved in CD pathogenesis, lacks a clear genetic hallmark but exhibits intestinal colonization and virulence traits, raising questions about the evolutionary forces promoting its emergence among select individuals. Here, we investigated how chronic exposure to two common dietary emulsifiers, carboxymethylcellulose (CMC) and polysorbate 80 (P80), along with host inflammation, drives AIEC genomic evolution and pathogenic potential. Wild-type and Il10-deficient mice were monocolonized with AIEC and chronically exposed to CMC, P80, or water. Bacterial isolates were collected and analyzed for genomic diversification, mutations, and phenotype both in vitro and in vivo. Emulsifiers accelerated AIEC genomic diversification and selected for mutations linked to increased motility, invasion, and pro-inflammatory activity. Moreover, dietary emulsifier-evolved strains displayed a marked fitness advantage in vivo, outcompeting their counterparts in murine hosts, with the greatest advantage observed when evolution occurred under inflammatory conditions. Notably, evolutionary pathways and phenotypic outcomes were shaped by both emulsifier and the host’s inflammatory status, highlighting synergy between diet and host genetics in fostering pro-inflammatory pathobionts. These findings provide an evolutionary framework connecting modern dietary habits to the emergence of pathogenic AIEC strains, and underscore the importance of dietary interventions in individuals at risk for inflammatory bowel disease.
Rytter H, Chevarin C, Martin L, Bruder E, Denizot J, Tenaillon O, Espéli O, Birer A, Barnich N, Viennois E
Integrative single-cell transcriptomics and mendelian randomization identifies BTN3A2 as a shared protective factor in Behçet’s disease and inflammatory bowel disease. Frontiers in immunology | 2026-06-24
Behçet’s disease (BD) and inflammatory bowel disease (IBD) are immune-mediated chronic inflammatory disorders. Although they exhibit significant overlap in clinical manifestations and immunological features, whether they share molecular targets and pathogenic links remains unclear. This study aimed to explore the possible linking and shared treatment target between these two diseases. We analyzed scRNA-seq data from the peripheral blood of BD and IBD patients to delineate the immune cell landscape and identify key subsets via differential proportion analysis. Combining expression quantitative trait loci (eQTL) and genome-wide association study (GWAS) data, Mendelian Randomization (MR) analysis was performed to infer causal relationships between the key gene expressions in BD and IBD. Finally, validation was performed using the experimental autoimmune uveitis (EAU) mouse model, external datasets, and blood samples from BD uveitis patients. scRNA-seq analysis revealed a significant decrease in the proportion of CD4+ TEM_TH1-like cells in both BD and IBD. We identified 45 key signature genes within this subpopulation, among which the BTN3A2 gene was identified as a protective one in both BD and IBD. Co-localization analysis indicated spatial consistency between the BTN3A2 eQTL and BD GWAS signals. At the cellular functional level, BTN3A2+ and BTN3A2- CD4+ TEM_TH1-like cells exhibited distinct cell-cell communication networks and pathway enrichment characteristics. The interactions between BTN3A2+ and BTN3A2- cells were mediated by distinct signaling pathways in IBD and BD respectively. The EAU mouse model, which recapitulates BD-like ocular inflammation, was found for the first time to display IBD-like colonic pathological, including inflammatory infiltration, crypt dilation, goblet cell loss, and barrier disruption, accompanied by elevated IL-1β expression. Transcriptomic analysis using EAU mouse retina further revealed that the IBD pathway was one of the most significantly enriched disease-related pathways. Independent external datasets showed a significant downregulation of BTN3A2 at mRNA level in IBD, whereas downregulation of BTN3A2 at mRNA and protein levels was found in BD patients with uveitis. This study identifies BTN3A2 as a shared protective factor in BD and IBD and provides experimental evidence linking BD-associated ocular inflammation to intestinal pathology, establishing a new basis for comorbidity-targeted therapeutic strategies.
Dai Q, Wu Y, Geng W, Li M, Zhang W, Lai Y, Zhang P, Zhou C, Wang Y, Cao Q
Integrated multi-omics analysis reveals distinct microbiota-metabolite signatures and a novel HCN2-2-hydroxybutyric acid interaction in inflammatory bowel disease. Frontiers in nutrition | 2026-06-23
Gut microbiota-derived short-chain fatty acids (SCFAs) exert critical regulatory functions in inflammatory bowel disease (IBD). However, integrated profiling of fecal SCFA signatures alongside gut microbiota composition in ulcerative colitis (UC) and Crohn’s disease (CD) remains insufficiently characterized. Furthermore, the molecular mechanisms through which microbiota metabolites engage host protein targets warrant systematic investigation. This study enrolled 30 patients with UC, 20 with CD, and 30 healthy controls, with paired fecal collection. Gut microbiota composition was analyzed by deep metagenomic sequencing, and SCFA concentrations were quantified by gas chromatography-mass spectrometry. Multi-omics integration, correlation network analysis, and Bayesian kernel machine regression were employed to resolve microbiota-metabolite associations. An integrated computational pipeline incorporating molecular dynamics simulations was constructed to evaluate the thermodynamic stability and binding modalities of metabolite-protein interactions. Both UC and CD patients exhibited significantly reduced gut microbial α-diversity and characteristic community structure alterations. Fecal metabolomic profiling revealed synchronous elevation of 2-Hydroxybutyric acid (2-HB) and isocaproate in both patient groups, whereas butyrate reduction was restricted to UC. Multi-omics correlation analysis identified significant associations between 2-HB and unclassified Veillonella species as well as specific functional modules. Molecular dynamics simulations with an aggregate sampling time of 100 ns revealed a structural basis for the formation of a stable complex between 2-HB and the hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2). This interaction was primarily mediated by electrostatic interactions involving Arg659, Arg618, and Arg617 residues alongside hydrophobic contacts, suggestive of potential allosteric modulation. This study identifies 2-HB and isocaproate as shared fecal metabolic markers across IBD and provides a structural rationale for the interaction between 2-HB and HCN2. The druggability profile of HCN2 supports its prioritization for mechanistic investigation, with the caveat that functional validation is prerequisite to any inference of therapeutic relevance.
Zhang M, Jiang J, Yang B, Zhao W, Zhang J, Ma T, Wang H
Surgery & Complications (13 papers)
Refractory Chronic Inflammatory Bowel Disease in Childhood and Adolescence: Options in Primary Non-Response or Secondary Treatment Failure.Review Deutsches Arzteblatt international | 2026-10-02
The incidence of inflammatory bowel disease among children and adolescents in Europe is approximately 10 per 100 000 per year. Refractory disease courses are clinically significant and associated with delayed growth and development, recurrent hospitalizations, and the need for surgery. 10-40% of patients have a primary nonresponse to anti-TNFα therapies, and a further 5-20% per year have secondary treatment failure, defined as loss of response after an initial response while on maintenance treatment. The aim of this review is to summarize current treatment options for primary non-response or secondary treatment failure. This narrative review is based on current guidelines and pertinent publications retrieved by a selective search in the PubMed, Ovid MEDLINE, and Cochrane databases. Before switching to another drug class, a standardized reevaluation is essential, incorporating clinical findings, biomarkers, endoscopy and/or imaging, and therapeutic drug monitoring. Following failure of anti-TNFα therapy, ustekinumab (approved for Crohn’s disease for patients older than 2 years) and vedolizumab (currently exclusively off-label) represent the best-established options in pediatric care. Reported clinical remission rates are 51% at week 52 for ustekinumab and 32% (Crohn’s disease) and 42% (ulcerative colitis) at week 14 for vedolizumab. For IL-23p19 antibodies, Janus kinase inhibitors, and sphingosine-1-phosphate receptor modulators, the available evidence is still derived predominantly from adult studies, with very limited data from pediatric practice. Surgery remains an important option in complicated disease courses. Given the limited pediatric evidence and the frequent off-label use of newer agents, there is a need for prospective studies, registry data, and structured treatment algorithms to more reliably define the efficacy and long-term safety of treatments for pediatric chronic inflammatory bowel disease. In our view, children and adolescents with refractory inflammatory bowel disease should be managed by an interdisciplinary team in a center with the requisite experience.
Rommel F, Bergheim C, Melchior R, Krause T, Zilbauer M, Jenke A
Capsule retention in Crohn’s disease requiring surgical management: two case reports.Case report Journal of surgical case reports | 2026-07-11
Capsule endoscopy is an established diagnostic modality for small bowel evaluation, particularly in Crohn’s disease. Capsule retention remains its most significant complication, especially in patients with stricturing disease. We report two cases of asymptomatic capsule retention in patients with established Crohn’s disease. In both cases, cross-sectional imaging failed to predict clinically significant stenosis. Capsule retention was confirmed radiologically after 2 weeks. Corticosteroid therapy did not result in capsule passage, and both patients ultimately required surgical intervention. Surgical management allowed capsule retrieval and definitive treatment of underlying strictures through bowel resection and stricturoplasty. These cases highlight the importance of appropriate pre-procedural risk stratification and multidisciplinary management. Routine use of cross-sectional imaging and, when available, patency capsule testing is strongly recommended in patients at risk of small bowel stenosis.
Khyat C, Salihoun M, Serraj I, Kabbaj N
Crohn’s Disease: From Immune Dysregulation to Intestinal Damage.Review Inflammation | 2026-07-11
Crohn’s disease (CD) is a long-lasting, recurring inflammatory bowel disease (IBD) marked by segmental, transmural inflammation that may affect any part of the gastrointestinal tract. Growing evidence suggests that CD does not originate from a single pathogenic mechanism, but instead results from the convergence of various biological disturbances that collectively disrupt intestinal homeostasis. Genetic alterations that weaken microbial detection, autophagy, and epithelial protection appear to establish initial vulnerabilities, enabling microbes to trigger exaggerated immune responses. This vulnerability is further exacerbated by environmental factors that intensify host microbial imbalance. The ensuing microenvironment fosters a significant production of effector molecules, which exacerbate the existing inflammation and activate stromal cells, which in turn drive tissue remodeling and structural complications such as ulceration, strictures, and fistulas. In this article, we synthesize the knowledge on the molecular and cellular mechanisms involved in CD pathogenesis, emphasizing the dynamic interplay between immune and stromal components that contributes to a disease-permissive environment. We also examine key inflammatory pathways and signaling networks involved in disease progression and discuss how these mechanistic insights inform existing and emerging therapeutic strategies.
Salvatori S, Frascatani R, De Vico P, Marafini I, Monteleone G
Impact of Diet and Body Mass Index on the Development of Pouchitis in the First Year After Ileal Pouch-Anal Anastomosis. Digestive diseases and sciences | 2026-07-10
Although pouchitis is the most common complication after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), the influence of diet on pouchitis is poorly understood. Thus, evidence-based dietary recommendations after IPAA are limited. We evaluated dietary intake in the period after the final stage of IPAA for UC and Body Mass Index (BMI) to identify potential associations with pouchitis. We used the Dietary Screener Questionnaire (DSQ) to assess dietary intake among patients in a prospective cohort enrolled within 2 weeks of the final stage of IPAA for UC. We compared food group and fiber intake of those who developed pouchitis within 12 months of the final stage of IPAA with those who did not. These were also compared to the United States Department of Agriculture (USDA) recommended daily goals. Among 89 patients, there was no significant difference in individual fiber intake when comparing those who developed pouchitis and those who did not. In comparison with USDA guidelines, both groups (pouchitis and no pouchitis) exhibited decreased intake of several food groups, such as fruits, vegetables, fiber, and dairy. Patients who developed pouchitis had a significantly higher median body mass index (BMI) at the time of surgery compared to patients who did not develop pouchitis (median 29.2 vs. 24.8, P = 0.022). In a prospective cohort, we identified no association between dietary intake and development of pouchitis within the first year after IPAA. However, elevated BMI may represent a unique target for intervention to prevent pouchitis occurrence.
Goldbeck S, Anderson C, Barr J, Axelrad J, Long MD, Herfarth HH, Barnes E
Small bowel obstruction secondary to Strongyloides stercoralis: a rare cause and mimic of inflammatory bowel disease.Case report BMJ case reports | 2026-07-09
An immunocompetent man in his 60s with no prior medical or surgical history presented with 1 week of progressive abdominal pain, vomiting and obstipation. CT demonstrated a distal ileal small bowel obstruction with segmental inflammatory changes raising concern for new Crohn’s disease. Further history revealed ingestion of untreated tank water, prompting suspicion for a parasitic infection. This was further supported by the presence of peripheral eosinophilia. Empirical treatment with ivermectin was commenced, resulting in complete clinical resolution and normalisation of eosinophils. This case highlights Strongyloides infection as an important mimic of inflammatory bowel disease and an under-recognised cause of small bowel obstruction. Misdiagnosis poses a significant risk to the patient, as this could lead to life-threatening hyperinfection if corticosteroid therapy is initiated.
Malkopoulos A, Subhaharan D, Kamal S, Haig A
SMOC2 mediates GLI1+ mesenchymal cell-driven fibrostenosis and predicts postoperative recurrence in Crohn’s disease.★ Gut | 2026-07-08
Fibrostenosis is a common and disabling complication of Crohn’s disease (CD) with no reliable early biomarkers, limited treatment options and high postoperative recurrence. To investigate the contribution of glioma-associated oncogene homolog 1 (GLI1+) mesenchymal cells to fibrostenotic progression and their potential as a therapeutic target. Fibrotic and non-fibrotic tissue samples were collected from patients with CD undergoing surgery for fibrostenotic obstruction. Chronic colitis was induced in mice using dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Single-cell RNA sequencing was performed on human and murine intestinal tissues. Gli1-CreERT2; R26-tdTomato and Gli1-CreERT2; R26-iDTR mice were used for lineage tracing and targeted cell ablation. GLI1+ mesenchymal cells were isolated to identify pathogenic determinants. A surgical CD fibrostenosis cohort was analysed. Single-cell transcriptomics and immunofluorescence revealed enrichment of GLI1+ mesenchymal cells at fibrotic sites. Lineage tracing showed that these cells expanded and adopted a myofibroblast phenotype in chronic colitis, whereas their ablation alleviated fibrosis. GLI1+ mesenchymal cells exhibited a distinct transcriptional expression profile with prominent expression of SPARC-related modular calcium-binding protein 2 (SMOC2). SMOC2 was upregulated in human and murine fibrosis, and its knockdown in vivo and in vitro attenuated fibrosis. Mechanistically, GLI1+ mesenchymal cells secreted SMOC2, promoting extracellular matrix deposition and fibroblast activation. In surgical CD cohorts, high SMOC2 expression in intestinal tissue correlated with postoperative recurrence, confirmed in the validation cohort. GLI1+ mesenchymal cells drive intestinal fibrostenosis through SMOC2-mediated niche formation. SMOC2 may serve as a predictive biomarker for postoperative recurrence and a potential therapeutic target for CD.
Wang D, Zhao X, Yang Q, Zhu D, Liao Y, Zhao Y, Sun S, Wang J, Zhuang H, Zhang S
Addressing real-world data gaps: estimating the uk population cost of crohn’s disease and ulcerative colitis using a flexible cost-of-illness model informed by the optimal patient journey and IBDUK patient survey 2023. BMC health services research | 2026-07-08
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic conditions affecting around 500,000 people in the UK and carries rising prevalence and substantial economic burden. Despite expanding therapeutic choice, contemporary UK cost analyses are scarce. A flexible cost of illness model was developed to estimate the excess costs associated with CDUC in the UK at a population level, including direct NHS costs and societal costs. The model estimates how the direct healthcare and indirect societal costs of IBD change over time, helping to analyse and manage key cost drivers. This supports planning and policy decisions by outlining how interventions and external influences affect long-term spending patterns. The study used public data, published research, and the 2023 IBD UK survey to create a cost model covering prevalence, diagnosis, management, complications, and mortality of CD and UC. Clinical management inputs included resource use associated with the ideal pathways in line with IBD Standards. This model estimated and compared healthcare use and complications in people with CD and UC to the general population over 15 years, including costs from flare-ups, remission, and societal impacts. The estimated total annual direct healthcare cost based on an optimal patient journey for CD and UC is £3 billion. Ongoing management makes up around 93% of this cost (£2.8 billion), of which 84% of this makes up remission-related treatment in people with active disease. The ongoing management costs of active disease is almost 3 times higher costs in remission, at £185,903,000 and £67,557,000 respectively. The annual lost productivity cost of CD and UC is estimated at around £0.8 billion, mostly due to inability to work. The total healthcare costs are £3.8 billion. In the absence of robust population based real-world data, and given the complexity of IBD care, this model offers a practical solution for estimating population costs, which are likely underestimated, and can be adapted as more accurate datasets become available. Although pharmacological treatment accounts for a substantial proportion of IBD expenditure, effective control of inflammation and maintenance of remission are likely critical for reducing downstream complications, hospitalisation, surgery, disability, and productivity losses.
MacDonald R, Hex N, Uzdzinska B, Umpleby B, Pocock J, Hawthorne AB, Pollok R, Blackwell J, Din S
Mast cell-derived IL-13 as a driver of Crohn disease-associated intestinal fibrosis.★ Inflammatory bowel diseases | 2026-07-08
Crohn disease is a chronic, immune-mediated disease that can lead to intestinal fibrosis, strictures, and bowel obstruction. The Src homology 2 domain-containing inositol polyphosphate 5’-phosphatase-deficient (SHIP-/-) mouse develops spontaneous Crohn disease-like ileal inflammation and fibrosis. Fibrosis depends on increased phosphatidylinositol 3-kinase p110δ activity downstream of interleukin 4 (IL-4) or IL-13. Because current anti-inflammatory treatments do not prevent or reverse fibrosis, we aimed to identify the key cytokine(s) and its cellular source(s). We blocked IL-4 or IL-13 in mice by use of neutralizing antibodies or genetic ablation. Intestinal inflammation and fibrosis were assessed by gross pathology, histopathology, collagen accumulation, muscle thickening, immune cell infiltration, and tissue IL-1β concentrations. IL13 and its cellular source in stricturing Crohn disease were examined using single-cell RNA sequencing and RNAscope. Mast cells and Il13 were also assessed in ileal cross-sections from SHIP+/+ and SHIP-/- mice. Blocking or genetic ablation of IL-13, but not IL-4, significantly reduced ileal fibrosis in mice, including collagen accumulation, smooth muscle thickening, vimentin + cells, and proliferating vimentin + cells. Blockade of IL-13 also reduced intestinal inflammation, including immune cell infiltration and ileal IL-1β concentrations. Single-cell RNA-sequencing analyses identified mast cells as the exclusive source of IL13 in stricturing Crohn disease. Human resection tissues confirmed increased mast cells in diseased small intestine and identified mast cells as the source of IL13. SHIP-/- mice similarly showed increased ileal mast cells that were also a source of IL13. IL-13 is critical for intestinal fibrosis in SHIP-deficient mice, and mast cells are a source of IL13 in Crohn disease-associated intestinal fibrosis.
Safari K, Ma WJ, Sekhon P, Rai P, Menzies SC, Hoshino T, Fratzscher AS, Roth A, Madsen K, Sly LM
Timing of biologic prophylaxis and postoperative recurrence in Crohn’s disease: A real-life cohort study using propensity score weighting.★ Inflammatory bowel diseases | 2026-07-08
Postoperative recurrence is a major challenge in the management of Crohn’s disease after ileocolonic resection. Although international guidelines recommend early initiation of biologic prophylaxis, the optimal timing remains uncertain in real-world practice. We conducted a retrospective cohort study of Crohn’s disease patients undergoing ileocolonic resection. All patients received biologic prophylaxis within 16 weeks after surgery. Patients were stratified into 3 timing groups: <8 weeks, 8 to 12 weeks, and >12 and ≤16 weeks. To account for baseline differences, a propensity score-based inverse probability of treatment weighting approach was applied. The primary outcome was endoscopic recurrence (ER) at 6 to 12 months. Among 173 patients, 79 (46%) initiated biologic prophylaxis within 8 weeks after surgery, 32 (18%) between 8 and 12 weeks, and 62 (36%) between >12 and ≤16 weeks. ER at 6 to 12 months occurred in 103 (59.5%) patients. In the inverse probability of treatment weighting-weighted analysis, initiation of biologic therapy more than 12 weeks after surgery was associated with a significantly higher risk of ER compared with initiation within 8 weeks (risk ratio, 1.96; 95% confidence interval, 1.45-2.65; P < .001), whereas no significant difference was observed between initiation within 8 weeks and 8-12 weeks (risk ratio, 1.44; 95% confidence interval, 0.93-2.23; P = .10). In multivariable logistic regression analysis, smoking, prior intestinal resections, and delayed initiation of biologic prophylaxis were independently associated with ER. In half of patients, prophylactic biologic therapy was initiated more than 8 weeks after ileocolonic resection. Initiation of biologic prophylaxis beyond 12 weeks after surgery was associated with a significantly increased risk of ER.
Del Gaudio A, Di Vincenzo F, Cuccia G, Coppola G, Laterza L, Sacchetti F, Caprino P, Sofo L, Dragoni G, Foscarini E
Anorectal fibrosis in 3 murine models of chronic intestinal fibrosis: a comparative analysis.★ Inflammatory bowel diseases | 2026-07-07
Anorectal fibrosis is a poorly understood condition of Crohn’s disease (CD)-associated perianal complications, characterized by transmural fibrotic remodeling that may contribute to luminal narrowing. Despite well-established animal models for intestinal fibrosis, the anorectal region remains largely unexplored. This study aimed to compare anorectal fibrotic remodeling across 3 commonly used chronic intestinal fibrosis protocols. Male C57BL/6 mice were assigned to control and 3 chronic colitis groups: dextran sulfate sodium (DSS; cyclic oral administration), 2,4,6-trinitrobenzenesulfonic acid (TNBS), and dinitrobenzene sulfonic acid (DNBS; weekly intrarectal administration). Anorectal fibrosis was assessed using pelvic MRI, histopathological analysis (H&E, Masson’s trichrome, Sirius red staining), polarized light microscopy for collagen typing, and immunohistochemistry for fibrosis markers (α-SMA, TGF-β1, collagen I) and inflammatory cells (F4/80, MPO, CD3). Molecular analysis included quantitative RT-PCR and hydroxyproline assay. All 3 models developed comparable colonic inflammation and fibrosis. However, at the anorectal transition zone, DSS-treated mice exhibited significantly greater wall thickness on MRI, more severe collagen deposition, elevated type I/III collagen ratio indicative of mature fibrosis, and enhanced myofibroblast activation with TGF-β1 upregulation, muscularis propria thickening, and reduced luminal area on histologic cross-sections. In the anal squamous epithelium, DSS mice demonstrated significantly increased subepithelial fibrosis, epithelial hyperplasia, and diffuse inflammatory cell infiltration throughout both epithelial and subepithelial layers. Under these standard protocols, the chronic cyclic DSS model produced the most prominent anorectal fibrotic remodeling, while TNBS and DNBS showed less severe anorectal changes despite comparable colonic fibrosis. These protocol-dependent differences may inform preclinical investigation of anorectal fibrosis and evaluation of anti-fibrotic therapeutic strategies.
Ge Y, Li M, Li T, Guo D, Yu M, Yue J, Liu X, Liu Y, Leng Q, Ding K
Granzyme K CD8⁺ T cells with tissue-resident features promote intestinal inflammation in patients with Crohn’s disease. Experimental & molecular medicine | 2026-07-06
The role of CD8+ T cells in Crohn’s disease (CD) pathogenesis remains incompletely understood. This study aimed to characterize CD8+ T cells in CD and elucidate their potential contribution to intestinal inflammation. T cells from blood and intestinal tissues of 15 patients with CD were analyzed using single-cell RNA and T cell receptor sequencing. Spatial transcriptomics was conducted on inflamed intestinal tissues from two patients. Analysis of 41,699 CD8+ T cells identified distinct subsets characterized by differential granzyme expression: granzyme B (GZMB+) CD8+ T cells, predominantly in blood with high cytotoxic potential, and granzyme K (GZMK+) CD8+ T cells, enriched in intestinal tissue with lower cytotoxic potential. In the small intestine, GZMK+CD8+ T cells displayed enhanced tissue residency signatures (for example, CXCR6) and downregulated egress-related genes (S1PR1and S1PR5). GZMK+CD8+ T cells displayed robust interactions with myeloid cells via the CXCR3-CXCL9/10 axis, coupled with notable colocalization in the small intestine. Pharmacological inhibition of GZMK alleviated intestinal inflammation and tissue damage in a murine model of intestinal injury, supporting its role in modulating inflammatory responses. Together, these findings highlight GZMK as a potential modulator of intestinal inflammation and a candidate for further therapeutic investigation.
Lee Y, Kim TY, Kim Y, Baek J, Park H, Yoon DK, Hwang SW, Lee JL, Park SH, Kim J
Rising Burden and Clinical Impact of Metabolic Syndrome in Inflammatory Bowel Disease: A Real-World Cohort Study.★ United European gastroenterology journal | 2026-07
Metabolic syndrome (MetS) and its cardiometabolic complications are recognized in inflammatory bowel disease (IBD); however, longitudinal trends and their impact on outcomes remain incompletely defined. We aimed to evaluate temporal trends in cardiometabolic comorbidities and assess the impact of MetS on cardiometabolic, hepatic, renal, and IBD-related outcomes. We conducted a real-world cohort study (2010-2024) including adults (≥ 18 years) with Crohn’s disease or ulcerative colitis. Annual prevalence and incidence rates (per 1000 person-years) of cardiometabolic comorbidities were calculated by the calendar year. Propensity score-matched analyses compared outcomes among IBD with MetS, IBD alone, and MetS alone. Primary outcomes included major adverse cardiovascular events (MACE), heart failure, stroke, thromboembolism, chronic kidney disease (CKD), hepatic outcomes, all-cause mortality, and IBD-related events. Among adults with IBD, prevalence increased substantially from 2010-2011 to 2023-2024, including hypertension (12.7%-39.1%), obesity (3.6%-20.5%), diabetes (5.0%-16.0%), and MASLD/MASH (0.9%-8.7%), with parallel rises in incidence rates. Compared with MetS alone, IBD + MetS was associated with higher risks of MACE (adjusted hazard ratio [aHR] 1.19), CKD (1.27), MASLD/MASH (1.75), and cirrhosis (1.94). Compared with IBD alone, IBD + MetS conferred markedly higher risks of MACE (2.05), heart failure (2.17), CKD (2.07), and MASLD/MASH (2.36), as well as higher rates of hospitalization (1.48), corticosteroid use (1.43), and surgery (1.17). Mortality was higher in IBD + MetS than in IBD alone. Cardiometabolic comorbidities have risen sharply in IBD, and the coexistence of MetS substantially amplifies systemic and disease-specific morbidity, supporting the need for integrated, metabolism-informed IBD care.
Tariq R, Parmar K, Desai M, Sterling RK, Sanyal AJ
Auricular Relapsing Polychondritis in a Patient With Crohn’s Disease: A Case Report.Case report Sisli Etfal Hastanesi tip bulteni | 2026-06-29
We report the case of a 30-year-old female patient with Crohn’s disease who was receiving infliximab and mesalazine therapy. She presented with left ear pain accompanied by bloody diarrhea and abdominal pain. Initial treatment with ciprofloxacin and aluminum acetate was ineffective, requiring hospitalization. She was treated with intravenous meropenem, clindamycin, and prednisolone, which led to symptom resolution after 12 days. However, 7 months later, the patient developed similar symptoms in the right ear without intestinal involvement. She was hospitalized and treated with intravenous antibiotics, followed by prednisolone treatment.
Ulas BN, Cagdas BM, Yigit O, Hatemi I
Quality of Life & PROs (12 papers)
Intestinal Fibrosis in IBD: Rethinking the Inflammatory Paradigm and Emerging Therapeutic Opportunities.Review Digestive diseases and sciences | 2026-07-11
Intestinal fibrosis is a common and severe complication in the progression of inflammatory bowel disease (IBD). Its pathological essence lies in the excessive synthesis and abnormal deposition of extracellular matrix (ECM) components within the intestinal tissue, leading to structural remodeling and dysfunction of the intestinal wall. As the disease progresses, fibrosis is primarily characterized by the pathological thickening of the muscularis propria, which subsequently triggers irreversible structural damage, such as intestinal strictures, severely impacting patients’ quality of life and prognosis. Currently, clinical interventions for intestinal fibrosis are relatively limited, mainly relying on pharmacotherapy and surgical resection. However, existing drugs primarily focus on controlling the inflammatory response in IBD rather than directly targeting the fibrotic process, making it difficult to effectively block or reverse ECM accumulation. Although surgery can temporarily relieve obstruction, it is associated with a high postoperative recurrence rate and fails to fundamentally intervene in the pathological mechanisms of fibrosis. Therefore, a deeper understanding of the mechanisms underlying the initiation and progression of intestinal fibrosis is of great significance for developing specific anti-fibrotic therapeutic strategies and improving long-term patient outcomes. This review aims to systematically summarize the cellular and molecular mechanisms of intestinal fibrosis, with a focus on the roles of fibroblast activation, epithelial-mesenchymal transition, and immune microenvironment regulation in the fibrotic process. The goal is to provide a theoretical basis and novel research insights for the subsequent development of targeted drugs and the optimization of clinical treatment strategies.
Wang W, Sun Y, Li J
Short-Term Psychiatric Risk After IBD Surgery: A Propensity Score-Matched Analysis by Disease Severity. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract | 2026-07-10
Inflammatory bowel disease (IBD) can be associated with psychiatric comorbidity, including anxiety and depression. Prior studies suggest increased mood disorders after IBD surgery, but the magnitude and timing of risk as related to disease severity remain incompletely defined. Using the TriNetX US Collaborative Network, we conducted a cohort study of adults aged 18-65 years with newly diagnosed IBD between 1/1/2016-6/30/2020. Patients who underwent IBD-related surgery within five years of first IBD diagnosis were matched to nonsurgical controls. Two treatment strata were analyzed: 5-aminosalicylates (5-ASAs) and biologics. Primary outcomes were incident anxiety and depression within six months of the index event. Propensity score matching yielded 1,255 patients in each of the 5-ASA cohorts (surgical and nonsurgical) and 2,492 patients in each of the biologic cohorts. Among patients treated with 5-ASAs, incident anxiety occurred in 8.77% of surgical patients versus 8.05% of nonsurgical patients (risk difference [RD] 0.72%, 95% CI -1.45 to 2.89;p=0.52). Depression occurred in 6.93% versus 5.10%, respectively (RD 1.83%, 95% CI -0.03 to 3.69;p=0.053). In biologic-treated patients, surgery was associated with significantly higher incidence of anxiety (12.08% vs 6.86%; RD 5.22%, 95% CI 3.60-6.84;p<0.0001) and depression (6.74% vs 4.09%; RD 2.65%, 95% CI 1.39-3.90;p<0.0001). IBD-related surgery was associated with increased short-term incidence of anxiety and depression among patients receiving biologic therapy but not among those treated with 5-ASAs. These findings suggest that postoperative psychiatric vulnerability may be greater among patients with more advanced disease, highlighting the need for perioperative mental health screening and support in this population.
Orbe V, Clarke K, Dalessio S, Hussaini Z, Coates MD, Panganiban RP, Tinsley A, Williams ED, Kulaylat AS
Healthcare professionals’ knowledge, attitudes, and practice with addressing sexual health among people living with inflammatory bowel disease: A UK cross-sectional survey.★ Inflammatory bowel diseases | 2026-07-10
Inflammatory bowel diseases (IBDs) affect multiple aspects of well-being, including sexual health (SH). Although sexual dysfunction (SD) is widely prevalent among people living with IBD, patients report a lack of proactive discussion of SH by healthcare providers (HCPs). The study aimed to assess HCPs’ knowledge, attitudes, and barriers to assessing SH in patients living with IBD in the United Kingdom. An adapted 32-item questionnaire survey was conducted between January and September 2024. The survey was distributed to various IBD HCPs through diverse professional and organizational networks in the United Kingdom. The survey collected information on HCP demographics and practice patterns regarding SH. Logistic regression analysis identified factors that were associated with HCP comfort in discussing SH. The survey was completed by 249 eligible participants (53% female). Forty-one percent of HCPs estimated SD prevalence at 10% to 25% in general for IBD patients, while 33% did not know the SD prevalence among their IBD patients. Despite 65% of HCPs feeling “very” or “somewhat” comfortable discussing sexual function, only 9% routinely discussed this with patients. While HCPs stated lack of time (70%), unclear referral pathways (55%) and insufficient knowledge (51%) as main barriers, HCPs (95%) were interested in further education on SH. Although HCPs recognize SD as an important aspect of IBD care, it is often neglected. Time pressures, limited knowledge, and unclear referral pathways are key barriers that hinder HCPs from engaging with patients on SH. HCPs express a strong interest in further education on SH.
Kuriakose Kuzhiyanjal AJ, Rhodes S, Sethi-Arora K, Hancock L, Selinger C, Lamb CA, Rubin DT, Limdi JK
Redefining Neutrophil Function in Inflammatory Bowel Disease: From Tissue Injury to Immune Resolution.Review Molecular biology reports | 2026-07-10
Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation driven by dysregulated immune responses and impaired mucosal homeostasis. Although neutrophils have traditionally been viewed as short-lived pro-inflammatory effector cells that contribute to epithelial injury, emerging evidence indicates that they also possess important pro-resolving and tissue-repairing functions. This narrative mini-review critically evaluates recent advances in understanding neutrophil functional heterogeneity in IBD, with particular emphasis on CD177⁺ neutrophils, neutrophil extracellular trap formation, efferocytosis, and mechanisms involved in immune resolution and mucosal healing. Accumulating data suggest that specialized neutrophil subsets can balance antimicrobial defense with controlled inflammatory signaling, thereby contributing to epithelial protection and restoration of intestinal homeostasis. In parallel, efficient efferocytosis of apoptotic neutrophils by macrophages emerges as a central mechanism promoting resolution of inflammation, whereas impaired clearance sustains chronic inflammatory responses. Recent studies further highlight the therapeutic potential of targeting pro-resolving neutrophil pathways and enhancing efferocytosis; however, most current evidence remains preclinical, and significant challenges persist in translating these findings into human therapies. Collectively, these insights redefine neutrophils as dynamic regulators of both tissue injury and immune resolution in IBD and support the development of therapeutic strategies aimed at restoring immune balance and durable mucosal healing.
Khademi M, Kazemifard N, Ghavami SB, Farmani M, Shahrokh S
Brain network correlates of fatigue, depression, and anxiety in patients with Crohn’s Disease in different disease states. BMC gastroenterology | 2026-07-09
Symptoms of fatigue, depression or anxiety are frequent in Crohn’s Disease (CD) and may relate to disturbed brain-gut interactions. While more prevalent in active disease, these symptoms are also experienced by many individuals with CD during remission. Little is known about neural networks underlying such extraintestinal symptoms in CD and their relationship with the current disease state. Using a data fusion approach for functional MRI, this study investigated spatiotemporal markers of resting-state brain activity and associations with neurotransmitter systems and symptoms of fatigue, depression or anxiety in an active disease state or remission. We examined n = 71 patients with CD in an active disease state (aCD; n = 47) or in remission (rCD; n = 24) and healthy controls (HC; n = 35). All participants underwent resting-state fMRI, completed symptom assessments for fatigue, depression and anxiety, and provided stool samples for analysis of faecal calprotectin (fCal; aCD and rCD only). Joint independent component analysis (jICA) of two resting-state brain activity parameters (temporal and spatial features) identified neural networks exhibiting disease-state-dependent alterations. Network connectivity strength was correlated with symptoms of fatigue, depression, and anxiety, as well as fecal calprotectin (fCal). We further explored associations of the networks with neurotransmitter receptor maps. JICA revealed three networks differentiating between disease states and/or between patients and controls. One network comprising affective orbitofrontal and temporal brain regions, exhibited reduced connectivity in active disease (HC vs. aCD: p = 0.003, pFDR = 0.01; aCD vs. rCD: p < 0.001, pFDR < 0.001) and was linked to serotonergic/dopaminergic transmission, fatigue, and fCal. Another network comprised sensorimotor brain regions and showed diminished connectivity in patients in remission (HC vs. rCD: p = 0.034, pFDR = 0.06; aCD vs. rCD: p = 0.003, pFDR = 0.01), correlating with depression, anxiety, and dopaminergic activity. The third network reflected the default-mode network topography and distinguished patients irrespective of disease status from controls (HC vs. aCD: p = 0.013, pFDR = 0.01; HC vs. rCD: p = 0.037, pFDR = 0.06), but showed no associations with symptoms. Resting-state brain network connectivity in patients with CD differed between active disease and remission, and was associated with symptoms of fatigue, depression, and anxiety. Alterations in sensorimotor networks were linked to depressive and anxiety symptoms, whereas affect-related networks were associated with fatigue. These observations suggest that distinct brain networks may contribute to specific neuropsychiatric symptom clusters in Crohn’s disease and underscore the role of brain-gut axis mechanisms in these manifestations.
Thomann AK, Schmitgen MM, Stephan JC, Knoedler LL, Thomann PA, Szabo K, Ebert MP, Reindl W, Wolf RC
Integrin β7 sustains ileal humoral immunity and microbial biogeography during chronic TNF-driven ileitis. Mucosal immunology | 2026-07-08
Integrin α4β7 directs lymphocyte trafficking to the intestinal lamina propria (LP) and is a major therapeutic target in inflammatory bowel disease (IBD). Although integrin (Itg) β7 has been extensively studied in T-cell recruitment, its role in protective mucosal humoral immunity during chronic ileitis remains unclear. To investigate the role of itg β7 in intestinal immune compartmentalization, we crossed TNFΔARE mice, which develop Crohn’s-like ileocolitis with Itg β7-deficient mice. Intestinal inflammation, lymphocyte trafficking, ileal LP immune cell composition, IgA responses, and microbial community structure were assessed using histopathology, competitive homing assays, flow cytometry, mass cytometry, ELISA, and 16S rRNA gene sequencing. β7 deficiency exacerbated TNF-driven ileitis in an age-dependent manner. Competitive homing assays demonstrated early impaired recruitment of β7-deficient lymphocytes to the ileal LP. This defect resulted in a selective reduction of intestinal B cells and antibody secreting cells (ASC), whereas T-cell migration to ileum remained largely preserved, indicating differential reliance of lymphocyte subsets on β7-mediated trafficking. Mass cytometry analysis of ileal leukocytes showed enrichment of α4β7 expression on B cells and ASC, providing a mechanistic basis for their selective dependence on β7. Consistent with impaired mucosal humoral immunity, β7-deficient mice exhibited significantly reduced fecal and serum IgA levels, associated with altered microbial community structure and disruption of normal mucosal-luminal microbial biogeography, with partial overlap with microbial community changes observed in IgA-deficient mice. These findings identify β7 integrin as a non-redundant regulator of ileal mucosal humoral immunity during chronic TNF-driven ileitis. Beyond its established role in T cell trafficking, β7 sustains B-cell recruitment, IgA production, and microbial organization in the inflamed ileum, thereby limiting ileitis severity, although additional β7-dependent immune compartments, including αEβ7-associated intraepithelial lymphocyte populations, may also contribute to disease regulation.
Shen Z, Lebsack MDP, Boyer JD, Tyler C, Chilukuri A, Holton M, Jedlicka P, Urtecho G, Rivera-Nieves J
Caffeic acid attenuates stress-induced colon inflammation and barrier disruption in Sprague-Dawley rats. Cytokine | 2026-07-08
Chronic stress promotes colonic inflammation by sustaining activation of the hypothalamic-pituitary-adrenal (HPA) axis, inducing oxidative stress, and disrupting barrier integrity, thereby exacerbating inflammatory bowel disease and irritable bowel syndrome. Therefore, there is a need for therapeutic compounds that can ameliorate stress-induced colonic inflammation. Caffeic acid (CA), a naturally occurring polyphenol found in coffee and tea, has shown potential anti-inflammatory and antioxidant properties. This study evaluated the effect of CA in a chronic unpredictable stress (CUS)-induced colon inflammation in rats. Animals were exposed to CUS for 14 weeks, with CA (50 mg/kg, p.o.) administered during the final 4 weeks as an intervention. CUS exposure induced depression-like behaviors, elevated stress hormone levels, and redox imbalance, as evidenced by increased malondialdehyde (MDA), nitrite, and reactive oxygen species (ROS), along with decreased reduced glutathione (GSH) and superoxide dismutase (SOD). Histological analysis revealed significant colonic damage, including crypt shortening, mucosal thickening, goblet cell loss, and mast cell infiltration. These changes were accompanied by reduced expression of tight junction proteins (ZO-1, claudin-1, and occludin) and increased expression of inflammatory mediators (PAR-2, IL-6, IL-1β, and NF-κB). CA treatment ameliorated behavioural alterations, restored redox balance and antioxidant defenses, and preserved mucosal architecture and goblet cell integrity. Mechanistically, CA suppressed PAR-2-mediated NF-κB signalling, thereby restoring intestinal barrier integrity. Collectively, these findings indicate that CA has therapeutic potential to attenuate stress-induced colonic inflammation by modulating stress-associated gastrointestinal disorders.
Mazumder S, Dubey I, Gupta A, Bhardwaj S, Gautam RK, Nalla SV, Kushwaha S
Genetic Etiologies and Risk Factors for Regressive Autism and Childhood Disintegrative Disorder: A Scoping Review.Review Journal of child neurology | 2026-07-06
Autism spectrum disorder (autism) is diagnosed by persistent deficits in communication and social interaction, along with restricted, repetitive behaviors or interests. About a third of children with autism appear to develop normally but subsequently regress and eventually present with autism. This condition is termed regressive autism and the associated regression termed autistic regression. Children undergoing autistic regression after 2 years are described as having childhood disintegrative disorder. We aimed to conduct a scoping review to identify and summarize the genetic etiologies and correlates of regressive autism and childhood disintegrative disorder. Using key words, we searched 4 databases for papers published from January 2010 to February 2024. Thirty-two papers were retained. Nearly 90 genetic variants were associated with these conditions, and some treatments improved proband functioning. Epigenetic involvement, immune dysfunction and toxicant exposures were related to autistic regression while recurring comorbidities were inflammatory bowel disease, fever and mitochondrial disease. Regressive autism is variably defined, impeding research. The development of a precise definition is needed. Furthermore, regressive autism and its subtype, childhood disintegrative disorder, have many causes, which means that developing biomarkers and endotypes to explore etiologies would likely pay dividends. Because of the increasing prevalence of autism, regressive autism is no longer a rare condition, emphasizing the grave need to promote research in this area. Expected benefits might be improved outcomes for those affected and genetic counselling for at-risk family members. Longer-term benefits might be reduced prevalence, less emotional and financial burdens for families, and lower fiscal burdens for governments.
Fairthorne J, Rae F, Gupta A, Voisey J
Acute Kidney Injury Associated with Boswellia serrata for Radiation Necrosis. Practical radiation oncology | 2026-07-06
Boswellia serrata is an herbal natural health product derived from the Boswellia serrata tree. Although not approved by regulatory agencies, it possesses anti-inflammatory properties and is used for inflammatory bowel disease, osteoarthritis, and rheumatoid arthritis. Radiation necrosis is a complication of cranial radiation therapy (RT) characterized by cellular injury to the vascular endothelium and cerebral white matter. Acute kidney injury as an adverse effect of Boswellia serrata has not been reported previously. We report a 72-year-old female who developed acute kidney injury after taking Boswellia serrata capsules for eight days to manage radiation necrosis. Her symptoms resolved upon discontinuation of Boswellia serrata and presentation to the emergency department for treatment. In summary, Boswellia serrata may potentially cause acute kidney injury when taken at high doses and underscores the need for careful supervision.
Li M, Daftarian M, Chahal M, Oh J
Evaluation of sleep, fatigue, and quality of life in patients with primary immunodeficiency.Observational study Allergologia et immunopathologia | 2026-07-01
Primary immunodeficiency (PID) is a heterogeneous group of genetic disorders characterized by recurrent infections and immune dysregulation. Despite advances in therapy, many patients experience impaired quality of life (QoL), fatigue, and sleep disturbances. This study aimed to evaluate sleep quality, fatigue, and health-related QoL in adults with PID and to explore the associations between comorbidities and treatment modalities. This retrospective, observational, single-center study was conducted at the University of Health Sciences, Gülhane Training and Research Hospital between May and August 2024. Forty-nine adult patients with PID, diagnosed according to international criteria, completed validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), and SF-36 QoL scale. Clinical and demographic data were retrieved from the medical records. Statistical analyses included t-tests, Mann-Whitney U, chi-square, and Pearson’s correlation, with significance set at P < 0.05. Of 49 patients (55.1% males, mean follow-up 9.9 years), 36.7% had poor sleep quality, 42.9% reported severe fatigue, 49% showed impaired SF-36 physical scores, and 87.8% had preserved mental scores. Poor sleep quality was correlated positively with fatigue (r = 0.623, P < 0.001) and negatively correlated with physical QoL (r = -0.491, P < 0.001). Patients with autoimmune and inflammatory bowel disease had significantly worse PSQI and FSS scores, whereas bronchiectasis was associated with reduced SF-36 physical scores. No differences were observed between the IVIG and SCIG groups in fatigue or mental scores; however, SCIG recipients had significantly higher physical scores (P = 0.018). Patients with PID experience substantial impairment in physical QoL, with fatigue and poor sleep quality frequently coexisting. Comorbidities, such as autoimmunity, bronchiectasis, and inflammatory bowel disease, exacerbate these impairments. SCIG therapy confers better physical outcomes than IVIG therapy. Comprehensive care strategies that address psychosocial and physical health are essential for the management of PID.
Kalkan F, Yeşillik S, Demirel F, Sönmez E, Selçuk A, Balaban Y, İnan Mİ, Kartal Ö
Caregiver burden in owners of dogs with chronic enteropathies-a survey-based assessment. Journal of veterinary internal medicine | 2026-07
Chronic enteropathy (CE) in dogs requires lifelong management and may cause caregiver burden (CB), potentially affecting owner well-being and, indirectly, veterinarians. We aimed to determine whether owners of dogs with CE experience CB compared to owners of healthy dogs and to assess emotional, social, and financial aspects, as well as the owner-dog relationship. The questionnaire was completed by 223 owners of dogs with CE and 447 owners of healthy dogs. Cross-sectional study using an owner-reported questionnaire. Items were adapted from the Zarit Burden Interview and the Monash Dog Owner Relationship Scale. Disease severity was assessed using the canine inflammatory bowel disease activity index. Owners of dogs with CE reported substantial psychological burden and lower quality of life (QoL) for themselves compared with controls. More frequent episodes of severe clinical signs were associated with CB and decreased QoL. Despite this, the owner-dog relationship remained largely intact with most owners maintaining emotional closeness and attachment to the dog. Contributing factors to CB included veterinary visits, the perception of dogs with CE as time-consuming, and financial factors. However, concerns for the dog’s well-being-such as suffering, recurrence of severe clinical signs, or death-were ranked as the most important source of burden. Chronic enteropathy can cause substantial CB and negatively affect owners’ QoL, while the emotional bond with the dog remains preserved. These findings highlight the importance of considering caregiver well-being as part of veterinary care.
Stumpf C, Pape C, Zablotski Y, Busch K
Effect of a nurse-led individualized patient education program on fatigue and quality of life in patients with inflammatory bowel disease. European journal of gastroenterology & hepatology | 2026-06-29
This study aimed to evaluate the effect of a nurse-led individualized education program on fatigue and quality of life in patients with inflammatory bowel disease (IBD) in remission. IBD negatively affects patients’ energy levels and quality of life. However, the impact of individualized patient education on these outcomes remains underexplored. A pretest/posttest control group design was used in this study. Data were collected using a patient information form, disease activity indices, the IBD Fatigue Scale, and the IBD Quality of Life Questionnaire. The intervention group received individualized education and follow-up reminder calls at weeks 2 and 3; the control group received routine care. All patients were reassessed after 4 weeks. A total of 84 patients were included in the study, with no significant differences in sociodemographic characteristics between the intervention and control groups (P > 0.05). At baseline, fatigue and quality of life scores were comparable (P = 0.068 and P = 0.632, respectively). Following the intervention, the intervention group demonstrated a significant reduction in fatigue levels (-16.80 vs. 0.97; P < 0.001) and a marked improvement in quality of life scores (22.30 vs.1.47; P < 0.001) compared to the control group. Also, improvements in IBD Quality of Life Questionnaire were significantly associated with reductions in fatigue. Individualized nurse-led education has the potential to reduce fatigue and improve quality of life in patients with IBD. These findings highlight the critical role of nurses in assessing educational needs and providing tailored education as part of comprehensive fatigue management.
Ince Ozgenel F, Tulek Z, Temel T
Epidemiology & Outcomes (8 papers)
A Longitudinal Disease Progression Model Characterizing Endoscopic Response and Remission in Crohn’s Disease.RCT Journal of pharmacokinetics and pharmacodynamics | 2026-07-11
Crohn’s disease (CD) is a heterogeneous, progressive inflammatory bowel disease in which substantial placebo effects often confound assessment of therapeutic efficacy. A placebo-based disease model was developed using Simple Endoscopic Score for Crohn’s Disease (SES-CD) within an item-level response theory-bounded integer (IRT-BI) and full random effects models (FREM) framework. Longitudinal SES-CD data from 155 placebo-treated patients in the Phase 3 BERGAMOT-trial were analyzed. Each SES-CD subscore, across five intestinal segments, was described by a bounded-integer model and linked through a latent disease variable capturing a mono-exponential placebo trajectory. Endoscopic response (≥50% reduction from baseline SES-CD) and remission (SES-CD 0-2) were defined according to the FDA guidance. IRT-BI model adequately characterized longitudinal trajectories of all SES-CD subscores and accurately predicted individual patient endoscopic response and remission, with predictive accuracy exceeding 89% for responders and 85% for non-responders. Visual predictive checks showed that observed mean trajectories for all 20 SES-CD subscores were within the 90% confidence intervals across the 66-week trial. Population maximum placebo response (RMaxPL) was estimated at -0.220 with a time to half-maximal effect of 13.8 weeks. Covariate analysis identified elevated baseline C-reactive protein and fecal calprotectin correlated to reduced RMaxPL, whereas TNF-naïve status was associated with increased RMaxPL. This is first application of an integrated item-level IRT-BI-FREM approach in CD, enabling robust characterization of placebo response and identification of clinically relevant covariates. By providing quantitative framework for isolating drug-effects from placebo-response, this model aligns with FDA model-informed drug development priorities and supports efficient, targeted, and informative clinical trials.Clinical Trial RegistrationNCT02394028 Registered March 20, 2015.
Moein A, Langenhorst J, Kassir N
Acneiform Eruption with Deucravacitinib: Systematic Review and Meta-Analysis. Clinical and experimental dermatology | 2026-07-10
Deucravacitinib, an oral selective tyrosine kinase 2 (TYK2) inhibitor, is an effective treatment for chronic plaque psoriasis. Its use is widening to treat other autoinflammatory conditions, but acneiform eruptions have been increasingly reported. The objective was to quantify the incidence of acneiform eruptions with deucravacitinib and compare odds versus placebo, with exploratory analyses by dose and indication. A search of Medline, Embase, and CENTRAL was made for interventional and observational studies. Primary outcome was incidence of acneiform eruption (acne, folliculitis, dermatitis acneiforme, rosacea). Random-effects meta-analysis pooled proportions and odds ratios (OR) was performed. Of 672 records, 14 studies met inclusion. Overall, 467/5,280 (8.8%) developed an acneiform eruption (acne 71.3%, folliculitis 23.3%, dermatitis acneiforme 3.2%, rosacea 2.1%). Across eight controlled studies, pooled incidence was 6.4% (95% CI: 0.05 - 0.09; I2 = 74.9%). Events occurred in 145/2,539 (5.71%) on deucravacitinib versus 9/1,070 (0.84%) controls; pooled OR 4.56 (95% CI 2.28-9.12; I2=9.4%). Discontinuations for acneiform events were uncommon (7/3,317; 0.21%). Dose- and indication-specific analyses suggested higher odds at greater total daily doses and in psoriasis/inflammatory bowel disease. In conclusion, acneiform eruptions are a frequent cutaneous adverse event with deucravacitinib and occur significantly more often than with placebo yet rarely lead to discontinuation.
Gaston J, Maxwell A, Ha HC, Antony A, Lai FYX, Lee S
Racial and Ethnic Patterns Observed in Inflammatory Bowel Disease Prevalence, Clinical Burden, and Healthcare Resource Utilization in the United States: Findings from an Administrative Claims Database. Advances in therapy | 2026-07-09
Inflammatory bowel disease (IBD) is a chronic, immune-mediated gastrointestinal disorder comprised of Crohn’s disease (CD) and ulcerative colitis (UC). Real-world data on racial differences in disease burden, treatment patterns, and healthcare resource utilization (HCRU) remain limited. The retrospective observational study was conducted using Optum’s de-identified Clinformatics® Data Mart Database (Optum® CDM) in the US. Data from adult patients with a diagnosis of CD and/or UC between January 1, 2010, and September 30, 2022, were extracted and analyzed to assess the prevalence of IBD, complicated/penetrating CD, and extraintestinal manifestations (EIMs) across different races/ethnicities in the US. The treatment use, HCRU, and symptomatic and psychosocial burden among patients pre-and post-IBD diagnosis were also assessed among patients stratified by race/ethnicity. A total of 271,059 patients included in the analysis were predominantly White (76.6%) followed by Black (7.9%), Hispanic (6.1%), and Asian (2.6%). IBD prevalence rose from 0.5% (2010) to 2.2% (2022). In 2022, prevalence was highest among White (2.5%) followed by Black (1.9%), Asian (1.4%), and Hispanic individuals (1.3%). Among patients with CD and UC, respectively, EIM prevalence rose from 38.4% and 31.5% in 2016 to 57.5% and 43.2% in 2022. Corticosteroids and biologics were prescribed to 38.8% and 52.8% of patients with CD and UC post-diagnosis, respectively. IBD-related HCRU increased after diagnosis, particularly among acute care patients, and was highest in Black individuals. The results highlight an increased prevalence of IBD among patients from different racial and ethnic backgrounds. The study further provides insights into the IBD-related outcomes, treatment use, and HCRU patterns among diverse racial and ethnic groups and underlines the present unmet need for further research.
Patel AA, Ferrante S, Sanon M, Kachroo S
TTC7A deficiency: A retrospective international study on treatment and outcomes from the Inborn Errors Working Party of EBMT. Journal of human immunity | 2026-07-08
Tetratricopeptide repeat domain 7A (TTC7A) deficiency is a primary immunodeficiency due to mutations in the TTC7A gene. It causes intestinal disease and a poorly characterized immunodeficiency, with poor long-term survival. We describe the clinical and immunological characteristics, management, and outcomes of an international cohort of patients with genetically confirmed TTC7A deficiency. Data from 61 patients from 13 countries were retrospectively analyzed. Overall survival was 64% (median follow-up 4.2 years), significantly higher in the inflammatory bowel disease than in the hereditary multiple intestinal atresia group (80 vs. 48%, P < 0.05). Infections represent the leading cause of death. Allogeneic stem cell transplantation was performed in 16 patients to correct the immunodeficiency but was associated with a significant transplant-related mortality (44%). Solid organ transplantation of the small bowel remains exceptionally rare (two patients). Malignancy/autoimmune disorders developed in 4 (6.5%) and 17 (28%) patients, respectively. TTC7A remains difficult to treat, and prognosis is dismal for affected patients. Further understanding of the disease mechanisms and development of innovative treatment approaches are required.
Prunotto G, Parreillet M, Neven B, Moshous D, de Saint Basile G, Lindemans C, Leahy TR, Haddad E, Pichler H, Farela Neves J
Disparities in robot utilization in colorectal surgery: the widening gap. Surgical endoscopy | 2026-07-08
Robot-assisted surgery has expanded in adoption and indication among multiple surgical specialties, including colorectal surgery. It is unclear if access to robotic surgery is increasing equally among all patient populations. (1) Identify the factors that may influence type of surgical approach and (2) evaluate disparities in access and subsequent outcomes of colectomy and proctectomy from years 2013-2020 using a national database. We performed a retrospective study using the National Surgical Quality Improvement Program to identify adult patients who had undergone colectomy and/or proctectomy from years 2013-2020. We performed multivariate analysis to identify factors that may influence the likelihood of receiving robotic surgery. Tertiary care medical center. 18 years and older, received colectomy and/or proctectomy from 2013-2020. Frequency of robotic colorectal surgery, postoperative complications, and mortality. A total of 125,776 patients met inclusion criteria. Mean age was 61.4 years; 12.8% (16,086) of patients were non-White. In multivariate analysis, patients who were female, non-White, underweight or had inflammatory bowel disease were less likely to undergo robot-assisted surgery (p < 0.05). Although the total number of robotic cases increased year-to-year, the gap between White and non-White patients widened. In 2014, a White patient was 1.51 times more likely to have robot-assisted surgery compared to a non-White patient; odds increased to 1.96 in 2020 (p < 0.001). Patients who underwent robot-assisted surgery were less likely to have a postoperative complication (OR 0.86, CI 0.82-0.9) or serious adverse event (OR 0.9, CI 0.84-0.97), and had lower odds of 30-day mortality (OR 0.72, CI 0.57-0.91). Retrospective, limited coding in national databases, and database variables. Despite increased awareness of racial and ethnic disparities in surgical care, non-White patients’ decreased access to robot-assisted surgery is troublesome. Interventions must focus on closing this gap if we are to provide equitable healthcare.
Donaldson AE, Jochum SB, Knight J, Underhill JM, Grimes C, DeCesare LA, O’Donnell B, Ritz EM, Govekar HR, Bhama AR
Knowledge gaps in tubular gut tumours: a critical appraisal of the 6th edition of the World Health Organization classification of tumours.Review The Journal of pathology | 2026-07-07
Gastrointestinal cancer is a global health problem. In the new 6th edition of the World Health Organization Classification of Tumours (WCT) of the Digestive System, updated evidence and guidance is provided for the aetiology, pathogenesis, diagnosis, classification, grading, staging and prognosis of these tumours. However, significant knowledge gaps remain, some of which are addressed in this review. To provide for a research framework to fill these knowledge gaps, we focused on precursor lesions and rare cancers, where the need for new evidence is most urgent. Areas with a need for further research are discussed for neoplastic precursors of the oesophagus (squamous epithelium), stomach (gastric dysplasia and adenomas), ampulla-duodenum, jejunoileum, anal canal, as well as for colorectal serrated polyposis and inflammatory bowel disease associated dysplasia (conventional and non-conventional). Knowledge gaps are also presented as they exist in rare cancers of the oesophagus (mixed type), appendix (mucinous neoplasms and mucinous adenomas), colorectum (three new subtypes) and anus, as well as for neuroendocrine tumours (grading, necrosis and two new gastric subtypes) and undifferentiated carcinomas (deficiencies of the SWI/SNF chromatin remodelling complex and mesenchymal differentiation). We identify and present research questions and persistent challenges for these entities and thus propose research frameworks that focus on specific priority areas. Progress in these core research topics for both neoplastic precursors and rare cancers will hopefully be reflected in future editions of the WCT, but many of these knowledge gaps will only be resolved with collective registries and collaborative research efforts. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Nagtegaal ID, Montgomery EA, Polydorides AD, Gill AJ, Kojima M, Arends MJ
Association Between Socioeconomic Conditions and Biologic Prescriptions for Inflammatory Bowel Diseases in the Brazilian Public Healthcare System: An Ecological Study. Pharmacoepidemiology and drug safety | 2026-07
Inflammatory bowel diseases (IBD) are chronic conditions affecting millions of people globally. Brazil’s public healthcare system provides free access to IBD medications. However, socioeconomic conditions may affect prescribing patterns. This study examined associations between income inequality, human development, and biologic prescription rates for IBD in the Brazilian public health system (SUS). Data from the SUS Outpatient Information System (2008-2022) were analyzed. The biologic prescription rate (percentage of biologic prescriptions among all IBD prescriptions) was the outcome of interest. Random-effects negative binomial regression for panel data evaluated associations between the Gini Index, Municipal Human Development Index (MHDI), and biologic prescriptions while controlling for demographic, social, and healthcare variables. Biologic prescription rates for IBD in Brazil increased from 3.03% to 16.69%. Municipalities with higher income inequality had 6% lower prescription rates than those with higher income equality (RR 0.94; 95% CI 0.92-0.96). Using low MHDI as the reference, municipalities with medium (RR 0.79; 95% CI 0.70-0.91), high (RR 0.68; 95% CI 0.60-0.78), and very high MHDI (RR 0.66; 95% CI 0.58-0.76) had progressively lower rates. Income inequality and human development are associated with biologic prescription rates for IBD within the SUS. The paradoxical MHDI pattern probably reflects differential engagement of private health insurance across development levels, whereby biologic-eligible patients in wealthier municipalities access therapy outside the SUS and are not captured by SIA. These findings underscore the need for policies addressing structural disparities in IBD care and for future research integrating public and private sector prescription data. We investigated the association between socioeconomic factors and the prescription of biologic drugs for inflammatory bowel diseases (IBD) in the Brazilian public health system (SUS). Using data from 2008 to 2022, we found that the rate of biologic prescriptions for IBD increased from 3.03% to 16.69%. Municipalities with higher income inequality had lower prescription rates. Counterintuitively, municipalities with higher human development also showed lower SUS‐based biologic prescription rates, a pattern that most likely reflects the fact that patients in wealthier municipalities tend to access biologic therapy through private health insurance rather than the SUS, making them invisible to the public system’s data. These findings highlight the fragmented landscape of IBD care in Brazil and underscore the need for policies and data systems that capture both public and private care pathways.
de Castro CT, de Oliveira LCF, Santos CAST, Dos Santos DB
Hospitalization, ICU admission, and mortality among diabetic patients with inflammatory bowel disease receiving SGLT-2 inhibitors: a retrospective cohort study from the global collaborative network. Annals of translational medicine | 2026-06-29
Patients with coexisting type 2 diabetes mellitus (T2DM) and inflammatory bowel disease (IBD) represent a high-risk population with competing comorbidities, complex medication regimens, and overlapping inflammatory pathways. Although the role of sodium-glucose co-transporter-2 (SGLT2) inhibitors in managing type 2 diabetes is well-established, their impact on outcomes in diabetic patients with coexisting IBD remains unclear. This study aimed to investigate the association between SGLT2i use and hospitalization, intensive care unit (ICU) admission, mortality, IBD-related complications, and surgical procedures in diabetic patients with IBD. We conducted a retrospective cohort study using the TriNetX Global Collaborative Network. Cohort 1 comprised diabetic patients with IBD who received SGLT2 inhibitors with at least three dispensations within one year of IBD diagnosis, and Cohort 2 comprised diabetic patients with IBD never prescribed SGLT2i, matched on baseline characteristics, comorbidities, IBD-specific medications, and laboratory values, yielding 3,950 patients per cohort. Clinical outcomes were evaluated at 1 and 5 years following the index event. At 1 year, hospitalization, ICU admission, and mortality were significantly lower in Cohort 1 [risk ratio (RR): 0.886, P<0.001; RR: 0.851, P=0.03; and RR: 0.525, P<0.001, respectively]. Kaplan-Meier analysis demonstrated improved survival in Cohort 1 [94.27% vs. 88.76%, P<0.001; hazard ratio (HR): 0.490]. IBD-related complications and surgical procedures were also significantly reduced (RR: 0.879, P=0.004 and RR: 0.548, P=0.02, respectively). At 5 years, hospitalization, ICU admission, and mortality remained significantly lower in Cohort 1 (RR: 0.932, P=0.002; RR: 0.848, P=0.003; and RR: 0.545, P<0.001, respectively). Kaplan-Meier analysis continued to demonstrate improved survival in Cohort 1 (85.01% vs. 74.95%, P<0.001; HR: 0.532), whereas IBD-related complications and surgical procedures were numerically lower but no longer statistically significant (RR: 0.954, P=0.18 and RR: 0.741, P=0.15, respectively). SGLT2i therapy in diabetic patients with IBD was associated with reduced hospitalization, ICU admission, and mortality, with persistent benefits observed at both 1 and 5 years of follow-up. Reductions in IBD-related complications and surgical procedures were observed, particularly at 1 year. These findings suggest a potential disease-modifying role warranting further prospective investigation.
Abdelhalim O, Youssef MY, Al-Lababidi S, Eldesouki MH, Mohamed A, Abusuliman M, Nassar M, Abushanab M, Salem A, Shaheen H
Guidelines & Consensus (7 papers)
Adherence to guideline-recommended management in acute severe ulcerative colitis: a retrospective audit. Proceedings (Baylor University. Medical Center) | 2026-07-10
Acute severe ulcerative colitis (ASUC) is a life-threatening complication of ulcerative colitis that requires hospitalization and prompt guideline-directed management. We evaluated adherence to recommended inpatient management in hospitalized patients with ASUC. We conducted a single-center retrospective audit of patients hospitalized with ASUC at a tertiary care center from 2014 to 2024. ASUC was defined using Truelove and Witts’ criteria. Patients <18 years were excluded. The primary outcome was venous thromboembolism (VTE) prophylaxis. Secondary outcomes included Clostridioides difficile and cytomegalovirus (CMV) testing, specialist consultation, intravenous steroid failure, colectomy, 30-day readmission, and mortality. Adherence was also compared between preguideline (2014-2018) and postguideline (2019-2024) time periods. Among 530 encounters reviewed, 35 patients met inclusion criteria, accounting for 56 admissions. VTE prophylaxis was administered in 43% of admissions, CMV testing in 30%, and C. difficile testing in 82%. Gastroenterology consultation occurred in 98% of admissions, whereas colorectal surgery consultation occurred in 30%. Intravenous steroid failure occurred in 18%, colectomy in 16%, and 30-day readmission in 23%. No in-hospital deaths occurred. Following guideline publication, VTE prophylaxis increased from 25% to 75% (P = 0.001) and CMV screening from 14% to 60% (P = 0.001). Adherence to guideline-recommended ASUC management was variable, particularly for VTE prophylaxis and CMV testing, both of which improved significantly following the 2019 ACG guideline publication, underscoring the impact of guideline dissemination and highlighting remaining targets for quality improvement.
Alvarez D, Battepati D, Johnson C
Inflammatory bowel disease in the aging population.★ Inflammatory bowel diseases | 2026-07-08
As the prevalence of inflammatory bowel disease (IBD) rises rapidly among older adults, gastroenterologists and other health care providers increasingly face challenges in managing age-related comorbidities, polypharmacy, and functional impairments such as frailty and sarcopenia. This narrative review proposes a dual approach to management by optimizing care for patients aged >60 years while promoting the healthy aging of those aged 40-60 years. For patients aged >60 years, we emphasize prescribing effective corticosteroid-sparing medications to control inflammation, conducting medication reconciliations to assess appropriateness and drug interactions, and evaluating baseline hepatic and renal function for necessary dose adjustments. For patients aged 40-60 years, we advise regular screening and nutritional counseling to delay the onset of age-related comorbidities and recommend targeting endoscopic remission to modify the disease course and reduce complications and disability later in life. Given that patients with IBD receiving long-term immunosuppression are at increased risk of infections, adherence to age-appropriate vaccination schedules is also recommended. A proactive and personalized approach to disease management has the potential to optimize quality of life for older adults with IBD. The prevalence of inflammatory bowel disease is rising rapidly among older adults. This review presents considerations for the management of patients aged >60 years and discusses strategies to promote the healthy aging of patients aged 40-60 years.
Faye AS, Kochar B, Choi D, Gift T, Kamp KJ, Rider NL, Kaplan GG
The relationship of apical periodontitis with chronic diseases and smoking habits: an umbrella review.Review Odontology | 2026-07-07
Growing evidence suggests a potential association between apical periodontitis (AP), chronic diseases, and smoking habits. However, findings from individual studies and systematic reviews remain fragmented, and high-level synthesis of available meta-analyses is limited. This umbrella review aimed to comprehensively evaluate and synthesize evidence from published meta-analyses examining the association between AP, chronic diseases, and smoking. A systematic literature search was conducted across major electronic databases from inception to February 12, 2026, to identify relevant meta-analyses. Eligible studies included meta-analyses assessing the association between AP and chronic diseases or smoking, reporting pooled effect estimates. Data extraction was performed independently by two reviewers. Methodological quality was assessed using AMSTAR 2, and certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Pooled effect estimates were synthesized using random-effects models. A total of 15 meta-analyses were included in this umbrella review. Significant associations were identified between AP and several chronic conditions, as well as smoking habits. The pooled estimates indicated that diabetes mellitus (OR = 2.43, 95% CI: 2.03-2.90), cardiovascular disease (OR = 1.98, 95% CI: 1.30-3.00; RR = 1.32, 95% CI: 1.07-1.63), inflammatory bowel disease (IBD) (OR = 1.65, 95% CI: 1.27-2.15), and smoking (OR = 2.45, 95% CI: 1.98-3.02) were significantly associated with AP. The methodological quality of the included reviews varied, with most reviews rated as low quality (60.0%), followed by high quality (20.0%), moderate quality (13.3%), and critically low quality (6.7%); substantial heterogeneity was observed in some analyses. According to the GRADE assessments, the certainty of evidence varied from low to moderate. Evidence synthesized from meta-analyses suggests significant associations between AP and diabetes mellitus, cardiovascular disease, inflammatory bowel disease, and smoking. However, limitations in methodological quality and heterogeneity reduce the strength of the conclusions. High-quality prospective studies and rigorously conducted meta-analyses are needed to further clarify these relationships and strengthen the evidence base for clinical decision-making.
Alshehri M, Alshail F, AlQwizany IR, Almalik TM, Alshahrani O, Asiri FA, AlQahtani A, Alshehri O, Al-Hawwas A
Patient Identification of the most important outcomes in a gastrointestinal behavioral health program. Journal of patient-reported outcomes | 2026-07-06
Brain-gut behavior therapies (BGBTs) are evidence-based treatments for patients with disorders of gut-brain interaction (DGBI) and inflammatory bowel disease (IBD). While BGBT clinical trials prioritize decreasing symptom severity and improving anxiety, depression, and quality of life, these outcomes are not designed based on patients’ priorities. We aimed to determine the optimal patient-centered outcome measures to assess change following BGBT using a stakeholder-engaged qualitative process. We interviewed patients 1:1 with DGBI and IBD with and without BGBT experience. Interview data were analyzed using rapid qualitative analysis. Subsequent focus groups reviewed the qualitative findings to verify accuracy, identify high-priority and missing constructs, and create clinical use recommendations. Measure recommendations were developed based on patients’ perspectives and the extant literature. Qualitative interviews (N = 20) yielded five domains: lived experience of disease, how to cope with illness, perceived value of behavioral intervention, outcomes and measurement, and behavioral intervention effects. Focus group participants (N = 14) broadly confirmed that the qualitative themes represented their experience with BGBTs and prioritized confidence in symptom management, social connectedness, lived experience with disease, and mental/behavioral health symptoms. They highlighted the importance of brevity, semi-regular re-evaluation, and access to results. Resultant measures included: Brief Illness Perception Questionnaire, PROMIS Self-Efficacy for Managing Chronic Conditions-Symptoms, UCLA Loneliness Scale, IBD DISK (adapted), and PHQ-2/GAD-2. The identified treatment targets differed from those prioritized in clinical trials. However, DGBI and IBD literature suggests that many of the identified constructs supersede traditional outcomes such as anxiety and depression. These results can guide integration of patient-reported outcome measures into gastropsychology programs and highlight the value of involving patients in program development.
Brady RE, Duarte BA, Siegel CA, Salwen-Deremer JK
ECCO Guidelines on the Prevention, Diagnosis, and Management of Infections in Inflammatory Bowel Disease.★ Journal of Crohn’s & colitis | 2026-07
Abstract not available.
Yanai H, Ellul P, Verstockt B, Greuter T, Kopylov U, Casanova MJ, Dragoni G, Eder P, Estevinho MM, Abreu C
Third N-ECCO Consensus Statements on the Nursing Roles in Caring for Patients with Inflammatory Bowel Disease.★ Journal of Crohn’s & colitis | 2026-07
Abstract not available.
Jäghult S, Adamina M, Farrell D, Bager P, Czuber-Dochan W, Kemp K, Boontje N, D’Amico F, Dewitte G, Haj O
ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment.★ Journal of Crohn’s & colitis | 2026-07
Abstract not available.
Gisbert JP, Chaparro M, Verstockt B, Kienle P, Minozzi S, Allocca M, Atreya R, Avellaneda N, Barreiro-de Acosta M, Battat R
AI & Machine Learning (6 papers)
Human gut flagellome profiling using FlaPro reveals TLR5-related phenotype-specific alterations in IBD.★ Gut microbes | 2026-07-09
Flagellin, the structural protein of bacterial flagella, activates the innate immune receptor Toll-like receptor 5 (TLR5). However, the ability of different flagellins to bind and stimulate TLR5 varies widely, suggesting that the composition of an individual’s flagellin repertoire, defined as flagellome, may influence host-microbiome interactions and inflammation. Here, we developed FlaPro, a computational pipeline for quantification and functional annotation of human gut flagellomes. Functional categories in FlaPro are derived from a machine learning model trained on experimentally characterized flagellins with defined TLR5-binding and stimulatory activities. Application of FlaPro to a multi-omics inflammatory bowel disease (IBD) cohort revealed a marked depletion of flagellome diversity and a reduced ratio of silent to stimulatory flagellins in Crohn’s disease and ulcerative colitis. These alterations were consistent across genomic and transcriptional layers, indicating a disease-associated shift toward more stimulatory flagellome profiles. Our findings suggest that specific features of the gut flagellome contribute to TLR5-mediated immune activation and may serve as functionally interpretable microbiome markers for future microbiome-wide association studies in health and disease. The workflow implemented in Snakemake is openly available at https://github.com/leylabmpi/FlaPro.
Bogdanova AA, Borbón-García A, Ley RE, Tyakht AV
AI-Powered Discovery of Rosmarinic Acid as a Novel Ferroptosis Inhibitor for Ulcerative Colitis via Targeting the ALOX15-VDAC1 Axis. Research (Washington, D.C.) | 2026-07-08
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited mechanism-based therapies, and ferroptosis-an iron-dependent lipid peroxidation-driven cell death-has emerged as a critical pathogenic event. Using a machine learning model that combines molecular fingerprints and transfer learning representations to screen for ALOX15 inhibitors, we identified rosmarinic acid (RA) from natural product libraries. RA exhibited high-affinity binding to ALOX15 and maintained stable complex conformation in molecular dynamics simulations. In dextran sulfate sodium-induced colitis mice and lipopolysaccharide-treated intestinal epithelial cells (IEC-6 and mouse colonic epithelial cell), RA alleviated disease activity index, colon shortening, histological damage, and barrier protein loss (ZO-1, Occludin, and Claudin-1). Mechanistically, RA suppressed ferroptosis by restoring GPX4, SLC7A11, and FTH1; reducing ACSL4, COX-2, and lipid reactive oxygen species (ROS); and lowering intracellular Fe2+ and malondialdehyde. Crucially, RA disrupted the ALOX15-VDAC1 protein complex, preserved mitochondrial membrane potential, and reduced mitochondrial ROS, effects that were abrogated by ALOX15 knockdown or VDAC1 knockdown. Serum metabolomics further revealed that RA remodels lipid metabolism pathways (arachidonic acid and linoleic acid metabolism) linked to ferroptosis. Collectively, this artificial intelligence-driven discovery positions RA as a novel ferroptosis inhibitor that targets the ALOX15-VDAC1 axis, offering a promising therapeutic candidate for UC.
Fang G, Ao J, Li X, Wang W, Alioui Y, Huang Y, Peng J, Tang B, Luo L
Enterococcus hirae Y-HS Alleviates Ulcerative Colitis by Activating PXR/Nrf2-mediated Metabolic-immune Crosstalk. Probiotics and antimicrobial proteins | 2026-07-07
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited non-invasive biomarkers and variable responses to probiotics. This study investigates the probiotic potential of Enterococcus hirae Y-HS isolated from healthy beef cattle and its mechanisms in alleviating UC. In vitro probiotic properties of Y-HS were assessed. Public transcriptomic datasets (GSE179285, GSE87466, GSE206285) were analysed to identify differentially expressed genes in UC patients. Machine learning integrated with protein-protein interaction network analysis identified core diagnostic genes. A DSS-induced murine colitis model was established to evaluate Y-HS intervention effects. Y-HS exhibited excellent gastrointestinal tolerance, no haemolytic activity and antibiotic susceptibility. Transcriptomic analysis identified 768 DEGs in UC patients. Machine learning yielded four metabolism-associated signature genes-CYP3A4, UGT1A6, HSD17B6 and SRD5A3-with diagnostic accuracy (AUC 0.72-0.84). In DSS-induced colitis, Y-HS dose-dependently attenuated disease activity, remodelled gut microbiota (increasing Lactobacillus, decreasing Escherichia-Shigella), activated PXR/Nrf2 signalling, upregulated detoxification enzymes (CYP3A4, UGT1A6) and tight junction proteins, while downregulating HSD17B6, SRD5A3 and cleaved caspase-3. These changes were accompanied by reduced pro-inflammatory cytokines and elevated IL-10. E. hirae Y-HS alleviates UC through coordinated modulation of gut microbiota, host metabolism, inflammation and barrier function. The identified metabolic gene signature offers potential non-invasive biomarkers for UC.
You F, Bao H, Li W, Zhang H, Li Y, Li J, Sun M, Yang Y, Chao L
Scleral image analysis via artificial intelligence to evaluate inflammatory status in inflammatory bowel disease. International journal of colorectal disease | 2026-07-07
Among the extraintestinal ocular manifestations of patients with inflammatory bowel disease (IBD), episcleritis is associated with the inflammatory activity of IBD. The use of artificial intelligence to evaluate scleral images may help establish a non-invasive method for assessing the degree of inflammation. This study aims to provide a new approach for evaluating IBD inflammation by analyzing scleral images. We collected scleral images from patients with IBD across different inflammatory states and from controls. Then, we analyzed the images using the MASK R-CNN and HRNet method to build models for assessing the degree of inflammation. A total of 942 scleral images were collected and divided into 5 groups: the control group, inflammatory Crohn’s disease (ICD) group, CD in remission (RCD) group, inflammatory ulcerative colitis (IUC) group, and UC in remission (RUC) group. In the training set, the accuracy and F1-score for discriminating between IBD and non-IBD controls, inflammatory IBD and IBD in remission, ICD and RCD, IUC and RUC were 99.02%, 97.99%, and 98.44%, 98.34%, and 99.04%, 98.98%, and 100%, 100%, respectively. In the test set, the accuracy, F1-score and the Area Under the Curve (AUC) were 95.59%, 92.5%, 92.9%, and 85.1%, 81.2%, 85.8%, and 74.2%, 72.5%, 77.9%, and 92.9%, 91.1%, 91.3%, respectively. The inflammatory ulcerative colitis group exhibited the most prominent scleral congestion, which was correlated with disease severity. In this small-sample exploratory study, we propose that the evaluation of ocular manifestations in patients with IBD may serve as a non-invasive method for assessing inflammatory activity, especially in patients with UC.
Li Y, Huang P, Wang L, Chen S, Lian G, Li F, Liu X, Lu F, Yin Y
Machine learning prediction of increased healthcare utilization in colectomy for inflammatory bowel disease. International journal of colorectal disease | 2026-07-06
Healthcare spending for patients with inflammatory bowel disease (IBD) has steadily increased over the past few decades. While some of the increase is due to the rise in the use of biologics, surgery and postoperative care contribute significantly to healthcare spending. We aimed to analyze the preoperative factors associated with increased healthcare resource utilization (HRU) by developing and internally validating machine learning prediction models for increased HRU. We analyzed the ACS-NSQIP database from 2018 to 2022 to identify preoperative factors that could predict increased HRU in patients undergoing non-emergent colectomy for Crohn’s disease or ulcerative colitis. Increased HRU was defined as a composite of either (a) discharge destination other than home, (b) readmission within 30 days of surgery, or (c) prolonged length of stay. A total of six machine learning algorithms were utilized to find the best-performing model determined by area under the curve. Models were internally validated with an 80:20 training and testing split. A total of 7535 patients were analyzed. The overall rate of increased HRU was 33%. The best-performing model was the random forest, achieving an AUC of 0.75, an accuracy of 0.73, and an F1 of 0.82. The most important preoperative variables for model accuracy were albumin, hematocrit, and creatinine. Machine learning may assist in identifying IBD patients at risk for increased healthcare resource utilization. Here, we propose a predictive model in the preoperative setting that may allow targeted perioperative planning to optimize outcomes and resource use.
Salgado-Garza G, Ballato E, Araradian C, Walsh M, Fang SH, Tsikitis VL
Agentic artificial intelligence in inflammatory bowel disease: toward autonomous and adaptive care. Crohn’s & colitis 360 | 2026-06-27
Inflammatory bowel disease (IBD) is a chronic, heterogeneous condition requiring ongoing monitoring and iterative therapeutic adjustment. Current management relies on multiple clinical, biochemical, imaging, and molecular data sources that are collected intermittently and rarely integrated into a unified representation of disease activity, leading to reactive clinical decision-making. Although artificial intelligence (AI) has demonstrated promise in IBD, most applications remain task-specific and operate on data collected at isolated time points, failing to capture the longitudinal nature of disease. Agentic AI offers a shift toward continuous and adaptive care by integrating diverse data streams into an evolving representation of disease state. This enables early detection of change and supports proactive intervention through a closed-loop system linking monitoring, interpretation, and action. Despite its potential, challenges related to data quality, interpretability, and clinical integration must be addressed for implementation.
Acharjee A, Santos D
Drug Safety & Pharmacovigilance (6 papers)
From copper imbalance to immunometabolic remodeling: cuproptosis-related vulnerability and therapeutic hypotheses in autoimmune diseases.Review Inflammation research : official journal of the European Histamine Research Society … [et al.] | 2026-07-11
Autoimmune diseases (AIDs) are characterized by disrupted immune tolerance, chronic inflammation, and organ-specific tissue injury. Their pathogenesis involves the interplay between genetic susceptibility and environmental factors. Although current biological agents and glucocorticoid therapies have improved clinical outcomes, long-term remission rates remain limited, with persistent risks including infection, organ toxicity, and immunogenicity. Emerging evidence indicates that copper homeostasis imbalance, mitochondrial dysfunction, redox stress, and immunometabolic remodeling coexist in multiple systemic and organ-specific AIDs. Cuproptosis, a newly identified form of regulated cell death, provides a potential mechanistic framework to understand the convergence of these pathological processes. However, direct in vivo evidence of canonical cuproptosis in autoimmune lesions remains scarce, and most relevant studies rely on transcriptomic associations, public dataset mining, or model-dependent experiments. There is an urgent need to clarify conceptual boundaries and the hierarchy of evidence. This review aims to systematically distinguish the conceptual differences among copper dysregulation, copper-associated mitochondrial/redox stress, cuproptosis-related vulnerability, and canonical cuproptosis. It seeks to summarize the hierarchical levels and limitations of existing evidence, evaluate the translational potential of copper-modulating strategies in AIDs, and provide references for future research directions and clinical translation. 1. A hierarchical evidence grading system for cuproptosis was established, categorizing existing evidence into six levels: bioinformatic inference (e.g., transcriptomic differential expression, immune infiltration correlation), disease-associated phenotypic evidence, functional perturbation evidence, rescue-based evidence, direct biochemical validation, and in vivo disease validation. It was clarified that canonical cuproptosis can only be confirmed when copper dependence, involvement of the Ferredoxin 1 (FDX1)-lipoylation axis, aggregation of lipoylated proteins, destabilization of Fe-S clusters, and functional rescue are demonstrated. 2. The characteristics of copper metabolism disorders and cuproptosis related molecular remodeling in systemic AIDs (e.g., systemic lupus erythematosus, rheumatoid arthritis) and organ-specific AIDs (e.g., inflammatory bowel disease, ankylosing spondylitis) were summarized. Findings mostly reflected copper-associated metabolic stress or susceptibility markers rather than definitive functional activation. 3. The immunometabolic regulatory roles of cuproptosis in immune cells-including macrophages, dendritic cells, and T cells-were analyzed, highlighting that their effects are cell-type and context dependent. 4. The limitations of copper-modulating strategies, such as copper chelators and copper ionophores, were evaluated, emphasizing that these currently represent hypothesis-generating approaches. Clinical application requires consideration of toxicity, targeting specificity, pharmacokinetics, and disease-context dependence. Current research on cuproptosis in AIDs is largely correlative, bioinformatic, or model dependent, and is insufficient to confirm canonical cuproptosis as a primary pathogenic mechanism in AIDs. Cuproptosis should be regarded as a conditional and hypothesis-generating framework. Future studies should adopt a rigorous evidence hierarchy, optimize diseaserelevant model selection, and validate its pathophysiological significance through direct biochemical assays. The clinical translation of copper-targeted therapeutic strategies still requires substantial foundational and clinical research support.
Shao Y, Zhang RF, Wang Z, Gan J, Jiang XJ, Yang L, Song ZJ
SHIP1 is required for T cell surveillance of occult malignancies. Cellular and molecular life sciences : CMLS | 2026-07-07
SHIP1-deficient mice develop severe, transmural Crohn’s-like ileitis and die prematurely. Recent analysis of a human Crohn’s disease (CD) cohort revealed a significant subset of patients have severely reduced levels of SHIP1 expression suggesting SHIP1 deficiency leads to CD in both rodents and humans. The mucosal inflammatory disease that causes the premature death of SHIP1-/- mice is a consequence of the requirement of SHIP1 expression for the survival of effector T cells in mucosal tissues. T cell specific ablation of SHIP1 expression in CD4CreSHIP1flox/flox mice also results in Crohn’s disease-like ileitis, but less severe than in their germline SHIP1-/- counterparts due to the absence of a SHIP1 deficient neutrophil compartment. Consequently CD4CreSHIP1flox/flox mice live much longer than their SHIP1-/- counterparts. As Crohn’s disease is associated with an increased risk of intestinal cancers in humans and that T cells are proposed to protect from occult malignancies, we hypothesized that CD4CreSHIP1flox/flox mice would develop malignancies originating in the gut. Here we show that CD4CreSHIP1flox/flox mice with ileitis develop spontaneous metastatic cancer originating in the small intestine, including widely disseminated histiocytic sarcoma and intestinal adenocarcinomas. Our findings demonstrate that T cells in the gut are essential to protect against occult intestinal cancers and that SHIP1 is essential for this function. These findings may aid our understanding of the increased susceptibility to intestinal cancer in IBD patients, and particularly since a significant subset of adult IBD patients have defective expression of SHIP1.
Fernandes S, Srivastava N, Pedicone C, Sudan R, Engelman RW, Kerr WG
Inflammasomes in Intestinal Inflammation: Guardians of Mucosal Homeostasis, Amplifiers of Disease, and Targets for Intervention. Internal medicine (Tokyo, Japan) | 2026-07-04
The intestinal mucosa is continuously exposed to dietary antigens, commensal microorganisms, and enteric pathogens, thereby depending on innate immune pathways that detect danger without compromising tissue tolerance. Inflammasomes are cytosolic signaling platforms linking microbial- or stress-sensing to caspase activation, interleukin-1 family cytokine maturation, and gasdermin-dependent membrane responses. In the gut, these pathways support epithelial restitution, mucus and antimicrobial secretion, epithelial cell expulsion, and pathogen containment. Nonetheless, these pathways can drive chronic inflammation through sustained interleukin (IL)-1β production, pyroptosis, neutrophil recruitment, and pathogenic adaptive immunity reinforcement. This review synthesizes the current view of how canonical and noncanonical inflammasomes operate in intestinal epithelial and immune cells, with an emphasis on NLR family pyrin domain-containing (NLRP) 3, NLRP6, NLR family CARD domain-containing (NLRC) 4, Absent in melanoma (AIM) 2, and pyrin. We discuss how cell-intrinsic programs intersect with the microbiota, why protective and pathogenic findings coexist, and how human genetics is beginning to define inflammasome-rich subsets of intestinal diseases. Recent retrospective cohort data sharpen the clinical relevance of pyrin biology: among 396 Japanese patients with inflammatory bowel disease unclassified, 60.1% carried Mediterranean fever (MEFV) variants, and colchicine response among evaluable mutation-positive cases reached 84.6%, thus supporting a distinct colchicine-responsive, IL-1β-skewed enterocolitis subset. Finally, biomarkers and therapeutic opportunities are outlined, and unresolved questions most likely to shape precision-medicine approaches for inflammatory bowel disease and related intestinal autoinflammatory syndromes are identified.
Nakase H, Shimomori Y, Kurumi H
Lymphomatous transformation in mass-forming chronic active EBV-associated enteritis initially misdiagnosed as ulcerative colitis: A case report.Case report Medicine | 2026-07
Chronic active Epstein-Barr virus (EBV) disease is a group of refractory and progressive lymphoproliferative disorders characterized by both inflammatory and clonal proliferative features. Gastrointestinal involvement is highly uncommon and can often be misdiagnosed as inflammatory bowel disease. A 63-year-old man presented with diarrhea and bloody stools and was initially diagnosed with ulcerative colitis at a local hospital. After multiple courses of biologic therapy, progressive development of a mass-forming lesion was observed on serial endoscopy. Detection of EBV nucleic acid in serum and colon biopsies showed a high viral load. Serial pathological consultations confirmed the diagnosis of EBV-associated lymphoproliferative disorder. Positron emission tomography/computed tomography revealed disease progression involving the bone marrow, and bone marrow examination confirmed peripheral T-cell non-Hodgkin lymphoma. Biological therapy was discontinued. Allogeneic hematopoietic stem cell transplantation was recommended, but the patient declined. After progression to lymphoma occurred, chemotherapy was administered. The patient responded poorly to chemotherapy, with rapid disease progression, and ultimately succumbed to multisystem organ failure. This rare case underscores the critical importance of differentiating between chronic active EBV-associated enteritis and inflammatory bowel disease, as their management strategies and prognoses are divergent. The clinical course of chronic active EBV-associated enteritis is aggressive, and the prognosis is poor. Misdiagnosis may delay treatment and potentially accelerate disease progression.
Yang T, Ding L, Tao M, Chen M, Qin Y
Clinical isolates of Fusobacterium nucleatum display strain-specific virulence and modulation by indole derivatives. Microbiology (Reading, England) | 2026-07
Pathogenic bacteria adapt to distinct disease environments, but whether these adaptations create therapeutic vulnerabilities remains unclear. Fusobacterium nucleatum has emerged as a key microbial player in colorectal cancer (CRC), yet its strain-specific virulence mechanisms remain poorly defined. In this pilot study of 16 clinical F. nucleatum isolates from CRC patients (n=6), Crohn’s disease patients (n=6), colon of healthy individuals (n=3) and an oral lesion (n=1), a subset of CRC-derived strains produced three- to fourfold higher levels of endogenous indole. Exogenous indole treatment differentially affected growth and biofilm formation, with some strains increasing biofilm despite growth inhibition. Notably, sensitivity to exogenous indole was independent of endogenous production and revealed that isolate 7-1 (EAVG002), a member of the tumourigenic Fna C2 clade, was uniquely hypersensitive to I3CA- and IPA-mediated stress. Invasion assays further showed that indole and its derivatives (I3A, I3CA) reduced the invasion of a highly indole-tolerant CRC-derived isolate (SB-CTX3Tcol3) into CRC cells by ~50%, comparable to antibiotic treatment. Furthermore, in two CRC cell lines, exposure to indole or indole derivatives resulted in substantial variability in adherens junction and tight junction transcript levels, with I3A having the strongest effect on tight junction (CLDN1, CLDN7) transcripts. Collectively, these findings reveal profound strain-level heterogeneity and indole derivative effects, highlighting vulnerabilities that could enable precision therapeutic targeting of pathogenic F. nucleatum populations within the host environment while preserving beneficial commensals.
Scano C, Choudhury A, Rojo MG, Hawkins J, Crowhurst L, Zaharas G, Lavado R, Greathouse L
Immune cell-derived membrane nanovesicles: A promethean fire for autoimmune disease therapy through immune cell mimicry.Review Bioactive materials | 2026-06-27
Autoimmune diseases (AIDs) constitute a heterogeneous group of disorders characterized by immune dysregulation, loss of self-tolerance, and chronic inflammation, which leads to tissue damage and organ dysfunction. Current therapies for AIDs are often limited by their lack of specificity, systemic side effects, and insufficient restoration of immune tolerance. Recent advances in nanotechnology and bioengineering have introduced immune and associated cell-derived membrane vesicles (IACMVs) as a promising therapeutic platform. Derived from macrophages, dendritic cells, neutrophils, platelets, or red blood cells, IACMVs inherit key surface proteins and receptors from their parent cells, conferring endogenous biocompatibility, inflammation-specific targeting, and intrinsic immunomodulatory capabilities. These vesicles can be engineered to carry therapeutic cargoes (e.g., peptide inhibitors, nucleic acids) or modified with surface ligands to enhance disease-site specificity, making them versatile tools for specific immunomodulation. This review provides a comprehensive overview of IACMVs, focusing on their preparation techniques, functional mechanisms, and therapeutic applications in prototypical AIDs such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), autoimmune hemolytic anemia (AIHA), type 1 diabetes (T1D), multiple sclerosis (MS), and autoimmune myocarditis (AM). We highlight translational challenges, including production scalability, membrane integrity, immunogenicity, and cargo-loading efficiency, that must be addressed to advance clinical translation. Finally, we discuss future directions for optimizing IACMVs as next-generation, safe, and targeted immunotherapeutic platforms for AIDs.
Li Y, Jan N, Zhang J, Qin Y, Liu G, Liu C
Genetics & Genomics (5 papers)
Integration of genetic evidence to identify approved drug targets. Genome medicine | 2026-07-06
Drugs targeting genes supported by human genetic evidence are more likely to succeed in clinical trials. While previous approaches have benchmarked individual methods such as genome-wide association studies (GWAS), rare variant burden testing, and quantitative trait locus (QTL)-informed Mendelian randomization, it remains unclear how best to integrate these signals for drug target discovery. We compared gene-prioritization strategies across 30 complex traits, evaluating their ability to recover approved drug targets compiled into lenient and moderate gold-standard sets from six curated databases. Gene-level association scores from GWAS, expression QTL, protein QTL, and exome-based analyses were integrated using five unsupervised approaches. Predictive performance was assessed with area under the receiver operating characteristic curve (AUROC) and enrichment-based statistics. Across traits, GWAS alone ranked known drug targets on average ∼652 ranks (3.42%) above random expectation, and the minimum-rank-based integration strategy further improved performance by approximately ∼558 positions (2.93%), achieving the best AUROC in 23 of 30 traits. Genetic correlation and drug target overlap across trait pairs showed a significant positive association ([Formula: see text]). Cross-trait analyses further revealed that prioritization scores derived from related diseases could at times equal or even surpass a trait’s own performance. For instance, coronary artery disease data improved the prediction of stroke targets ([Formula: see text]), while inflammatory bowel disease data enhanced the prioritization of chronic kidney disease targets ([Formula: see text]). These results demonstrate that using the strongest signal from complementary genetic prioritization methods, combined with information from genetically related traits, systematically strengthens drug target identification across complex diseases.
Moix S, Sadler MC, Kutalik Z
A genetic variant of adenylate cyclase 7 associated with ulcerative colitis shows impaired function and G-protein-coupled receptor signaling. Human genetics | 2026-07-04
A missense variant of adenylate cyclase 7 (AC7), p.Asp439Glu, has been significantly associated with ulcerative colitis (UC) in genome-wide association studies. Previous work suggested that this variant is reduced in expression and exhibits impaired cyclic adenosine-3’,5’-monophosphate (cAMP) synthesis, thus skewing T-cell cytokine profiles. Here, we investigated the variant’s function measuring dynamic cAMP responses in live HEK293 cells. We show that p.Asp439Glu generates significantly reduced basal cAMP levels despite normal expression. Stimulation with sphingosine-1-phosphate (S1P) and phorbol 12-myristate 13-acetate (PMA) induced a reduced cAMP increase in cells expressing mutant AC7, indicating reduced responsiveness to G-protein-coupled receptor (GPCR) and protein kinase C (PKC) activation. Western blot analysis showed altered downstream phosphorylation of cAMP response element-binding protein (CREB) and cAMP-dependent transcription factor (ATF1) in cells expressing the variant. Higher levels of phosphorylated CREB and ATF1 were observed in cells expressing p.Asp439Glu AC7 under basal conditions while stimulation with S1P had no effect on protein phosphorylation. Our findings provide direct biochemical evidence for strongly impaired AC7 function caused by the variant p.Asp439Glu. These results may pave the way for more causally defined and genotype-specific treatment strategies in UC.
Loers G, Cangüzel S, Rading S, Kubisch C, Karsak M
FCGR2A promoter variant reveals shared genetic susceptibility between IBD and stroke. Molecular and cellular biochemistry | 2026-07-04
While the epidemiological association between inflammatory bowel disease (IBD) and stroke is well-established, the shared genetic architecture underlying these diseases remains unclear. This study utilized genome-wide association studies (GWAS) summary statistics to explore genetic overlaps between IBD and stroke subtypes. Mendelian randomization (MR) was applied to assess potential causal relationships. Cross-trait meta-analysis identified shared loci, followed by colocalization testing to pinpoint causal variants. Furthermore, functional prediction analysis of variants and verification through in vitro experiments. Finally, use mediation MR to explore potential mechanisms in multiple dimensions. We identified eight pairs with potential genetic correlations, with common genetic variants contributing more on ulcerative colitis (UC) and multiple stroke subtypes than Crohn’s disease (CD). Among them, there is a potential causal relationship between IBD/UC and large arterial atherosclerotic stroke (LAS), which is consistent with previous epidemiological statistics. In addition, one locus (rs7522794) was initially identified through cross-trait analysis, and colocalization pointed out that the variant rs7522794 on the FCGR2A promoter was the culprit of the comorbid phenotype. The rs7522794-T allele predicted to be more prone to bind SPI1, thereby increasing FCGR2A expression and susceptibility to stroke in IBD patients. Finally, evidence suggests that gut microbes, blood metabolites, and immune cells may play a crucial regulatory role in the shared pathophysiology of IBD/UC and LAS. The study highlights the shared genetics architecture that exists between IBD and stroke, and demonstrates two different (FCGR2A-mediated immune pathways and other indirect regulation) but complementary verification mechanisms, providing new insights into IBD-stroke comorbidities.
Wang X, Zhu Z, Li H, Gao J, Ding M, Li Y, Shi L, Zhu S, Cheng L
The causal relationship between the palmitoylation gene ZDHHC13 and ulcerative colitis: A Mendelian randomization study implicating CD62L-monocyte AC. Medicine | 2026-07
This study explores the potential mechanisms between palmitoylation and ulcerative colitis (UC) through Mendelian randomization, bioinformatics analysis combined with eQTL and protein quantitative trait loci. This study selected a dataset of 5034 UC patients from the Finnish database and conducted Mendelian randomization analysis with palmitoylation target genes to explore the causal relationships between the two. Sensitivity and pleiotropy tests were performed alongside bioinformatics analysis to screen for the best target genes, ensuring the robustness of the results. Finally, immune cells were included for mediation analysis between palmitoylation and UC to explore potential mechanisms. Through Mendelian randomization analysis combined with sensitivity and pleiotropy tests, 5 target genes related to palmitoylation were identified to have a significant causal relationship with UC. Subsequent bioinformatics analysis confirmed ZDHHC13 and PPT1 as potential gene targets. By including immune cells in the mediation analysis, it was ultimately found that there is a potential mechanism involving ZDHHC13, CD62L- monocyte AC, and UC. There is a significant causal relationship between palmitoylation and UC. Furthermore, the palmitoylation gene ZDHHC13 can regulate CD62L- monocyte AC immune cells, inhibiting the occurrence of UC.
Chen Y, Luo M, Li K
Shared inflammatory architecture and therapeutic tensions between psoriasis and Crohn’s disease.Review Frontiers in immunology | 2026-06-26
Psoriasis and Crohn’s disease are chronic immune-mediated inflammatory diseases affecting distinct barrier organs, yet epidemiological, genetic, transcriptomic, and therapeutic evidence supports partial immune convergence between them. This review argues that the relationship between psoriasis and Crohn’s disease reflects partial immune convergence shaped by tissue context, rather than a single shared disease entity. TNF-α and IL-23-centered type 17 immunity represent the most clinically relevant shared upstream programs, whereas downstream effector pathways, especially IL-17-related responses, are shaped differently by skin and gut barrier architecture, resident immune ecology, microbial exposure, and repair demands. We discuss the gut-skin axis with caution: barrier dysfunction, dysbiosis, microbial metabolites, and immune-cell trafficking may connect skin and intestinal inflammation, but direct causal evidence in humans remains limited. TNF inhibitors, IL-12/23 blockade, and selective IL-23 inhibitors are the most plausible options for selected patients requiring treatment compatible with both skin and gut disease, whereas IL-17 blockade and paradoxical psoriasiform reactions illustrate organ-specific therapeutic tensions. Future progress will depend on patient stratification using clinical phenotypes, biomarkers, tissue profiling, and treatment history to identify patients in whom skin and intestinal inflammation are driven by overlapping immune mechanisms.
Wang X, Li J, Yu K, Wu X, Luo Q
IBD-associated Neoplasia (5 papers)
Early and late-onset colorectal cancers: a case-case comparison of risk factors. Cancer causes & control : CCC | 2026-07-11
Examine which demographic, lifestyle, and clinical risk factors differ between patients with early-onset colorectal cancers (EOCRC) compared to late-onset colorectal cancers (LOCRC). We conducted a case-case comparison of risk factors and symptoms for EOCRC and LOCRC, utilizing the Ohio Colorectal Cancer Prevention Initiative (OCCPI) data, a statewide study of newly diagnosed CRC among Ohio residents, aged 20-92 years. Unconditional logistic regression (odds ratios (OR) and 95% confidence intervals (CI)) was used to compare risk factors by age-at-diagnoses; those diagnosed < 50 years (EOCRC, N = 288) compared to those diagnosed ≥ 50 years (LOCRC, N = 1,018), adjusting for sex, race/ethnicity, education, smoking status, and family history of CRC. Compared to LOCRC, EOCRC cases had higher odds of ever consuming alcohol (OR = 2.47, CI: 1.55-3.91), consuming more alcohol in their teens/twenties than in other decades (OR = 1.85, CI: 1.36-2.51), and binge drinking (OR = 3.15, CI: 2.31-4.30). EOCRC cases were more likely to have Lynch syndrome (OR = 4.61, CI: 2.72-7.84), and report experiencing pre-diagnostic CRC symptoms (OR = 6.08, CI: 3.77-9.82), including blood in stool (52.3 vs. 30.7%), change in bowel habits (37.2 vs. 19.8%), and bowel obstruction (13.9 vs. 7.7%). Birth weight, inflammatory bowel disease, irritable bowel syndrome, and sex did not differ by age-at-diagnosis. However, when birthweight was compared between the youngest EOCRC to the oldest LOCRC cases (< 40 vs. ≥ 65 years), odds of birthweight of < 6lbs was higher in the youngest cases (OR: 2.15, CI: 0.95-4.87). Alcohol consumption, consuming the most alcohol in one’s teens/twenties, binge drinking, having Lynch syndrome, and pre-diagnostic CRC symptoms were more associated with EOCRC than LOCRC.
Rees S, Pearlman R, Paskett ED, Shields PG, Hampel H, Freudenheim JL
Cancer risk of Janus kinase inhibitors and other advanced therapies in immune-mediated inflammatory diseases: a systematic review and Bayesian network meta-analysis of RCTs. Annals of the rheumatic diseases | 2026-07-10
The Oral Rheumatoid Arthritis Trial Surveillance trial identified increased malignancy risk with tofacitinib vs tumour necrosis factor inhibitors (TNFis) in rheumatoid arthritis (RA), leading to class-wide regulatory warnings for Janus kinase inhibitors (JAKis). Comparative cancer risk vs other advanced therapies and across immune-mediated inflammatory diseases (IMIDs) remains uncertain. The objective was to estimate relative and absolute cancer risk associated with JAKi vs other advanced therapies across IMIDs. MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception to February 2026 for phases II to IV randomised trials and long-term extension studies of licensed advanced therapies in adults with RA, psoriasis (PsO)/psoriatic arthritis (PsA), or inflammatory bowel disease (IBD) reporting malignancy outcomes. Bayesian class-level network meta-analyses using Poisson models estimated incidence rate ratios (RRs) vs standard care (placebo or methotrexate monotherapy). It includes all malignancies including nonmelanoma skin cancer. A total of 305 studies (164,824 participants; 264,100 person-years exposure) were included, comprising 174 studies across IMIDs, 123 in RA, 129 in PsO/PsA, and 54 in IBD. In the combined IMID network, JAKi were associated with higher malignancy risk than TNFi (RR: 1.60; 95% credible interval [CrI]: 1.27-2.02) and standard care (RR: 1.85; 95% CrI: 1.38-2.47). Similar directional findings were observed across RA, PsO/PsA, and IBD networks. Interleukin-6 (IL-6), Interleukin-17 (IL-17), Interleukin-23 (IL-23), Interleukin-12/23 (IL-12/23), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), B-lymphocyte antigen CD20 (CD20)-targeting therapies showed risks broadly comparable with TNFi. Absolute excess cancer risk with JAKi compared with TNFi was negligible in standard-risk populations (+0.037 cancers per 1000 person-years exposure [PYE]; ∼1 additional cancer per 27,000 PYE) but meaningful in higher-risk populations (+6.814 cancers per 1000 PYE; ∼1 additional cancer per 147 PYE). Across IMIDs, JAKi were consistently associated with higher malignancy risk relative to TNFi and standard care, extending regulatory warnings beyond RA and emphasising the need for risk-stratified treatment decisions.
Gibson M, Allen V, Adas M, Muzafar I, Muzafar S, Suresh N, Yoon Y, De Gracia L, Chavali R, Hussain H
Diverging incidences of low-grade dysplasia and advanced neoplasia in inflammatory bowel disease: a nationwide Danish cohort study. Scandinavian journal of gastroenterology | 2026-07-09
In individuals with inflammatory bowel disease (IBD), low-grade dysplasia (LGD) is a risk factor for advanced neoplasia, that is, high-grade dysplasia and colorectal cancer. Over recent decades, advances in IBD management and endoscopic surveillance have been implemented; however, it remains unclear whether these developments have influenced the incidence of LGD and advanced neoplasia. To describe contemporary trends in the population-level incidence of LGD and advanced neoplasia in IBD. We conducted a nationwide Danish cohort study (1990-2022) using national healthcare registers. IBD was defined at the second recorded healthcare contact with an IBD diagnosis. Annual age-standardised incidence rates (IRs) per 1,000 IBD patient-years were calculated for LGD and advanced neoplasia. Incidence rate ratios (IRRs) relative to 1990 were estimated using Poisson regression. Among 78,126 individuals with IBD, we identified 6,814 incident cases of LGD and 1,987 of advanced neoplasia. The IR of LGD increased from 0.68 per 1,000 IBD patient-years in 1990 to 4.41 in 2022 (IRR 6.47, 95% confidence interval (CI) 3.99-10.49), with a sustained increase after the introduction of the national general colorectal cancer screening programme in 2014. In contrast, the IR of advanced neoplasia remained stable (IRR 1.10, 95% CI 0.59-2.07). The incidence of IBD-related LGD increased markedly over the study period, particularly after the introduction of the national general colorectal cancer screening programme in 2014, whereas the incidence of advanced neoplasia remained stable. These findings highlight the need for robust risk stratification to identify individuals who may benefit from surveillance.
Andersen JW, Troelsen FS, Krogh K, Hart A, Dige A
Combining genotoxic gut bacterial strains increases tumor burden and accelerates onset in a germ-free mouse model of colon carcinogenesis.★ Cell reports | 2026-07-07
To identify causal links between gut microbes and tumorigenesis, we colonized germ-free, colon tumor-susceptible mice (ApcMin/+;Il10-/-) with 19 cultured human fecal microbiotas from healthy individuals and patients with inflammatory bowel disease or colorectal cancer. Colonic tumor counts vary by donor microbiota but not by donor health status. In vitro screens of host cell proliferation, genotoxicity, and inflammation in bacteria-mammalian cell co-cultures reveal that genotoxicity best predicts tumorigenic microbes in vivo, with genotoxic microbes present in all tested individuals. The genotoxic subset of strains from each donor induces more tumors than the complete community-even when the complete community is not tumorigenic. Combining genotoxic microbes from multiple sources increases tumor number and decreases time to tumor onset. Together, these results suggest that most individuals harbor genotoxic bacterial strains and that the balance of genotoxic to protective strains determines the timing and severity of tumorigenesis in vivo.
Plitt T, Piessevaux A, Rajpal U, Fischer J, Spindler MP, Ruprecht C, Li Z, Mogno I, Yang Y, Desch AN
Intestinal cancer risk in Crohn’s disease: authors’ reply on methods, data integrity, and clinical implications.Editorial★ Journal of Crohn’s & colitis | 2026-07
Abstract not available.
Giusto EA, Pinton P, Giorgi C, Serino G, Giannelli G, Donghia R, Fiorica F
Extraintestinal Manifestations (4 papers)
Epidemiology of primary sclerosing cholangitis in general and IBD populations: a systematic review and meta-analysis. Hepatology international | 2026-07-11
Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic liver condition that is closely associated with inflammatory bowel disease (IBD). PSC is associated with substantial long-term hepatobiliary morbidity, including an increased risk of cholangiocarcinoma. Reported prevalence and incidence estimates of PSC vary widely across different populations and study designs. This meta-analysis aims to provide an updated estimate of the prevalence of PSC in the general and IBD populations, and PSC incidence in the general population. A systematic search of MEDLINE (Ovid) and Embase from inception to October 20, 2025, for population- or cohort-based studies reporting PSC prevalence or incidence was performed. Seventy-four studies met the inclusion criteria. Random-effects meta-analyses were performed to pool prevalence and incidence estimates. Subgroup analyses, meta-regression, and sensitivity analyses were conducted to assess robustness and sources of heterogeneity. Seventeen studies including 196,635,709 individuals showed a pooled overall PSC prevalence of 8.06 per 100,000 (95% CI 4.75-13.36) in the general population. Among 516,548 patients with IBD in thirty-four studies, pooled PSC prevalence was 15.2 per 1,000 (95% CI 10.7-21.7). PSC prevalence was higher in ulcerative colitis (20.6 per 1,000) than in Crohn’s disease (10.2 per 1,000). Using Crohn’s disease as the reference group, ulcerative colitis was associated with higher odds of PSC (OR 1.787, 95% CI 1.066-2.996, p = 0.028). Thirteen studies reported a pooled incidence of PSC in the general population of 0.892 per 100,000 person-years (95% CI 0.705-1.130). This meta-analysis provides an updated synthesis of PSC epidemiology, extending prior work by incorporating detailed subgroup analyses across IBD phenotype, PSC subtype, geographic region, socioeconomic context, diagnostic modality, case-ascertainment method, and time period, which are dimensions not comprehensively addressed in previous meta-analyses. PSC remains a rare disease in the general population but is substantially more prevalent among individuals with IBD. Marked geographic and methodological heterogeneity, with notable underrepresentation of data from lower-SDI regions and the African Region, underscores the need for standardized case definitions and improved epidemiological surveillance across diverse settings. Given the markedly increased risk of cholangiocarcinoma in PSC, these findings highlight the clinical importance of recognizing PSC in higher-risk IBD populations and provide an epidemiological foundation for future studies evaluating risk stratification, early detection, and surveillance.
Ho GJK, Selvakumar A, Yeo LYY, Eguchi M, Lim RY, Sim BKL, Tung D, Sasikumar AN, Bong SHS, Tham EKJ
Short, not skinny: The distinct sarcopenia phenotype of pediatric primary sclerosing cholangitis-inflammatory bowel disease. Journal of pediatric gastroenterology and nutrition | 2026-07-08
Sarcopenia is prevalent in pediatric liver disease and inflammatory bowel disease (IBD) and predicts adverse outcomes. We aimed to compare sarcopenia prevalence in pediatric primary sclerosing cholangitis (PSC)-colitis versus non-PSC colitis, characterize longitudinal anthropometric trajectories, and examine the association between sarcopenia and liver outcomes. This retrospective study compared children with PSC-colitis to matched non-PSC colitis controls. Total psoas muscle area (tPMA) was measured on magnetic resonance enterography. Sarcopenia was defined as tPMA <3rd percentile. Logistic regression examined the PSC-sarcopenia association adjusting for IBD factors. Anthropometric and gamma-glutamyl transferase (GGT) trajectories were analyzed using linear mixed-effects models. Of 85 patients (31 PSC-colitis, 54 non-PSC colitis), sarcopenia prevalence was 42% versus 26%. After adjustment, PSC-colitis patients had nearly fivefold higher odds of sarcopenia (adjusted odds ratio [aOR] 4.81, 95% confidence interval [CI] 1.33-17.36, p = 0.016). However, height-corrected tPMA was similar between groups (p = 0.97), and the PSC-sarcopenia association attenuated when adjusting for height (aOR 3.16, p = 0.085). Sarcopenic PSC-colitis patients demonstrated weight recovery yet persistent height deficits. Sarcopenic non-PSC colitis patients had persistent weight deficits without height impairment. GGT trajectories in PSC-colitis did not differ by sarcopenia status. Sarcopenia in PSC-colitis may reflect proportionate growth impairment, “short but not skinny,” rather than catabolic wasting. This phenotype, characterized by persistent height deficits despite weight recovery and mild colitis, may suggest hepatobiliary or other mechanisms distinct from the gut inflammation-driven sarcopenia in non-PSC colitis and the cachexia of end-stage liver disease.
Dahlwi G, Yodoshi T, O’Donnell JEM, Hadian F, Griffiths AM, Church PC, Ricciuto A
Primary sclerosing cholangitis displays distinct colonic mucosa topography yet a shared mast cell state with ulcerative colitis.★ Nature communications | 2026-07-07
Primary sclerosing cholangitis (PSC) is a chronic, progressing cholestatic disease that often co-occurs with inflammatory bowel disease (PSC-IBD). PSC-IBD affecting the colon (PSC-ulcerative colitis or PSC-UC) resembles clinical UC, but is characterised by less severe disease flares, right-colon predominance, and a greater lifetime risk of colorectal cancer than UC alone. To elucidate differences in the underlying biology between PSC-UC and UC, here we combine single-cell mRNA and antigen receptor sequencing, 16S ribosomal RNA gene analysis and spatial transcriptomics on biopsies from four colon regions of patients with PSC-UC and UC during endoscopic remission or at the time of relapse. We show that the PSC-UC colon, compared to healthy control (HC) or UC colon, harbours distinct and region-specific mucosal-adherent microbial communities and an enrichment of activated CD8 T and γδ T cells at the right colon, even in the absence of histological inflammation. By contrast, a TMEM176B+ mast cell population that may be pro-tumourigenic is enriched in the colon during disease relapse in both PSC-UC and UC colon. These results highlight that the PSC-UC and UC colonic mucosa are fundamentally different while sharing similar cell programmes during active disease. Our data thus provide insights to guide tailored clinical management and precision therapies.
Tearle JL, Sviriaeva E, Zhang F, Jackson KJ, Kaye J, Tavakoli P, Koentgen S, Warren J, Liang RR, Malhotra P
Recent Advances in the Pharmacological Management of Pediatric Spondyloarthritis.Review Paediatric drugs | 2026-07-06
Juvenile spondyloarthritis (JSpA) refers to a heterogeneous group of inflammatory diseases affecting peripheral joints and the axial skeleton during childhood and adolescence. Enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA), subtypes of juvenile idiopathic arthritis (JIA) under the International League of Associations for Rheumatology (ILAR) classification, are included in this group. They may be associated with human leukocyte antigen (HLA) B27 positivity. Apart from musculoskeletal involvement, pathologies that accompany the disease, such as psoriasis, uveitis, and inflammatory bowel disease, significantly affect patients’ quality of life and clinicians’ treatment approaches. Guidelines developed for the treatment of JSpA patients primarily address the use of nonsteroidal antiinflammatory drugs (NSAIDs), conventional disease-modifying antirheumatic drugs (csDMARDs), and tumour necrosis factor inhibitors (TNFi). However, not all patients respond adequately to or tolerate the currently available therapies, highlighting the need for novel treatment options. Recent advances in understanding immunopathogenesis have driven the development of new therapeutic targets, including TNF inhibitors, interleukin (IL)-17/IL-23 blockers, and Janus kinase inhibitors. Several of these agents, including secukinumab, have now received approval for the treatment of ERA and JPsA. However, since only a limited number of open-label and randomized controlled trials have specifically evaluated JSpA, current treatment strategies are also informed by evidence from other JIA subtypes and adult studies. Expanding the approved indications of existing biologics-supported by robust trial data-alongside the development of novel therapeutic agents, may broaden treatment options and ultimately improve outcomes for patients with JSpA.
Gul U, Konte EK, Yildiz M, Kasapcopur O
Pediatric IBD (4 papers)
IL-10-neutralising autoantibodies in paediatric-onset inflammatory bowel disease.★ Gut | 2026-07-08
Autoantibodies neutralising interleukin-10 (IL-10) have recently been described as a mechanism of inflammatory bowel disease (IBD); however, prevalence and clinical impacts are unknown. To determine the prevalence and longitudinal persistence of IL-10 autoantibodies in a population of paediatric-onset IBD and to assess associated clinical features. We analysed plasma IL-10 autoantibodies with a cross-sectional study of a paediatric cohort of patients diagnosed with either IBD (n=239), autoimmune enteropathy (n=37) or congenital diarrhoea and enteropathies (n=42). Functional testing to assess IL-10 response was performed using cell-based assays under biologically relevant stimulation. Five patients with autoantibodies neutralising 2.5 ng/mL of IL-10 were identified, three of whom were also neutralising at 5 ng/mL. All had IBD without a known monogenic cause. Longitudinal samples (available in three of five subjects) showed autoantibody persistence in two cases, 3 and 9 years after baseline. The patient without persistence had undergone haematopoietic stem-cell transplantation (HSCT) 2 years after baseline sampling. The prevalence of neutralising IL-10 autoantibodies was 2.1% (95% CI 0.7% to 4.8%), while the frequency was 2.6% in subjects without IBD-associated monogenic variants (n=192). In paediatric autoimmune and inflammatory gut diseases, IL-10 neutralising autoantibodies were detected only among patients with IBD without known genetic aetiology. Patients had heterogeneous clinical characteristics and IL-10 autoantibodies persisted under standard immunosuppressive treatment but disappeared following HSCT and may have declined with colectomy or ileostomy. Screening for IL-10 autoantibodies via functional assays may identify a subgroup of patients with distinct aetiology and therapeutic needs.
Yalcinkaya A, Sandström E, Degrace EJ, Pigneur B, Abi-Nader E, Berrebi D, Duclaux-Loras R, Nancey S, Collardeau-Frachon S, Gornet JM
Variation in the access and use of biologic and targeted synthetic DMARD in juvenile idiopathic arthritis: insights from a national UK survey. Pediatric rheumatology online journal | 2026-07-06
Biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) have transformed outcomes for juvenile idiopathic arthritis (JIA). However, contemporary understanding of real-world treatment selection, and access across the United Kingdom (UK), remains limited. Commissioning pathways, service configuration, and age- and specialty-based prescribing frameworks may contribute to variations in care. We describe current perspectives of paediatric and adolescent rheumatology multidisciplinary teams (MDTs) on the selection and access to b/tsDMARDs for JIA across the four UK nations. A 26-question survey was distributed to MDTs across UK paediatric and adolescent rheumatology centres via national networks. Data on MDT composition, b/tsDMARD choice, commissioned pathways, dosing constraints and barriers to access were analysed by JIA subtype, UK region, age, and specialty pathway. Heatmaps and non-parametric permutation testing were used to quantify treatment patterns. Free-text responses underwent qualitative thematic analysis. Responses were received from 13 of 17 (76%) tertiary and quaternary centres across the four UK nations, representing 123 MDT professionals. Adalimumab was most commonly used first-line for all JIA subtypes except systemic JIA (sJIA)/Still’s disease. Tocilizumab was frequently used second-line across multiple subtypes, including polyarticular disease and uveitis, and was widely used first- and second-line in sJIA/Still’s. Interleukin-1 inhibition with anakinra was commonly used in sJIA, particularly in macrophage activation syndrome (MAS). In England and Wales, access to canakinumab for sJIA was unavailable despite supportive trial evidence, and adalimumab was the only commissioned therapy for JIA-associated uveitis. Paediatric access to anti-IL-17 agents for enthesitis-related arthritis (ERA) was limited. Broader therapeutic choice and higher biologic dosing were more accessible via dermatology or gastroenterology pathways, for example, for psoriatic JIA and inflammatory bowel disease (IBD)-associated arthritis. Adult/adolescent rheumatologists reported wider biologic access, though reclassification to adult diagnoses was sometimes required. Biosimilars were universally adopted, but specialist pharmacy support for implementation was inconsistent. External advice was sought for refractory disease, including consideration of haematopoietic stem cell transplantation and combination biologic therapy. Selection and access to effective b/tsDMARD therapies for JIA varies considerably across the UK, shaped by commissioning structures, age thresholds and specialty pathways rather than clinical need. National alignment of services is urgently required to ensure equitable, timely access to evidence-based therapies for children and young people with JIA.
Cooray S, Rajani K, Compeyrot-Lacassagne S, Sen ES, Anderson C, Fell A, McKenna D, Danielsen C, Cortina-Borja M, Ciurtin C
[COMORBIDITY IN THE HEALTH STATUS OF ADOLESCENTS AND YOUNG ADULTS - REPRESENTATIVES OF GENERATION Z WITH FUNCTIONAL GASTROINTESTINAL DISORDERS]. Problemy sotsial’noi gigieny, zdravookhraneniia i istorii meditsiny | 2026-06-27
In the young population, a persistent trend toward an increase in functional gastrointestinal disorders (FGIDs) is observed, with Generation Z representatives showing higher rates. The phenomenon of increased referrals of Generation Z individuals to gastroenterologists for FGIDs is indicative: these conditions account for nearly half of all initial consultations in this age group, driven by a combination of high medical awareness, a tendency toward self-diagnosis, and heightened sensitivity to somatic manifestations of psychoemotional stress. Emotional burnout, resulting from academic and professional workloads amid constant digital engagement, acts as a significant risk factor for reduced adaptive potential and deterioration in somatic and mental health indicators. In adolescents and young adults, multiple concomitant FGIDs are often identified, such as combined irritable bowel syndrome, functional dyspepsia, functional abdominal pain disorders, functional constipation, inflammatory bowel diseases, obesity, and others. FGIDs are frequently classified as disorders of gut-brain interaction (DGBI), reflecting the key role of bidirectional communication between the gut and the brain in their development and their impact on the comorbidity of psychological conditions. Accounting for the specific manifestations of comorbidity in the health status of adolescents and young adults with FGIDs is essential for developing effective treatment and preventive programs. В молодёжной популяции определяется устойчивая тенденция к росту функциональных расстройств желудочно-кишечного тракта (ФР ЖКТ), причём представители поколения Z демонстрируют более высокие показатели. Показателен феномен повышенной обращаемости представителей поколения Z к врачам-гастроэнтерологам по поводу ФР ЖКТ: данные состояния составляют почти половину всех первичных консультаций в данной возрастной группе, что обусловлено сочетанием высокой медицинской информированности, склонности к самодиагностике и повышенной чувствительности к соматическим проявлениям психоэмоционального напряжения. Эмоциональное выгорание, обусловленное академическими и профессиональными нагрузками в условиях постоянной цифровой включённости, выступает значимым фактором риска снижения адаптационного потенциала и ухудшения показателей соматического и ментального здоровья. У подростков и молодёжи часто выявляют несколько сопутствующих ФР ЖКТ, например, сочетанные синдром раздражённого кишечника, функциональная диспепсия, функциональные болевые абдоминальные расстройства, функциональный запор, воспалительные заболевания кишечника, ожирение и др. ФР ЖКТ часто относят к расстройствам взаимодействия кишечника и головного мозга, что отражает ключевую роль двунаправленной коммуникации между кишечником и мозгом в развитии этих расстройств и их влияние на коморбидность психологических состояний. Учёт особенностей проявления коморбидности в состоянии здоровья подростков и молодёжи, имеющих ФР ЖКТ, необходим для построения эффективных лечебно-профилактических программ.
Zubareva NA, Mingazova EN
DOI: 10.32687/0869-866X-2026-34-s1-400-405 | View on PubMed →
School life in children with inflammatory bowel diseases: from a national survey to a patient-driven awareness initiative. Crohn’s & colitis 360 | 2026-06-23
School plays a crucial role in the daily life of pediatric patients with inflammatory bowel disease (IBD). Our study aimed to evaluate patients’ perspectives on school environment and identify improvement areas. An anonymized patient-driven school survey was distributed via an online platform between February and November 2024 to all pediatric IBD patients and families registered with the Italian IBD patient association (AMICI). Overall, 362 IBD patients responded, of whom 326/362 (90%) were in secondary school. Most respondents reported being aware of their disease (327/342, 96%). While the majority expressed a positive attitude towards school (269/342, 79%) and had disclosed their condition to at least 1 person at school (286/318, 90%), challenges were identified. Only 91/308 (30%) and 84/318 (26%) felt often understood by teachers and peers, respectively. Toilet access was problematic, with 225/318 (71%) expressing fear of using school bathrooms. Additionally, 80/313 (26%) experienced at least occasionally physical/verbal bullying. More than half (172/310, 55%) attended school despite feeling unwell to avoid criticism, with a minority having opportunities to catch up on missed lessons (95/261, 36%). To address these issues, patients’ suggestions included training programs to educate teachers/peers and practical improvements in restroom access and absence management. This national patient-driven survey highlights substantial unmet needs in the school environment for children/young adults with IBD, underscoring the need for targeted interventions to improve inclusion and quality of life. Patient associations play a key role in identifying everyday challenges and fostering collaboration among clinicians, institutions, and policymakers to implement meaningful change.
Gianolio L, Silvera V, Bianchi A, Penagini F, Previtali E, Leone S, Zuccotti G, Norsa L
Endoscopy & Imaging (non-IUS) (3 papers)
Vitamin D3 facilitates mucosal healing and modulates macrophage polarization in DSS-induced colitis, accompanied by restoration of epithelial Hippo-YAP signaling. European journal of pharmacology | 2026-07-09
Damage to the epithelial barrier and dysregulated immune responses are core features of ulcerative colitis (UC). Although vitamin D3 (VD3) is widely recognized for immunomodulatory actions, how it contributes to mucosal repair remains incompletely defined. We used a dextran sulfate sodium (DSS)-induced acute colitis model to assess epithelial regeneration, macrophage polarization, and Hippo-Yes-associated protein (YAP) signaling. Mice received 3% DSS in drinking water and were treated with VD3 or vehicle, after which clinical indices, epithelial injury/repair, immune phenotypes, and inflammatory mediators were evaluated. VD3 markedly alleviated colitis severity and partially preserved mucosal architecture. VD3 showed dual protective effects: it reduced epithelial apoptosis and increased the expression of Ki67, zonula occludens-1 (ZO-1), and Claudin-1, indicating enhanced epithelial restitution; in parallel, it shifted macrophage polarization toward an anti-inflammatory M2-like profile and lowered pro-inflammatory mediator levels. At the signaling level, VD3 attenuated DSS-associated Hippo pathway activation and was accompanied by partial normalization of Yes-associated protein 1 (YAP1) phosphorylation status and YAP-related readouts. Collectively, VD3 improved DSS-induced colitis with coordinated enhancement of epithelial repair and immune-resolution features, accompanied by partial restoration of Hippo-YAP signaling, supporting its relevance to mucosal healing.
Gao H, Hu Z, Zhang L, Zhao K, Asai Y, Li Y, Wang J, Zhang Z, Du G
Patient preferences toward the attributes of treatment used for inflammatory bowel disease in Saudi Arabia: Subgroup analysis from an international multicenter discrete choice experiment. Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association | 2026-07-06
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD), and ulcerative colitis (UC), are chronic autoimmune disorders with increasing prevalence in Saudi Arabia (KSA). Understanding patient treatment preferences is important for improving adherence and quality of life. This study evaluated treatment preferences in KSA within the context of the overall five-country cohort (Argentina, Australia, Brazil, Taiwan, and KSA), without conducting formal cross-country comparisons. A cross-sectional survey (October 2022-May 2023) used discrete choice experiments (DCE) to assess preferences for treatment attributes, including safety, efficacy, and route of administration (RoA). Adults (≥18 years) with self-reported CD or UC receiving treatment for ≥6 months were included. Data from 353 patients with CD and 353 with UC were analyzed, including 102 from KSA (51 CD, 51 UC). Preferences in KSA were largely consistent with the overall cohort. CD patients prioritized long-term remission, while UC patients valued corticosteroid-free remission at 1 year. Descriptively, KSA patients appeared to place relatively greater emphasis on safety attributes compared with the overall cohort-particularly serious adverse events (AEs) in both CD and UC, and mild AEs in UC-and less emphasis on mucosal healing and RoA. Abdominal pain (CD) and rectal bleeding (UC) most affected quality of life and daily activities. KSA patients also reported lower exposure to advanced therapies (0% in CD and 11.8% in UC). However, given the limited sample size and absence of formal statistical testing, these observations between countries should be interpreted as exploratory. Personalized IBD management in KSA is needed. Incorporating patient preferences into clinical decision-making may improve adherence and outcomes.
Azzam N, Mourad D, Mosli M, Al Sulais E, Altuwaijri M, Meeralam Y, Fadeeva O, Elgharbawy A
Optimizing bowel preparation regimens for colon capsule endoscopy: an umbrella review (overview of systematic reviews). Therapeutic advances in gastrointestinal endoscopy | 2026-07-02
Colon capsule endoscopy (CCE) is a minimally invasive alternative to colonoscopy, but its diagnostic performance depends entirely on adequate mucosal cleansing (adequate cleansing rate, ACR) and complete colonic transit (completion rate, CR). These requirements impose stringent preparation demands. Existing systematic reviews (SRs) show substantial heterogeneity in recommendations. To identify optimal CCE preparation strategies. Umbrella review (overview of SRs). A comprehensive literature search was conducted through November 2025 for SRs and meta-analyses (MAs) assessing CCE bowel preparation regimens. Methodological quality was assessed using AMSTAR2, and primary study overlap was quantified using the Corrected Covered Area (CCA). Outcomes included ACR and CR, stratified by preparation components. Fourteen SRs (11 MAs) encompassing 102 primary studies (moderate overlap, CCA 8.59%) were included. Pooled ACR (72.5%-76.8%) and CR (79.8%-83.0%) remained below colonoscopy benchmarks. In inflammatory bowel disease, ACR varied widely (49%-98.5%) with no superior regimen. In the general population, low-volume polyethylene glycol (PEG <4 L) yielded higher ACR (77.5%) than high-volume PEG (72.9%). Sodium phosphate (NaP) boosters outperformed PEG specifically for CR, with NaP + Gastrografin achieving the highest CR (93.1%). Castor oil improved excretion (OR 0.17 of incomplete CCE transit, 95% CI 0.09-0.32), and routine prokinetics improved CR compared with no use (OR 1.86, 95% CI 1.13-3.05). Low-fiber diets provided better cleansing than clear liquids (ACR 78.5% vs 70.0%). Current CCE bowel preparation regimens demonstrate variable performance relative to targets, with no single intervention demonstrating unequivocal superiority over others in pairwise comparisons. Evidence supports optimizing performance via low-volume PEG, NaP or Gastrografin-based boosters, routine prokinetics, and a low-fiber diet. A universal regimen is unlikely to suit all patients, highlighting the need for personalized protocols. Standardized cleansing scores and AI-assisted assessment are critical to improving reproducibility and cost-effectiveness. Optimizing bowel preparation for colon capsule endoscopy Colon capsule endoscopy is a non-invasive procedure that uses a swallowable pill-shaped camera to examine the large intestine to detect conditions like cancer or inflammation. While it offers a comfortable alternative to traditional colonoscopy, its success depends entirely on the colon being perfectly clean. Unlike standard endoscopes, the capsule cannot wash away debris or suction organic fluids. If the bowel is not completely clean, the examination may miss relevant lesion. Currently, there is no universally accepted standard for the best preparation protocol. To address this issue, we analyzed 14 major systematic reviews, encompassing data from 102 primary studies, to identify the most effective strategies for bowel preparation. The findings of this study highlight several key improvements for current protocols. First, a strict clear-liquid diet is not mandatory; allowing patients to eat low-fiber foods the day before the procedure actually improves cleansing results while enhancing patient comfort. Second, patients do not need to consume very high volumes of laxatives. Lower-volume solutions (under 4 liters) proved to be highly effective and are generally better tolerated by patients. Finally, keeping the capsule moving is critical, in order to avoid early battery depletion before the device is excreted. The routine use of specific medications that stimulate bowel movement (prokinetics), alongside targeted booster agents, is essential to ensure the capsule travels through the entire colon. In conclusion, the optimization and tailoring of laxative preparations significantly reduces the rate of incomplete examinations. This minimizes the need for repeat procedures, ultimately making colon capsule endoscopy a more reliable and cost-effective diagnostic tool.
Cortegoso Valdivia P, Gualandi N, Bonura GF, Manno M, Pennazio M, Toth E, Rey JF, Sidhu R, Koulaouzidis A
Nutrition & Lifestyle (3 papers)
p38 MAP kinase senses short-chain fatty acids to attenuate Toll-like receptor signaling and intestinal inflammation.★ Science advances | 2026-07-10
Toll-like receptor (TLR) signaling is critical for innate immune system. However, whether it is directly modulated by microbiota-derived metabolites remains unclear. Here, we show that the short-chain fatty acids (SCFAs) propionate and butyrate suppress TLR signaling by directly binding p38α MAP kinase, promoting its interaction with TAB1, thereby activating p38α via autophosphorylation. Activated p38α then phosphorylates TRAF3 at serine 85, inhibiting K63-linked polyubiquitylation of TRAF3 and disrupting TBK1-IRF3 activation, leading to reduced macrophage activation and intestinal inflammation. In ulcerative colitis patients, fecal levels of propionate and butyrate positively correlate with p38α activity and TRAF3 S85 phosphorylation, but inversely correlate with TBK1 activation, and cytokine levels. Notably, oral administration of propionate in three patients with ulcerative colitis markedly improved intestinal inflammation and clinical symptoms. These findings reveal p38α as a direct sensor for microbiota-derived SCFAs that suppress TLR signaling through nonmetabolic functions of propionate and butyrate, providing the first clinical evidence that propionate supplementation represents a practical dietary strategy for ulcerative colitis management.
Wu Q, Shi R, Xiao L, He X, Chen Z, Zhao H, Liu J, Luo S, Jiang X, Guo D
Metabolome remodeling with reverse-engineered exclusive enteral nutrition in children with active Crohn’s disease.★ Inflammatory bowel diseases | 2026-07-08
For children with Crohn’s disease (CD), dietary therapy with exclusive enteral nutrition (EEN) is effective in achieving clinical and biochemical remission. We investigated changes in metabolites in multiple clinical sample types from children with CD following a whole foods-blended (“reverse-engineered”) EEN formula and defined associations between these changes and remission. Stool, urine, serum, and plasma from a prospective study of newly diagnosed pediatric patients with CD enrolled in a 4-week trial of reverse-engineered exclusive enteral nutrition (RE-EEN) were analyzed using mass spectrometry targeting aqueous metabolites, bile acids, and short-chain fatty acids. Principal component analysis, mixed-effects models, and exploratory multivariate approaches including random forest and partial least-squares discriminant analysis were used to identify patterns associated with diet and metabolite abundances. Fecal, urine, serum, and plasma metabolomes changed significantly during RE-EEN treatment from baseline. These global changes were largely driven by increases in amino acids and related metabolites and decreases in different amino acids and metabolites reflecting carbohydrate and purine metabolism, in all sample types. While global bile acid profiles changed with the RE-EEN diet, no changes in specific bile acid levels reached significance, and no changes were found in short-chain fatty acid concentrations. Metabolomic profiles for pediatric patients with CD changed broadly during RE-EEN, indicating that this therapy may modulate key systemic and gut-associated metabolic processes. The findings further suggest that the gut metabolic processes influenced by RE-EEN, and that contribute to clinical improvement, may differ from those impacted by commercial EEN diets. Further research is crucial to validate these findings, uncover causal relationships, and optimize dietary protocols to enhance therapeutic outcomes in CD. In children with active Crohn’s disease, a whole-foods–based enteral diet (reverse-engineered exclusive enteral nutrition) induced remission and broadly altered metabolites in stool, urine, and blood. These findings suggest that reverse-engineered exclusive enteral nutrition influences distinct metabolic pathways compared with commercial formulas, highlighting potential for tailored nutrition.
Suskind DL, Hoffman LR, Lee D, Verster AJ, Zheng HB, Francis K, Nuding M, Vanamala J, Wahbeh G, Purcell H
Assessment of Malnutrition in Crohn’s Disease Patients: A Novel Risk Prediction Model with Dynamic Optimization Potential and Effectiveness Validation. Journal of visualized experiments : JoVE | 2026-06-22
This study aimed to construct and validate a malnutrition risk prediction model combining multivariable logistic regression and machine learning for patients with Crohn’s disease (CD), with the goal of improving the precision of malnutrition risk identification through integration of inflammatory markers and disease characteristics. PubMed, Web of Science, Cochrane Library, Embase, and China National Knowledge Infrastructure (CNKI) were systematically searched to identify risk factors associated with malnutrition in patients with CD. High-quality studies using the Global Leadership Initiative on Malnutrition (GLIM) 2019 criteria, European Society for Clinical Nutrition and Metabolism (ESPEN) 2015 criteria, or Malnutrition Universal Screening Tool (MUST) criteria were included in the meta-analysis, while the study cohort applied the ESPEN 2015 criteria exclusively to ensure consistent outcome definition. The prediction model was developed using data from 800 patients with CD from the Inflammatory Bowel Disease Cohort Database (IBDCD) and validated using bootstrap resampling and an independent non-overlapping hold-out subset of 280 patients from the same database. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), Hosmer-Lemeshow test, and Brier score. No significant baseline differences were observed between the training and validation cohorts. The model achieved an AUC of 0.987 in the training cohort and 0.967 in the validation cohort, demonstrating good discrimination and calibration. Decision curve analysis further demonstrated clinically meaningful net benefits across relevant threshold probabilities. This model effectively identifies malnutrition risk in patients with CD and may support personalized nutritional intervention, optimize clinical decision-making, and improve patient outcomes and quality of life. Future multicenter studies are required to further validate the model’s generalizability and to evaluate the integration of socioeconomic factors for further optimization.
Cai L, Xie L, Wan S, Chen C, Long F, Du J, Qian H, Yang L
Pregnancy & Reproductive Health (2 papers)
Per- and polyfluoroalkyl substances (PFAS) in early life is associated with childhood intestinal inflammation: analyses of three birth cohorts.★ Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association | 2026-07-10
Early life exposures shape intestinal and immune development and later risk of inflammatory bowel disease (IBD). Per- and polyfluoroalkyl substances (PFAS), or forever chemicals, are associated with intestinal inflammation and IBD. However, the impact of early life PFAS exposure on later intestinal inflammation is not known. We conducted untargeted PFAS analyses in early life samples from mother-offspring dyads across three cohorts. These included dried blood spots from offspring (n=84) and cord blood (n=93) from two prospective birth cohorts of mothers with and without IBD in New York, United States, and maternal serum during pregnancy (n=14) from a birth cohort in Mexico City, Mexico. Fecal calprotectin (FC), a biomarker of intestinal inflammation, was measured longitudinally in offspring stool. Covariate-adjusted weighted quantile sum regression models were used to estimate associations between PFAS and FC. PFAS metabolites were detected across all sample types. Higher levels of PFAS mixtures were associated with higher FC between 1 and 6 years of age in both dried blood spot and cord blood analyses (covariate-adjusted β estimates for change in log-transformed fecal calprotectin at age 6 years per decile increase in the PFAS mixture was 0.44, 95% CI 0.18, 0.70 and 0.69, 95% CI 0.53, 0.85, respectively) Similarly, higher levels of PFAS mixtures in maternal serum were associated with higher FC in late childhood (β 0.19, 95% CI 0.05, 0.33). Compared to mothers-offspring dyads without maternal IBD, those with maternal IBD were more likely to have higher perfluoro-1-octane sulfonamide acetic acid and 3-perfluorohexyl-2-hydroxypropyl acrylate levels in dried blood spots and cord blood, respectively; these PFAS metabolites were also the top contributors to offspring FC. PFAS chemicals are detectable in early life samples, indicating exposure during this period of vulnerability, and are associated with higher FC in childhood across three birth cohorts.
Midya V, Maroli AS, Picker M, Dolios G, Valvi D, Nguyen I, Kim T, Rendon A, Chen R, Weinstein K
Assessing confidence of community pharmacists in inflammatory bowel disease management: a cross-sectional study in Malta. The International journal of pharmacy practice | 2026-07-08
To evaluate community pharmacists’ confidence in the management of inflammatory bowel disease (IBD) and to identify areas in which pharmacist-led patient education and counselling could be strengthened. This cross-sectional study was conducted in three phases; questionnaire development and review by an expert panel, reliability assessment, and dissemination to 100 community pharmacies selected through stratified random sampling across Malta. Pharmacists’ confidence across 29 items was assessed using mean rating scores (MRS) on a 5-point Likert scale. Non-parametric analyses examined associations between confidence, demographic variables, and perceived barriers (P < .05 statistically significant). Ninety-four pharmacists completed the questionnaire; female (n = 65), > 5 years of community pharmacy experience (n = 56), worked 31-40 hours weekly (n = 39), Master of Pharmacy degree (n = 47). ‘High’ confidence (MRS ≥4/5) was reported for advice on diet and lifestyle, non-prescription medicines for symptom management, medicine storage/stability, and recognizing when referral was required. ‘Moderate’ confidence (MRS 3 to <4/5) was observed for adherence support, relapse, counselling on extraintestinal complications, dosage form administration, corticosteroids, methotrexate, aminosalicylates, and biologics. ‘Low’ confidence (MRS <3/5) was identified for counselling on thiopurines, non-prescription medicines associated with toxic megacolon, vaccines, and pregnancy and women of child-bearing age. The main reported barriers to providing advice were time constraints (n = 70) and patient-related communication challenges (n = 63). Years of experience, hours of practice, and inadequate private consultation space were not significantly associated with pharmacist confidence (P > .05). Community pharmacists were more confident in general counselling and referral-related support than in medication-specific counselling and more complex aspects of IBD care.
Diyab A, Wirth F
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