Introduction

Short bowel syndrome with intestinal failure (SBS-IF) is a severe organ failure condition associated with long-term parenteral support (PS) dependence. In the first years after resection, spontaneous intestinal changes occur. Previous studies have examined the effects of SBS-IF on microbiota composition (mainly fecal) and report an enrichment of facultative anaerobes. Analogs of the glucagon-like peptide-2 (GLP-2) have been introduced as disease-modifying treatments for SBS-IF and are hypothesized to boost intestinal adaptation in the host resulting in increased absorption and reduced PS needs. Apraglutide (APRA) is a novel, long-acting GLP-2 analog in development for SBS-IF. Here, we investigated the effect of APRA on microbiota composition after 4, 24, and 48 weeks (W) of treatment along the GI tract.

Aims & Methods

STARS Nutrition was a 52-W multicenter, open-label, phase 2 study in adult patients with SBS-IF and a colon-in-continuity (CiC) (Leuven n=7, Paris n=2) receiving weekly subcutaneous APRA injections. Biopsies of the duodenum, distal small bowel (if preserved), and sigmoid colon biopsies were collected at screening, 24 and 48W. In addition, fecal samples were collected at baseline and at 4, 24, and 48W. For baseline comparison, duodenal and sigmoid colonic biopsies from 10 control patients were collected. Relative (mucosa-associated and fecal) and quantitative (fecal, incl. pH, microbial load, moisture, calprotectin) microbiome profiling was performed.

Results

At baseline, per-subject microbiota analysis revealed that distal small bowel, sigmoid colon and stool samples from patients with SBS-IF-CiC were enriched in Lactobacillus, while duodenum harbored a distinct and variable microbiota. Compared to controls, the sigmoid colonic microbiota in SBS-IF-CiC showed a significantly lower richness (Wilcoxon rank-sum Benjamini-Hochberg (BH) corrected, p<0.001) and Inverse Simpson (Wilcoxon rank-sum BH corrected, p=0.0024). No significant differences in duodenal microbial composition between these groups were observed, but common colonic genera were enriched in the sigmoid biopsies from controls while in SBS-IF-CIC genera such as Lactobacillus, Sutterella, and Bifidobacterium were more dominant. APRA did not lead to significant changes in alpha-diversity, fecal pH, moisture, and calprotectin, but a trend towards increased microbial load was observed at 24W (ANOVA, p=0.07). Moreover, higher intra-subject dissimilarity in stool was observed and inter-subject variation decreased over time in sigmoid colon and stool. In addition, the abundance of Bifidobacterium decreased significantly in the sigmoid colon and feces. More location-specific changes included a lower abundance of Parabacteroides, Parasutterella, Sutterella in sigmoid colon and Fusobacterium and Streptococcus in stool. In contrast, Prevotella was significantly enriched in stool during APRA, which correlated negatively with fecal pH. Overall, Lactobacillus was still the most dominant taxa enriched in these locations.

Conclusion

This study was the first to assess the mucosa-associated and fecal microbiome in patients with SBS-IF-CiC in relation to GLP-2 analog therapy. Our results show that patients with SBS-IF-CiC present an immature sigmoid colonic and fecal ecosystem characterized by lactate producers. APRA treatment induced converging effects in the more distal locations, with an early shift towards more mature microbiota in some subjects, while still being highly dominated by Lactobacillus. Treatments targeting both host and microbiota should be explored.

Disclosure

This research was supported by VectivBio, now part of Ironwood Pharmaceuticals.
Astrid Verbiest, Daniel Ekhlas, Mira Stas, Lise De Meyere, Muriel Derrien, Jeroen Raes: Nothing to disclose.
Palle Bekker Jeppesen : PBJ has received grants/research support/honoraria or consultation fees from Albumedix A/S, ArTara Therapeutics, Bainan Biotech, Baxter, Coloplast, Ferring, Fresenius Kabi, GLyPharma, Naia Pharma, NPS Pharmaceuticals, Shire, Takeda, The Novo Nordisk Foundation, Therachon, VectivBio and Zealand Pharma.
Francisca Joly : FJ has received grants/research support/honoraria or consultation fees from Baxter, Fresenius Kabi, Nestlé Health Sciences, BBraun, Theradial, Mayoli, Biocodex, mobile3e Consulting, Carembouche, NPS Pharmaceuticals, Shire, Takeda, Therachon, VectivBio and Zealand Pharma.
Tim Vanuytsel : TV has served on the speaker bureau for Fresenius Kabi, Remedus, Takeda, and VectivBio. TV has provided clinical advice to Baxter, Shire, Takeda, VectivBio, Zealand Pharma. TV has received research grants from Takeda and VectivBio.

Introduction

Mirikizumab (miri), a humanized IgG4-variant monoclonal antibody that specifically binds to subunit p19 of interleukin-23, showed efficacy in phase (Ph)3 induction (LUCENT-1) and maintenance (LUCENT-2) studies involving patients with ulcerative colitis.¹
Here we report the efficacy and safety of the Ph3 LUCENT-2 study, a double-blind, randomized withdrawal maintenance study, in Chinese subpopulation who responded to miri induction therapy from LUCENT-1.

Aims & Methods

Miri clinical responders after 12-week induction therapy (54.3%)were re-randomized in a 2:1 ratio to receive blinded miri 200 mg or placebo (PBO) subcutaneously (SC) every four weeks (Q4W) for 40 weeks (Chinese primary efficacy population N=80). Randomization was stratified by biologic agent/tofacitinib failed status, induction remission status and baseline corticosteroid (CS) use.
The primary objective was to test the hypothesis that Miri was superior to PBO in achieving clinical remission at Week 40. Key secondary endpoints included alternate clinical remission, CS-free remission, endoscopic remission, histologic-endoscopic mucosal remission (HEMR), improvement in bowel urgency, bowel urgency remission, and maintenance of clinical remission. Analyses in Chinese subpopulation were descriptive.

Results

Baseline demographic and disease characteristics were generally balanced across the two treatment groups, including the proportion of baseline CS/ immunomodulator use, biologic agent/tofacitinib failure status and pancolitis.
A greater proportion of patients treated with miri achieved clinical remission at Week 40 (miri 50.0%, PBO 12.5%; Δ=40.4 [95% confidence interval (CI) 22.5, 58.4]). Miri also improved key secondary endpoints at Week 40 including proportion of patients who achieved alternate clinical remission (miri 55.4%, PBO 12.5%; Δ=45.4 [95%CI 27.3, 63.4]), and who achieved CS-free remission, clinical remission, bowel urgency remission and HEMR compared to PBO.
The frequencies of treatment-emergent adverse events were similar between groups in Chinese patients. There were fewer serious adverse events and discontinuations due to adverse events in miri patients compared to PBO. No deaths were reported in Chinese subpopulation during this study.

Conclusion

In Chinese patients who responded to miri induction therapy, miri's maintenance treatment provided positive efficacy and safety profiles consistent with LUCENT-2 overall population, supporting benefits of miri treatment in the Chinese ulcerative colitis patients.

References

1. Geert D'Haens, Marla Dubinsky, Taku Kobayashi, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2023 Jun 29;388(26):2444-2455.

Disclosure

Zhihua Ran, Jie Zhong, Chengdang Wang, Xiang Gao, Xiaolan Zhang, Yijuan Ding and Qian Cao have been investigators of Eli Lilly and Company; Dan Tang, Chenxi Qian, Jiao Yu are employees and minor stockholders of Eli Lilly and Company.

Introduction

Early identification of factors that predict disease course in ulcerative colitis (UC) is essential to guide therapeutic decisions and improve patient outcomes. Recognizing patients at higher risk of unfavorable evolution allows for more intensive monitoring and timely escalation of therapy. Clinical severity, disease extent, histological activity, and concomitant infections may all influence prognosis. Among these, Clostridioides difficile infection (CDI) is increasingly recognized in UC patients, but its independent impact on disease evolution remains uncertain. The objective of our study was to assess various baseline severity markers, including histological activity, and concomitant CDI at the time of UC diagnosis as potential predictors of disease-related morbidity during the first year following UC diagnosis.

Aims & Methods

We conducted a retrospective study on a cohort of 125 patients newly diagnosed with UC and followed for at least 12 months. Data collected included demographic characteristics, clinical presentation, biochemical markers, endoscopic findings, histologic disease activity (assessed using the Nancy Histological Index – NHI), and the presence of CDI at diagnosis. Disease-related morbidity was defined as any UC-related hospitalization occurring in the first year after diagnosis, excluding the initial admission for diagnostic purposes. Statistical analysis involved bivariate comparisons and multivariate logistic regression to identify independent predictors of hospitalization.

Results

Independent predictors of UC-related hospitalization were Mayo clinical score (OR = 1.32; p = 0.016), pancolitis (OR = 2.82; p = 0.024), and histological activity (NHI; OR = 1.97; p = 0.014). CDI was identified in 20% of patients and was associated with significantly higher histological activity (median NHI = 3.5 vs. 3.0; p = 0.036), but did not independently predict hospitalization (OR = 1.84; p = 0.265).

Conclusion

Clinical activity, disease extent, and histological severity, at the time of diagnosis are strong, independent predictors of UC-related morbidity within the first year, underscoring their prognostic value beyond the initial presentation. These parameters retain their significance over the medium-term disease course, supporting early risk stratification and individualized treatment planning. Although CDI is associated with greater histologic inflammation at baseline, it does not independently influence outcomes during the first year. Notably, the identification of UC in 20% of patients during a CDI episode suggests that acute infection may unmask previously subclinical disease. These findings highlight the need for comprehensive and careful diagnostic evaluation - including clinical, endoscopic, and histologic assessment, in all patients with newly diagnosed UC.

Introduction

Combination therapy targeting pathogenic pathways may overcome the current therapeutic efficacy ceiling and benefit patients with inflammatory bowel disease (IBD). Emerging preclinical evidence suggests that the costimulatory molecule OX40-ligand (OX40L) represents a promising target in both Crohn’s disease (CD) and ulcerative colitis (UC), particularly when inhibited in combination with anti-TNF agents. Despite these data, a comprehensive understanding of OX40L and its receptor, OX40, in IBD patients is lacking, especially related to potential synergy of OX40L and TNF blockade, particularly in previous anti-TNF non-responders.

Aims & Methods

We investigated OX40L biology in IBD using single-cell transcriptomic data from the terminal ileum of CD patients [n=73] and control subjects [n=106] (Open Targets Consortium) to query cell-specific gene expression profiles for OX40L and OX40 (TNFSF4, TNFRSF4). We also leveraged bulk transcriptomic studies profiling CD terminal ileum [n=99] and both UC [n=272] and control [n=18] colon, as well as available clinical metadata. We assessed enrichment of OX40L biology by gene set variation analysis (GSVA) using OX40L gene signatures. Patterns of gene and signature expression were then associated with endoscopic disease activity and longitudinal response to anti-TNF therapy.

Results

In cross-sectional analyses, increased mucosal OX40 gene expression was associated with higher endoscopic disease activity scores in both CD and UC patients (Simple Endoscopic Score, Mayo endoscopic score; p<0.05). Cellular estimates of lymphocyte subsets associated with resistance and/or residual disease post-anti-TNF therapy were found to correlate with mucosal enrichment of OX40L gene signature in both CD and UC (FDR<0.05; bicor range UC: 0.94-0.21, CD: 0.89-0.67). In longitudinal analyses, UC patients demonstrated elevated expression of OX40L gene signature in colon at baseline which, after anti-TNF therapy initiation, was progressively reduced in responders while persistently elevated in non-responders (p<0.05) throughout induction (week 4-8) and maintenance (week 30) phases. Exploratory single-cell analyses in CD terminal ileum showed cell type-specific increases in OX40L and OX40 gene expression relative to control, with enrichment in T-cell subsets (both), NK cells and dendritic cells (OX40L), myeloid and epithelial cells (OX40). In UC, stronger associations were found between OX40L gene signature enrichment and cellular estimates for multiple lymphocyte subsets (ILC1, PD1⁺CD4⁺ T-cells, plasma cells, mature and germinal center B-cells) as compared to TNF signature (FDR<0.05; bicor range OX40: 0.94-0.67, TNF: 0.69-0.37).

Conclusion

Expression of OX40L and its receptor OX40 is increased in pathogenic cell types from IBD intestinal tissue relative to control and operates in distinct cellular subnetworks compared to TNF. Additionally, increased OX40 gene expression is associated with higher disease activity in both CD and UC. OX40L signatures, which correlate with presence of lymphocyte subsets that may promote TNF resistance, are found to be persistently elevated in UC anti-TNF non-responders. These results provide a novel, data-driven rationale for combining anti-OX40L therapy with anti-TNF therapy in future experiments and clinical trials. This combination may optimize treatment efficacy in IBD by targeting mechanisms that are associated with anti-TNF resistance as well as residual disease following anti-TNF therapy.

Disclosure

CAR, RM, MRD, GF, MT, SK, EdR, CB, IW and HM are employees of Sanofi and may hold stock options or equity in Sanofi; ZH, HHB, RS, AC, ASM, YC are employees of CytoReason and may hold stock options or equity; SSO holds equity and is a consultant of CytoReason and holds an unpaid position with the Human Immunome Project

Introduction

Hepatobiliary disorders are recognised extraintestinal manifestations in inflammatory bowel disease (IBD). Up to 30% of patients exhibit abnormal liver function tests and 5% will develop chronic liver disease (1). IBD-associated liver diseases (IBDALD), comprising primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) and AIH/PSC overlap syndrome carry significant morbidity through progressive hepatobiliary damage and increased cancer risk. Early recognition is challenging due to non-specific biochemical derangement and heterogeneous presentation. No validated stratification tools exist for prospective risk identification. This study investigated whether routinely collected biomarkers convey predictive value for IBDALD, leveraging large-language model (LLM) refined phenotyping.

Aims & Methods

We analysed 1,571 paediatric and adult-onset IBD patients recruited to the “Genetics of IBD” study (Southampton, UK; 2010–). IBDALD cases were identified through LLM-assisted (Llama 3.1-70B-Instruct) structuring of 32,041 free-text imaging and histopathology reports, followed by clinician verification (2). Participants diagnosed with IBDALD prior to IBD were excluded from further analysis. Examined biomarkers included ALT, ALT and ESR (n=335,605 datapoints for the examined cohort). For each biomarker, patient-level medians were calculated from all available results within ±6 months of IBD diagnosis. A 1:4 individual matched case-control design was applied (matched on age at IBD diagnosis, gender, and IBD subtype) in R. Conditional logistic regression models assessed associations between IBDALD and biomarker values, treated as both continuous (patient-level medians) and binary – normal versus abnormal - (age- and sex-adjusted lab range flags) variables. Longitudinal biomarker trajectories were explored using LOESS and linear mixed-effects models.

Results

Thirty-five cases of IBDALD were identified (27 post-IBD diagnosis). Median follow-up duration was 11.5 (0.5–59.5) years and median 4.5 years (0.4–39.1) from IBD diagnosis to liver disease onset. In whole cohort analyses, ALT, ALP, and ESR were significantly elevated in IBDALD at diagnosis of IBD (p < 0.01). In matched case-control models, higher median ALT (OR = 1.04 per U/L increase, 95% CI: 1.01–1.07, p = 0.012), ALP (OR = 1.01, 95% CI: 1.00–1.02, p = 0.014), and ESR (OR = 1.05, 95% CI: 1.00–1.09, p = 0.034) were each associated with IBDALD. In a combined model including all three biomarkers, none retained statistical significance. When analysed as binary (normal/abnormal) variables, ALT and ALP remained significantly associated with IBDALD (ALT: OR = 5.10, 95% CI: 1.57–16.59, p<0.01; ALP: OR = 15.33, 95% CI: 1.87–125.77, p<0.05). ESR did not reach significance (OR = 3.71, 95% CI: 0.75-18.32 p=0.107). Longitudinal modelling supported distinct ALT and ALP trajectories in the IBDALD group and distinct trends over time were visualised for ALT, ALP and ESR in LOESS scatterplots.

Conclusion

These data suggest that routinely measured biomarkers may carry early predictive signals for IBD-associated liver disease, identifiable at the time of IBD diagnosis. The use of LLM-assisted phenotyping enabled high-fidelity case definition within real-world data. These findings should be interpreted cautiously given the rarity of IBDALD and potential overfitting in multivariable models. Future prospective studies are warranted to validate predictive models and support integration into IBD care pathways.

References

1. Scott JA, Mysko C, Purssell H, et al. Investigation of abnormal liver blood tests in patients with inflammatory bowel disease. Frontline Gastroenterology 2024;15:516-522.
2. Kadhim A, Green Z, Nazari I, et al. Application of Generative Artificial Intelligence to Utilise Unstructured Clinical Data for Acceleration of Inflammatory Bowel Disease Research. Article in PrePrint medRxiv 2025.03.07.25323569; doi: https://doi.org/10.1101/2025.03.07.25323569

Disclosure

JJA is a SAB member for Orchard Therapeutics.

Introduction

The intestinal mucosa undergoes constant renewal, with epithelial and immune cells routinely shed into the gut lumen. Recent findings suggest that these shed cells remain viable and retain transcriptomic signatures relevant to bowel pathology. Analysis of luminal content obtained during colonoscopy indicates that Fecal Host Transcriptomes (FHT) mirror histologic inflammation in IBD. This study aimed to evaluate whether sequencing of stool samples can noninvasively reflect the presence of intestinal inflammation in patients with IBD, predict the location of inflammation within the bowel and distinguish between IBD type; Crohn’s Disease and Ulcerative Colitis.

Aims & Methods

Our aim was to investigate whether transcriptomic analysis of stool samples that are taken ambulatory or at home could reveal the inflammation signature of inflamed IBD patients.
Bulk RNA sequencing of stool samples from 71 IBD patients and healthy controls was used to generate FHTs. Each sample was paired with an endoscopic assessment and clinical data to capture a time-matched view of intestinal inflammation. Three random forest classifiers were trained to: (1) distinguish active inflammation from remission; (2) predict inflammation location in Crohn’s disease (colon vs. small intestine). and (3) classifier based on gene modules expression was used to differ between CD and UC in patients with active inflammation.

Results

Fecal RNA quality was high, with a median of 2,140 human genes detected per sample. The FHT test demonstrated robust performance across all tested applications. The first model, designed to distinguish active inflammation from remission (n = 71), achieved a sensitivity of 85% and a specificity of 92%. The second model, which predicted the location of inflammation in Crohn’s disease patients (n = 21), achieved 100% sensitivity and 100% specificity. The third model, aimed at differentiating Crohn’s Disease from Ulcerative Colitis (n = 35), reached a sensitivity of 83% and a specificity of 100%. These findings underscore the potential of FHTs as a non-invasive tool for comprehensive inflammation profiling in IBD.

Conclusion

Fecal shed cell transcriptomics offers a novel, non-invasive approach for assessing mucosal inflammation at the endoscopic level in IBD patients. This approach enables differentiation between disease activity states, anatomical localization of inflammation, and IBD subtype classification. Ongoing studies aim to evaluate its utility in grading inflammation severity and predicting therapeutic response.

References

Dan et al., CMGH 2023
Ungar et al., GUT 2022

Introduction

Tyrosine kinase 2 (TYK2) inhibitors block signaling downstream of multiple pro-inflammatory cytokines involved in immune-mediated inflammatory diseases, including inflammatory bowel disease, and may have an improved safety profile relative to Janus kinase inhibitors. Phase 2 studies of the highly selective and potent TYK2 inhibitor zasocitinib in Crohn’s disease (CD; NCT06233461) and ulcerative colitis (UC; NCT06254950) are ongoing.^1,2 Here, we describe the design of a combined open-label extension trial (NCT06764615), which will include patients from both parent trials who are responsive to treatment.

Aims & Methods

Patients are eligible for the phase 2 parent studies in CD and UC if they are aged 18–75 years with moderately to severely active disease, and have inadequate or loss of response to, or intolerance of, ≥ 1 standard or advanced therapy. Patients who have failed treatment with ≥ 3 classes of advanced therapy are excluded. Patients are randomized to one of three (CD) or two (UC) doses of zasocitinib, or placebo, for a 12-week double-blind induction phase followed by a 40-week sponsor-open (CD) or open-label (UC) maintenance period. At the end of the parent trials, patients will be eligible for the combined open-label extension if they are clinical (CD) or symptomatic (UC) responders at Week 52, defined as: (1) CD: a ≥ 30% decrease in average daily very soft or liquid stools and/or a ≥ 30% decrease in average daily abdominal pain from baseline; and (2) UC: a ≥ 1-point and ≥ 30% decrease from baseline in partial modified Mayo score, and a ≥ 1-point decrease from baseline in rectal bleeding (RB) subscore or achievement of an absolute RB subscore of ≤ 1. All enrolled patients will receive the same dose of open-label, oral, once-daily zasocitinib for a maximum of 108 weeks, with study visits every 12 weeks, followed by a 4-week safety follow-up period. Data analysis will be descriptive, with no formal statistical comparisons performed.

Results

The primary objective of the study is to determine long-term safety and tolerability, assessed through the incidence of treatment-emergent adverse events or adverse events of special interest. Secondary endpoints will assess the long-term efficacy of zasocitinib, including clinical, symptomatic, or endoscopic response or remission by visit or at Weeks 48 and 108, according to indication, and effects on patient-reported outcomes, including fatigue, bowel urgency, abdominal pain, and disease-specific health-related quality of life.

Conclusion

This open-label extension trial will provide data on the long-term safety of zasocitinib, as well as durability of treatment response among patients with CD or UC who experience treatment benefit in the phase 2 parent studies.

References

1. Jairath V et al. UEG Journal 2024;12(S8):1033.
2. Peyrin-Biroulet L et al. UEG Journal 2024;12(S8):1041.

Disclosure

GP reports receiving personal payments, honoraria, or speaker fees from AbbVie, Allergan, BMS, Celltrion, Ferring, Galapagos, Janssen, Pfizer, Sorriso, Takeda, and Tillotts, travel grants or fellowships from AbbVie, Celltrion, Ferring, Janssen, Takeda, and Tillotts, and is a Director and shareholder in Ampersand Health. SGR, LZ, VAN, LA, FN, TF, LS, and NS are employees and shareholders of Takeda.