Introduction

Management of short bowel syndrome (SBS) patients with intestinal failure (IF) is multidisciplinary and multifactorial. The goal of treatment is to enhance oral/enteral nutrition as early as possible in a safe and well-tolerated manner. This can be achieved by increasing intestinal absorptive capacity to reduce parenteral support (PS) and in some patients avoid the need for central lines after achieving enteral autonomy. Glepaglutide is a novel long-acting GLP-2 analog in an aqueous formulation developed for subcutaneous (SC) weekly administration.

Aims & Methods

The aim of EASE (Efficacy and Safety Evaluation) SBS-1 trial was to assess the efficacy and safety of glepaglutide in reducing PS in SBS patients with IF. The design was a 29-center, placebo-controlled, randomized, parallel-group, double-blind, 24-week phase 3 trial. Adult SBS patients with chronic IF and requiring PS at least 3 days per week were eligible. Patients were randomized to SC injections of either 10 mg glepaglutide twice-weekly (TW), 10 mg glepaglutide once-weekly (OW), or placebo. PS volume requirements were adjusted using a predefined algorithm. Primary endpoint was change in PS volume from baseline to week 24 and two of key secondary endpoints were change in PS volume from baseline to week 12 and achieving enteral autonomy (complete weaning-off PS) at week 24.

Results

106 optimized stable patients were randomized and 96% completed the trial. Treatment arms were well balanced and as expected for demographics: mean age of 55 years and 57% were women. Similarly balanced for baseline characteristics: 51% with colon-in-continuity (CiC), mean PS volume requirement of 14.4 L/week; 33% and 58% of patients with mild to moderate hepatic and renal impairment, respectively. Glepaglutide TW treatment significantly reduced PS vs placebo (mean change of -5.13 vs -2.85 L/week; estimated difference of -2.28 L/week; p=0.0039) at 24 weeks. Significant reduction in PS with glepaglutide TW was observed by week 12 with mean change of -4.32 vs -1.90 L/week; estimated difference of -2.42 L/week; p=0.0019). These findings were preserved in both anatomical subgroups: patients without and with CiC. No statistically significant reduction in PS was observed with glepaglutide OW vs placebo at week 12 or 24. Enteral autonomy was achieved for 5 (14%) patients receiving glepaglutide TW and 4 (11%) patients receiving glepaglutide OW vs 0 patients receiving placebo. In a post-hoc analysis, circulating levels of citrulline, a marker for intestinal mucosal cell mass, increased and were sustained from baseline to week 4 and 24 with a ratio of 1.49 (p<0.0001) and 1.41 (p=0.0101) in glepaglutide TW treatment arm vs placebo, respectively. Treatment with glepaglutide was assessed to be safe with more adverse events reported in glepaglutide treatment arms vs placebo, primarily attributable to mild injection site reactions.

Conclusion

Treating SBS patients with chronic IF with glepaglutide was assessed to be safe, well tolerated and resulted in early (by 12 weeks of treatment) sustained reductions in PS needs including the achievement of enteral autonomy in a meaningful number of patients within 24 weeks. Data supports glepaglutide as a novel medical treatment option for the management of SBS patients that results in early and significant reductions in PS support.

Disclosure

Nothing to disclose

Introduction

Irritable Bowel Syndrome (IBS) is a prevalent and chronic gastrointestinal disorder that affects approximately 85 million Europeans. It predominantly impacts women and significantly impairs quality of life, presenting with recurrent abdominal pain and altered bowel habits in the absence of identifiable structural abnormalities. Beyond its gastrointestinal symptoms, IBS frequently co-occurs with mental and somatic conditions such as anxiety, depression, fibromyalgia (32.5%), and chronic fatigue syndrome (14%). Up to 60% of IBS patients experience mental comorbidities, highlighting the complex interplay between gut and brain—often referred to as dysregulation of the gut–brain axis. This dysregulation manifests in altered intestinal motility, increased gut permeability, visceral hypersensitivity, and significant shifts in gut microbiota composition.

Aims & Methods

We present the DISCOVERIE project (Development, dIagnostic and prevention of gender-related Somatic and mental COmorbitiEs in iRritable bowel syndrome In Europe), an international, multi-centre initiative aimed at characterizing IBS and its associated comorbidities, with a particular focus on sex- and gender-related differences. To this end, we generated a comprehensive multi-omics dataset from 743 individuals, including shotgun quantitative microbiome profiling and untargeted metabolomics. These molecular data were complemented by in-depth clinical phenotyping, capturing information on anxiety, depression, fibromyalgia, and chronic fatigue syndrome. Particular attention was given to age, sex/gender, lifestyle factors, and systemic inflammatory markers. Multivariate statistical models were applied, correcting for common microbiome confounders, to analyze the multi-omics layers and identify microbiome-related signatures and mechanistic links across IBS and its comorbid subgroups.

Results

Our microbiome analysis revealed that IBS subjects exhibit features of a dysbiotic bacterial community, characterized by an increased prevalence of the Bacteroides 2 enterotype (17–26% in IBS participants across comorbid groups vs. 17% in the general population and only 2% in the healthy control group; chi-squared test, FDR < 0.05), a reduced butyrate synthesis capacity, and increased levels of opportunistic taxa compared to non-IBS controls.
Interestingly, IBS individuals—regardless of comorbidities—showed enrichment of bacterial metabolic modules involved in the degradation of amino acids that serve as precursors for neurotransmitters. Specifically, we observed an increase in pathways associated with GABA degradation and a decrease in modules responsible for glutamate biosynthesis. This dysregulation of gut neurotransmitter metabolism may contribute to hallmark IBS symptoms.
Strikingly, pro-inflammatory IL-6 levels were strongly associated with specific bacterial genus (FDR < 0.05), as well as with a metabolic module responsible for the degradation of gamma-hydroxybutyric acid (GHB), a neurotransmitter and central nervous system depressant, suggesting a potential mechanistic link between low-grade inflammation and depressive symptoms in IBS.

Conclusion

The results from this large-scale, multi-center international study reveal a dysregulation of gut neurotransmitter metabolism that may contribute to IBS symptoms and associated comorbidities. These findings underscore a potential link between elevated IL-6 levels, microbial metabolism, and the gut–brain axis, offering new insights into the complex interplay between microbiota composition, host physiology, and IBS-related comorbidities.