LAUSR

BACKGROUND & AIMS G protein-coupled receptor (GPR) 120 has been implicated in regulating metabolic syndromes with anti-inflammatory function. However, the role of GPR120 in intestinal inflammation is unknown. Here, we investigated whether and how GPR120 regulates CD4+T cell function to inhibit colitis development. METHODS Dextran sodium sulfate (DSS)-induced colitis model, Citrobacter rodentium infection model, and CD4+T cell adoptive transfer model were utilized to analyze the role of GPR120 in regulating colitis development. The effect of GPR120 on CD4+T cell functions was analyzed by RNA sequencing, flow cytometry, and Seahorse metabolic assays. Mice were administered GPR120 agonist for investigating the potential of GPR120 agonist in preventing and treating colitis. RESULTS Deficiency of GPR120 in CD4+T cells resulted in more severe colitis in mice upon DSS insult and enteric infection. Transfer of GPR120-deficient CD4+CD45RbhiT cells induced more severe colitis in Rag-/- mice with lower intestinal IL-10+CD4+T cells. Treatment with GPR120 agonist, CpdA, promoted CD4+T cell production of IL-10 by upregulating Blimp1 and enhancing glycolysis, which was regulated by mTOR. GPR120 agonist-treated wild-type but not IL-10-deficient and Blimp1-deficient Th1 cells induced less severe colitis. Furthermore, oral administration of GPR120 agonist protected mice from intestinal inflammation in both prevention and treatment schemes. Gpr120 expression was positively correlated with Il10 expression in the human colonic mucosa, including patients with inflammatory bowel diseases (IBD). CONCLUSIONS Our findings demonstrate the role of GPR120 in regulating intestinal CD4+T cell production of IL-10 to inhibit colitis development, which identifies GPR120 as a potential therapeutic target for treating IBD.