Gut-derived glucagon-like peptides attenuate T cell-induced intestinal injury

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are produced in enteroendocrine L cells and control energy homeostasis. GLP-1 receptor (GLP-1R) activation improves glucose homeostasis and induces satiety and weight loss, whereas GLP-2 receptor (GLP-2R) signaling promotes intestinal growth and nutrient absorption. GLP-1R and GLP-2R agonism also reduce intestinal damage in preclinical studies. Here, we demonstrate that endogenous GLP-1R and GLP-2R signaling are essential for protecting the intestine from T cell-mediated enteropathy. Gut injury induced by T cell activation is increased in Glp1r^-/- and Glp2r^-/- mice, as well as in mice with selective loss of intestinal proglucagon gene expression (Gcg^Gut-/-). Conversely, the GLP-2R agonist teduglutide and the GLP-1R agonist semaglutide, administered separately or together, attenuate αCD3-induced intestinal damage in Gcg^Gut-/- mice. Collectively, these findings demonstrate distinct biological roles for endogenous GLP-1R/GLP-2R activity in immune-mediated intestinal injury and highlight the therapeutic potential of glucagon-like peptides, alone or together, for ameliorating T cell-mediated mucosal injury.