Introduction

Non-alcoholic fatty liver disease (NAFLD) prevalence is elevated in patients with inflammatory bowel disease (IBD) in Western nations. Both intestinal inflammation and metabolic factors contribute to IBD-associated NAFLD. However, the burden of NAFLD in non-Western populations remains unclear.

Aims & Methods

This study aimed to evaluate the prevalence of NAFLD and liver fibrosis in a cohort of Tunisian IBD patients.

Results

Conclusion

This study demonstrates a 28.57% prevalence of NAFLD in Tunisian IBD patients. Higher BMI and older age at IBD diagnosis were associated with NAFLD. Hepatic fibrosis occurred predominantly in Crohn's disease patients. Further longitudinal studies are warranted to elucidate the impact of IBD on hepatic complications.

Introduction

Short bowel syndrome (SBS) is a severe complication of extensive small intestinal resection, most commonly occurring in Crohn’s disease (CD), a chronic inflammatory disorder defined by transmural immune infiltration. Cytokines and chemokines are central mediators in the immune cascade driving intestinal inflammation and tissue damage^1,2. Despite advances in care, no biomarkers currently predict SBS onset or progression to intestinal failure (IF). Profiling systemic cytokine and chemokine signatures may thus offer novel insight into disease trajectory and risk stratification.

Aims & Methods

This study investigates circulating inflammatory mediators in patients with established IF/SBS and CD patients at high risk of progression. A total of 150 patients with CD were enrolled and stratified into five groups based on intestinal function and surgical history: A1, SBS with IF requiring parenteral nutrition (PN) or intravenous fluids; A3, SBS without IF and inactive disease; B, high risk of IF with multiple or extensive resections; C1, low risk for IF with no history of resection; and C2, low risk for IF with prior resection. Serum cytokine and chemokine profiles were quantified at baseline (T0) and after six months (T6) using the human 27-PLEX multiplex immunoassay.

Results

Serum cytokines and chemokines profiling at baseline (T0) and after six months (T6) revealed distinct inflammatory patterns across the study groups. Patients with SBS and IF (group A1) showed persistently elevated levels of IP-10, IL-12, MIP-1α, and G-CSF, reflecting sustained immune activation. Whereas, patients at high risk of IF (group B) displayed increased Eotaxin, bFGF, IL-15, and IL-6, indicative of subclinical inflammation and possible tissue remodelling.
A general reduction in cytokine levels was observed at T6, though anti-inflammatory mediators remained minimally modulated, suggesting ongoing low-grade inflammation. Comparisons between groups highlighted divergent cytokine signatures correlating with disease severity and nutritional support requirements.

Conclusion

These findings suggest that specific circulating cytokines may serve as potential biomarkers for early identification of patients at risk of IF. The differential expression patterns observed across groups support their relevance in stratifying disease severity in CD and SBS. Further large-scale studies are needed to validate these preliminary results and to fully establish their prognostic significance.
Funded by: 2.1 “Rafforzamento e potenziamento della ricerca biomedica del SSN”, finanziato dall’Unione europea – NextGenerationEU, CUP C53C22001140007. 2022 PNRR Project “Changing the future of intestinal failure in intestinal chronic inflammation: towards innovative predictive factors and therapeutic targets” code: PNRR-MAD-2022-12376791.

References

1. Friedrich M, Pohin M, Powrie F. Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease. Immunity. 2019;50(4):992-1006. doi:10.1016/j.immuni.2019.03.017
2. Singh UP, Singh NP, Murphy EA, et al. Chemokine and cytokine levels in inflammatory bowel disease patients. Cytokine. 2016;77:44-49. doi:10.1016/j.cyto.2015.10.008

Introduction

Cyclic vomiting syndrome (CVS) is a disorder of gut-brain interaction defined by episodes of uncontrollable vomiting and retching. CVS has four phases (inter-episodic, prodrome, emetic, recovery) and affects both children and adults. There is a lack of published qualitative research on disease-related and phase-specific symptoms that impact patients with CVS.

Aims & Methods

Two qualitative, cross-sectional, observational interview studies were conducted in adults (18-65 years) and adolescents (12-17 years) with CVS. The studies aimed to explore the patient experience, identify the symptoms and understand their relevance to patients with CVS. The two studies included participants clinically diagnosed with CVS and followed at the tertiary care CVS programs at Froedtert hospital (adults) and Children’s Wisconsin (adolescents). Adolescents participated in a dyad interview with their caregiver or separately. Interviews were conducted remotely using a semi-structured interview guide and analysed with an “open coding” approach using ATLAS.ti 9.0 (adults) or 22.0 (adolescents).

Results

Semi-structured concept elicitation interviews (each up to 90 minutes long) were conducted with 13 adults (mean ± SD age 45.3 ± 13.1 years) and 15 adolescents (mean ± SD age 14.6 ± 1.8 years) by professional qualitative interviewers. Each participant described their symptoms during the prodrome and emetic phases. Most frequently reported symptoms during the prodrome were nausea (92.3%), anxiety (76.9%) and abdominal pain (69.2%) in adults; and nausea (100%), abdominal pain (73.3%), headache (73.3%) and pale skin (73.3%) in adolescents. During the emetic phase, the most frequently reported symptoms were nausea (100%), tiredness (100%), dry heaves (100%), vomiting (92.3%) and retching (92.3%) in adults; and nausea (100%), vomiting (100%), abdominal pain (93.3%), dehydration (86.7%), tiredness (86.7%) and light-headedness (86.7%) in adolescents. The patients most frequently reported nausea (5/13 adults, 6/15 adolescents) and vomiting (5/13 adults, 5/15 adolescents) as the most bothersome CVS symptom. Adults reported anxiety (associated with an impending vomiting episode; 5/13); missing work (2/13); inability to: perform daily tasks (1/13), plan their life (1/13), or parent to their full capacity (1/13); being homebound (1/13); reduced emotional well-being (1/13); and avoiding events (1/13) as the most bothersome impact of CVS symptoms. Adolescents reported impact on school (7/13 with data); missing out on sports (4/13); impacts on: social activities (4/13), sleep (1/13), friendships (1/13), or emotions (1/13); and anxiety (1/13) as the most bothersome impact of CVS symptoms (some provided >1 response). Caregivers reported the emotional impact of seeing their child suffer from CVS (5/11 with data); impact on: their child’s schooling (3/11), social activities (2/11); sports, friends/social activities, effect on their child’s future, work, daily planning, and travel planning (1/11 each) as the factor most difficult for them or their family.

Conclusion

Patients with CVS experience considerable gastrointestinal as well as extra-intestinal symptoms during both the prodrome and emetic phases. The majority suffer from nausea, vomiting and abdominal pain; the associated anxiety in adults is also notable. The study also confirmed major impact of CVS on daily life such as work/school absences, lost time with family/friends and reduced emotional well-being. CVS also markedly affects caregivers to patients with CVS.

Disclosure

Katja Kovacic reports medical advisory board from AbbVie, and is a consultant for Neurogastrx. Yaozhu J. Chen, Melody Wu, Camilla A. Richmond and James Williams are employees of the study sponsor, Takeda, and hold Takeda stock or stock options. Danielle Rodriguez is an employee of Evidera, which were contracted by Takeda for work relating to this study. Karin S. Coyne is an employee of Evidera, which were contracted by Takeda for work relating to this study, and a scientific consultant to Takeda. Thangam Venkatesan reports consultancy fees from Takeda.

Introduction

Treatment options for patients with mild-to-moderate ulcerative colitis (UC) failing 5-ASA are limited. MH002 is an optimized live biotherapeutic product consisting of 6 non-pathogenic, well‑characterized commensal bacteria. Its anticipated mechanism in UC is reversion of dysregulated host inflammatory mechanisms and interactions with gut microbiota, and induction of mucosal healing.

Aims & Methods

In this 2:1-randomized, double-blind, placebo-controlled frist-in-disease study (EudraCT 2020-001355-33), 45 patients with mild-to-moderate active UC (Modified Mayo Score [MMS] =4-8 and centrally assessed Mayo Endoscopic Sub-score [MES] ≥2) received treatment with 400mg MH002 or placebo (PBO) once daily for 8wks, followed by an 8-wk extension with MH002 (same dose) unless responding to PBO. All patients were on stable 5-ASA for ≥4wks prior and during the study. Full colonoscopies with biopsies were performed at baseline and wk8. The primary endpoint was the rate of treatment-emergent adverse events. Exploratory efficacy endpoints included clinical remission (MMS≤2 with all sub-scores ≤1 and rectal bleeding =0), endoscopic improvement (MES≤1), clinical response (reduction of MMS of ≥3 points or a reduction of ≥1 point of the Mayo sub-scores for stool frequency and rectal bleeding), biomarker normalisation, and mechanistic effects of MH002. Here, changes in faecal microbiome (shotgun metagenomics) and gene expression of colonic mucosal biopsies (whole transcriptome RNAseq) are reported.

Results

MH002 treatment was safe and well tolerated, and resulted in clinically meaningful improvements in disease activity and inflammatory parameters¹. At wk8, endoscopic improvement was achieved in 6/28 (21%) and 2/14 (14%) patients treated with MH002 and PBO, respectively. In this MH002-treated subgroup, α-diversity (Pielou eveness, Shannon diversity) increased significantly as compared to baseline whereas the relative abundance of Enterobacterales decreased significantly over time (1-sided Wilcoxon p<0.05). Similar but less pronounced changes were observed in MH002-treated patients achieving clinical response or even no response.
Furthermore, a total of 1496 significantly differentially expressed genes (DEGs) at wk8 vs. baseline were found in the MH002-treated patients with endoscopic improvement (p<0.05; lnFC>1.5). Among the most significantly downregulated DEGs are the regenerating islet-derived (REG) genes (REG1α, REG1β, REG3α) and serum amyloid A (SAA) genes (SAA1, SAA2, SAA4). Since REG proteins have bactericidal, anti-inflammatory, and tissue repair functions, and SAA are acute-phase proteins induced by inflammatory stimuli, this could result from a state of lower inflammation and activation by bacterial components, from the resolution of tissue injury, and from lower local gut inflammation following treatment. Lastly, when intersecting these DEGs with UC-associated DEGs reported in 3 independent studies^2,3, 16-21% of intersecting DEGs showed fold changes in opposite polarity to UC vs. healthy individuals whereas 0-3% showed similar fold changes.

Conclusion

These observations suggest that MH002-treated patients had positive changes in gut microbial diversity and overall microbiome composition, coinciding with clinical improvement and downregulation of genes involved in immune and inflammatory responses, antimicrobial defense mechanisms, and resulting in dampening of immune cells’ activity, and associated with UC. MH002, therefore, represents a promising new treatment for mild-to-moderate UC patients insufficiently controlled with 5‑ASA. These results warrant further development in a phase 2/3 study.

References

1) Vermeire et al. JCC 2024 (S1)
2) Lloyd-Price et al. Nature 2019
3) Haberman et al. Nat Commun 2019

Disclosure

SB, MD, MdL, IP, KC, SP & LH: employee, paid consultant and/or shareholder of MRM Health
SV: financial support for research from AbbVie, J&J, Pfizer, Takeda and Galapagos; speakers’ and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MRM Health, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance, Tillots Pharma AG, VectivBio, Ventyx, Zealand Pharma