Semaglutide Drives Regional Re-Modeling of the Intestinal Stem Cell Niche

Abstract BACKGROUND An impaired intestinal stem cell (ISC) niche is a key feature of inflammatory bowel disease (IBD) and is associated with reduced tissue healing. Semaglutide is a GLP-1R agonist commonly prescribed for weight loss and diabetes that has effects on intestinal function; however, it’s impact on intestinal epithelial composition and the ISC niche is poorly understood. Here, we tested the role of semaglutide in driving regional changes in epithelial cell and ISC populations along the length of the intestinal tract in high fat diet-fed obese mice. METHODS C57Bl/6J mice were fed a high fat diet for 7 weeks to induce obesity and treated with or without semaglutide for 3 weeks (dose escalation to 50 μg/kg) prior to collection. Regional segments of small (duodenum, jejunum, ileum) and large intestine (proximal, middle, and distal) were collected for gene expression analysis. RNA sequencing was performed on some tissues to identify candidate genes for targeted analysis by qPCR. RESULTS Semaglutide induced regional-specific expression of ISC niche markers exclusively in the terminal regions of the small and large intestine. The crypt base stem and progenitor cell marker, Lrig1, was elevated in the ileum (3-fold; p 0.01) whereas Lgr5, a marker of cycling stem cells, was elevated in distal colon (1.5-fold; p 0.05). Bmi1, a marker of quiescent stem cells, was elevated in both the ileum (20-fold; p 0.01) and distal colon (1.5-fold, p 0.05). Analysis of mature epithelial cell lineage markers suggested cell fate changes along the secretory lineage in the ileum. Single cell transcriptomic analysis of colon showed that epithelial expression of the GLP-1 receptor, Glp1r, is largely restricted to enteroendocrine cells and a population of progenitor cells marked by Plet1, suggesting a potential role for semaglutide in directly regulating the epithelium. CONCLUSION Our data support a role for GLP-1R agonism in re-enforcing intestinal stem cell populations and shifting secretory cell allocation in obesity; an effect largely restricted to terminal small and large intestine. GLP-1R driven re-enforcement of the ISC niche, either through direct action on the epithelium or indirectly through non-epithelial feedback mechanisms, could potentially support protective skewing of secretory cell populations and improved tissue healing in intestinal injury and disease (e.g., IBD).