The intestinal epithelium integrates host- and environment-derived cues to coordinate barrier defense, nutrient absorption, and fluid homeostasis 1-3. Single-cell atlases have delineated key regional differences between the small and large intestines and revealed extensive epithelial rewiring in inflammatory gastrointestinal diseases. However, whether comparable epithelial alterations occur in the absence of active inflammation remains unknown. In particular, the epithelial landscape in functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), as well as in symptomatic patients with Crohn’s disease (CD) in remission, has not been defined. Here, using integrated single-cell and spatial transcriptomics, we generate a high-resolution map of the human colorectal epithelium across health, IBS, and symptomatic CD remission. In healthy tissue, we identify robust regional partitioning within absorptive lineages, with the rectum exhibiting transcriptional programs biased towards chloride secretion. Strikingly, in IBS and symptomatic CD remission, we observe the emergence of ectopic epithelial programs despite the absence of overt inflammation. These include antigen-sampling microfold cells in the rectum of patients with IBS and two aberrant absorptive subsets in the ascending colon of symptomatic CD patients in remission, both transcriptionally enriched for antigen sampling and chloride secretory pathways. Together, these findings reveal previously unrecognized epithelial rewiring that emerges or persists in patients with debilitating gastrointestinal symptoms despite the absence of overt inflammation.

BACKGROUND & AIMS:Secondary loss of response to ustekinumab is observed in patients with Crohn's disease (CD). Multiple dose-intensification regimens have been proposed. We aimed to test prospectively 2 different dose-intensification regimens with ustekinumab in patients with CD experiencing secondary loss of response. METHODS:This was an investigator-initiated, multicenter, randomized, placebo-controlled trial conducted at 15 hospitals in Belgium. Eligible patients were adults with CD treated with ustekinumab on maintenance dosing of 90 mg subcutaneous every 8 weeks and experiencing a secondary loss of response (Patient-Reported Outcomes 2: abdominal pain score >1 and liquid or very soft stool frequency >3 and an objective documentation of disease). Patients were randomized 1:1 to receiving a single intravenous reinduction with ustekinumab ≈6 mg/kg followed by either subcutaneous ustekinumab 90 mg every 4 weeks or every 8 weeks until week 48. The primary endpoint was the proportion of patients with steroid-free clinical remission at week 48, defined as Patient-Reported Outcomes 2 remission: (abdominal pain ≤ 1 and stool frequency ≤3) and fecal calprotectin <250 μg/g and no steroids in the 90 days before week 48. RESULTS:Between March 2020 and October 2023, 108 patients were randomized. Steroid-free clinical remission at week 48 was reached in 15% vs 19% of patients in the every 4 weeks vs the every 8 weeks group (difference 4%; P = 0.5). Serious adverse events occurred in 17% vs 13% of patients. CONCLUSIONS:In patients with CD and secondary loss of response to ustekinumab, dose intensification with a single intravenous administration and followed by 4 weekly subcutaneous dosing of ustekinumab was not more effective than 1 intravenous administration followed by 8 weekly subcutaneous dosing of ustekinumab. (ClinicalTrials.gov, Number: NCT04245215).

The intestinal epithelial barrier is essential for protection against pathogens and toxins while allowing nutrient and water absorption. Barrier dysfunction is increasingly recognized as a key pathophysiological mechanism in diseases affecting the gastrointestinal (GI) tract and distant organs. Hydrogen sulfide has emerged as an important regulator of intestinal homeostasis. This study investigates the effects of the H₂S-releasing compound 4-hydroxithiobenzamide (TBZ) on epithelial barrier integrity. Although TBZ did not prevent interferon-γ and tumor necrosis factor-α (IFN/TNF)-induced epithelial cell death, it reversed cytokine-induced increases in transepithelial permeability. Notably, TBZ alone increased paracellular permeability but normalized it under inflammatory conditions, indicating a context-dependent effect. H₂S-producing enzymes localized apically in IECs, suggesting subcellular regulation. Transcriptomic analysis identified oxidative phosphorylation as a pathway mediating TBZ’s effects. Functional studies confirmed that TBZ enhances oxidative phosphorylation, while inhibition of complex IV abolished barrier protection. In conclusion, our data indicate that hydrogen sulfide counteracts IFN/TNF-induced epithelial barrier dysfunction through transcriptional and functional enhancement of oxidative phosphorylation.

BACKGROUND:Gastrointestinal symptom-specific anxiety (GSA) is increasingly recognized as an important construct in the disease experience of inflammatory bowel diseases (IBD). However, it remains unclear to what extent GSA overlaps with general anxiety in the IBD population, and whether it is associated with disability beyond general anxiety and other clinical and demographic variables. AIMS:First, we examined how many patients with elevated GSA do or do not experience general anxiety, and vice versa. Second, we assessed the unique contribution of GSA to variance in IBD-related disability, keeping general anxiety, disease activity, and other variables constant. METHODS:In a cross-sectional survey study, over 1000 IBD patients completed questionnaires on general anxiety (the anxiety subscale of the Hospital Anxiety and Depression Scale [HADS]), GSA (the Visceral Sensitivity Index [VSI]), IBD-related disability (the IBD Disk), and self-reported clinical disease activity (Patient-Reported Outcomes [PRO] and Manitoba IBD Index [MIBDI]) alongside a set of general demographic and clinical questions. RESULTS:GSA and general anxiety frequently co-occurred, but 38.0% of patients reported GSA without general anxiety. Additionally, GSA was significantly associated with IBD-related disability (P < .001) even when general anxiety, disease activity, and other variables were controlled for. Although general anxiety showed the strongest association with disability (β = .27), the association for GSA (β = 0.22) was stronger than for clinical disease activity (β = .18) and other demographic and clinical variables. CONCLUSION:Overall, this highlights the clinical significance of GSA beyond general anxiety and disease activity in IBD.

Systematic bias between therapeutic drug monitoring assays may lead to inappropriate treatment decisions in clinical practice. While such bias is well recognized, its impact on model-informed precision dosing remains unexplored. In this study, we evaluate how assay bias affects the predictive performance of population pharmacokinetic models, using ustekinumab in patients with Crohn’s disease as an example. We repurposed data from 83 patients with Crohn’s disease. Ustekinumab concentrations were measured using both an homogeneous mobility shift assay and enzyme-linked immunosorbent assay. Two corresponding population pharmacokinetic models were developed. Bayesian forecasting was performed under matched and mismatched combinations of assay data and population pharmacokinetic models. Predictive accuracy and precision were assessed using relative bias and relative root mean square error, with predefined thresholds for clinical acceptability. Agreement between assays and clearance estimates was evaluated using Bland–Altman plots, Deming regression, and concordance correlation coefficients. Model prior flattening strategies were explored to mitigate mismatches between model priors and therapeutic drug monitoring data. Ustekinumab concentrations measured by the homogenous mobility shift assay were overall 8.1 mg/L higher than those measured by an enzyme-linked immunosorbent assay (95

Off-label ustekinumab benefits patients with chronic pouchitis, yet its pharmacokinetics (PK) and target concentrations remain unclear. We aimed to characterize its population PK in chronic pouchitis, identify concentration thresholds predicting clinical remission (modified pouchitis disease activity index <5 and a reduction by ≥ 2 points), and propose optimized dosing regimens. Twenty-two patients with chronic pouchitis were included.1 All received standard ustekinumab intravenous induction dosing (∼6 mg/kg), followed by 90mg subcutaneous maintenance dosing every eight weeks. Serum samples were collected at week (w)4, w8, w16, and w24. A popPK model was developed to characterize ustekinumab PK. A population pharmacodynamics (popPD) model using logistic regression was used to link drug concentrations and clinical remission and to identify the cutoff. Monte Carlo simulations (n = 1000) were conducted for the 22 patients comparing four induction dosing strategies: (1) standard label dosing, (2) exact 6 mg/kg, (3) 6 mg/kg rounded to the nearest 130 mg vial size, and (4) increased fixed-dose regimen (390 mg <55 kg, 520 mg 55–85 kg, 650 mg >85 kg). For each strategy, the rate of target attainment was calculated based on the identified cutoff. The PopPK model well captured the time course of ustekinumab concentrations (Figure 1a). Standardized to a 70-kg patient with albumin level 44 g/L, clearance (CL) was estimated at 0.348 L/day. The popPD model identified w4 drug concentrations as a predictor of clinical remission at w16, with a threshold of 15.0 mg/L (AUC 0.84; 95% CI 0.62–1.00) (Figure 1b). Simulations revealed that standard dosing achieved this target exposure in only 46.6% of patients (95% CI 46.0–47.3). An exact 6 mg/kg dosing improved this to 57.0% (95% CI 56.4–57.7), while vial-rounded dosing further increased target attainment to 60.9% (95% CI 60.3–61.6). The increased fixed-dose regimen achieved the highest target rate at 80.2% (95% CI 79.6–80.7). Notably, the vial-rounded dosing strategy provided consistent exposure across weight bands (58.6% <55 kg; 61.4% 55–85 kg; 60.4% >85 kg), mitigating underexposure in lighter patients (<55 kg), who had a target rate of only 10.4% under the standard regimen (Figure 2). Clearance of ustekinumab in patients with chronic pouchitis is 1.5–2 times higher than that in Crohn’s disease and ulcerative colitis. W4 concentrations were predictive of clinical remission at w16, with a cutoff of 15.0 mg/L. The vial-rounded induction strategy substantially improves target attainment, particularly in the lighter patients. Reference: [1] Outtier et al. Clin Gastroenterol Hepatol. 2024;22(12):2468-2474.e1 Conflict of interest: Ms. Zhang, Wei: No conflict of interest Outtier, An: No conflict of interest Dewit, Olivier: Consulting, lectures fees or travel accommodations: Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Galapagos, Janssen, MSD, Mylan, Pfizer and Sandoz. Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Ferrante, Marc: Research grants from AbbVie, EG Pharma, Celltrion, Janssen, Pfizer, Takeda and Viatris Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris Dreesen, Erwin: Erwin Dreesen received consultancy fees from Alimentiv and argenx, lecture fees from Celltrion and Galapagos, and financial support from Celltrion, Janssen, Pfizer, Prometheus Biosciences, R-Biopharm, and Sandoz, outside the submitted work, with all honoraria/fees being paid to KU Leuven and not to any personal account of Erwin Dreesen.

GOALS:This study aimed to develop and validate a set of quality indicators that can be used to improve clinical IBD care in Belgium. BACKGROUND:Several quality indicator sets have been developed to standardize, measure, and optimize IBD care. However, currently, no set exists for use in IBD in Belgium. STUDY:In a 2 round modified Delphi exercise, 221 quality indicators were scored on a 10-point Likert scale by 32 IBD experts. In a third ranking round, room for improvement benefitting the patient was prioritized to agree on a subset of indicators. In parallel, patient perspectives were collected through 2 patient focus groups. Indicators scoring 7 or higher by ≥80% of the participants during the second scoring round or based on agreement during a closing consensus meeting were included in the final set. RESULTS:To assess IBD care in Belgium, the following number of quality indicators were agreed upon: 41 structure, 123 process, and 35 outcome indicators (n=199). In the improvement subset, 18 indicators were retained that related to patient characteristics, endoscopy guidelines, infection prevention, steroid use, the IBD care team, services provided in the IBD clinic, the documentation of patient characteristics, the care pathway, and the monitoring of disease activity. Patients considered the latter 5 indicators particularly important. CONCLUSIONS:A set of quality indicators, including an improvement subset, was developed and validated, allowing Belgian IBD centers to assess care, set up quality improvement projects, and potentially a benchmarking exercise.

As therapeutic options for inflammatory bowel disease (IBD) expand, understanding patient preferences—and how these vary across subgroups—is critical for patient-centered drug development and evaluation. This patient preference study aimed to (1) determine the relative preference weights of IBD treatment- and disease-related attributes (i.e., which features most influence patients’ treatment choices) and (2) explain preference heterogeneity. A survey incorporating a discrete choice experiment (DCE) was disseminated worldwide. Patients repeatedly chose between hypothetical treatment profiles varying across 14 attributes using a partial profile design. The survey design was informed by literature review, qualitative research, and advisory boards. Mixed logit models were applied. Data from 1452 patients (51.0

BackgroundImmune-mediated inflammatory diseases (IMIDs) often affect women of childbearing age. Since active inflammatory disease is related with impaired reproductive outcomes, effective disease control is crucial. Clinical guidelines aim to support evidence-based shared decision-making. However, inconsistencies between guidelines across specialties may cause confusion, undermine adherence and lead to adverse health outcomes. This study aimed to assess consistency within and across perinatal IMID guidelines in gastroenterology, rheumatology and dermatology regarding medication use during pregnancy, lactation and among prospective fathers, and to identify medications with insufficient safety data.MethodsA review was conducted in August 2025 using most recent versions of leading international guidelines (N = 11), published between 2015 and 2025. Guideline recommendations for IMID medications were categorized by two independent authors. Data-analysis examined the prevalence and type of consistency, trimester-specific consistency, most common recommendation per medication and the agreement on preconception discontinuation timing.ResultsWithin medical specialties, guideline consistency for individual medications was highest for gastroenterology (61/74, 82.4%), followed by rheumatology (165/220, 75.0%) and dermatology (57/94, 60.6%). Across specialties, agreement was greatest between gastroenterology and rheumatology (pregnancy 86.2%, lactation 81.2%, paternal 88.5%) and lowest between gastroenterology and dermatology (pregnancy 51.3%, lactation 40.6%, paternal 47.1%). Trimester-specific recommendations were consistent across guidelines in 33.3% (2/6) of the cases. Agreement on preconception discontinuation timing was 41.7% (5/12) for maternal cases and 66.7% (2/3) for paternal exposure. At least one inconsistency was found in 75.0% of within-guideline and 87.5% of across-guideline comparisons. At medication-class level, most inconsistencies stemmed from insufficient safety data reporting (59.5%), particularly for small molecules (28.6%), immunomodulators (26.1%) and interleukin inhibitors (34.1%).ConclusionInconsistencies between guidelines, both within and across specialties, were frequent and pose challenges for reproductive decision-making in IMID patients. The lack of safety data in reproductive contexts contributed to guideline inconsistencies and revealed the need to prioritize future research on recently marketed pharmacotherapeutic classes, such as small molecules (JAK-inhibitors, PDE4-modulators) and interleukin inhibitors. In the future, guidelines should be updated regularly, include explicit recommendations, integrate reproductive contexts, and adopt unambiguous language, standardized categories and uniform methodological frameworks.