GLP-1 secretion by colonic enteroendocrine cells is stimulated by microbiota-derived succinate through SUCNR1 in male mice

GLP-1 is a key regulator of postprandial glucose metabolism, and its secretion is controlled by nutrient- and microbiota-derived signals. Here, we investigated the role of succinate, a bacterial fermentation product, in regulating GLP-1 secretion through its receptor SUCNR1. Postprandial luminal succinate from intestinal contents increased in a microbiota-dependent manner and enhanced colonic GLP-1 secretion via SUCNR1. In vitro and ex vivo studies confirmed Sucnr1 expression in colonic L-cells and demonstrated that SUCNR1 activation directly stimulates GLP-1 secretion through Gq- and Gs-dependent pathways. Inducible deletion of Sucnr1 in the intestinal epithelium impaired succinate-induced and postprandial GLP-1 secretion, establishing epithelial SUCNR1 as a requirement for this response. Germline Sucnr1 deficiency was additionally associated with intestinal remodeling and inflammation. In diet-induced obese mice, the succinate/SUCNR1 axis was attenuated, with a blunted postprandial rise in intestinal succinate and reduced secretory responsiveness despite preserved receptor expression. In humans, circulating succinate correlated positively with GLP-1 under fasting and fed conditions, supporting the potential translational relevance of this regulatory axis.