Investigation of the stool microbiome of short bowel syndrome patients before and after a 24-week treatment with the glucagon-like peptide 2 analog glepaglutide

BACKGROUND AND AIMS: Glepaglutide is a long-acting glucagon-like peptide 2 (GLP-2) analog under development for the treatment of short bowel syndrome (SBS). Glepaglutide enhances intestinal absorption, which may hypothetically lead to changes in the intestinal microbiota, mainly by slowing gastrointestinal transit time. This study evaluated whether glepaglutide affects bacterial load and composition of the intestinal microbiota in SBS patients enrolled in a phase 3b trial assessing its 24-week efficacy on intestinal wet weight and energy absorption. METHODS: In this single-center, open-label, EASE SBS-4 phase 3b study, 10 patients with SBS (8 of the 10 with intestinal failure and 8 of the 10 without colon-in-continuity) were treated with glepaglutide 10 mg by subcutaneous injection once weekly for 24 weeks. While the primary trial findings demonstrated increased intestinal wet weight and energy absorption assessed by metabolic balance studies, this study investigated whether these adaptations were associated with changes in bacterial load and composition of the intestinal microbiota. Samples were obtained from either stool or ostomy effluent at baseline and after 24 weeks of treatment with glepaglutide. Bacterial load was quantified using a spike-in approach, and microbiota composition was assessed by V3V4 16S rRNA gene sequencing. RESULTS: cells per gram feces. Microbiota composition also differed markedly by intestinal anatomy: patients without a colon-in-continuity had higher abundances of genera mainly associated with the upper gastrointestinal tract, such as Streptococcus, while those with a colon-in-continuity exhibited greater abundance of genera more commonly found in the lower gastrointestinal tract, including Bifidobacterium. CONCLUSIONS: Treatment with the GLP-2 analog glepaglutide increased intestinal wet weight and energy absorption without altering the intestinal bacterial microbiota in the majority of the SBS patients participating in this study. Differences in bacterial load and composition were influenced by intestinal anatomy. CLINICALTRIALS: gov no: NCT04991311; ClincalTrialsRegister.eu EudraCT no: 2020-005194-27.