The free fatty acid receptor GPR164 maintains intestinal homeostasis and barrier function

GPR164 is a free fatty acid receptor, activated by both short-chain fatty acids and medium-chain fatty acids, and expressed throughout the gastrointestinal tract. Although GPR164 is reported to be involved in the release of gut hormones, the physiological functions of this receptor in the maintenance of intestinal homeostasis remain unclear. In this study, we explore the role of GPR164 in regulating intestinal barrier function using mice lacking Gpr164 gene (Gpr164^-/-). A loss-of-function mutation in Gpr164 promotes cell proliferation and disrupts the intestinal barrier function in both Caco-2 cells and mice. Genome-wide RNA-seq analysis reveals that Gpr164 deletion causes aberrant Wnt/β-catenin signaling, and the intraperitoneal injection of the Wnt/β-catenin inhibitor PNU-74654 ameliorates intestinal hyperproliferation, differentiation and barrier permeability phenotypes of Gpr164^-/- mice. Gpr164^-/- mice also exhibit gut microbial dysbiosis and inflammation. Thus, our findings uncover the pivotal role of GPR164 in the maintenance of intestinal homeostasis through regulating barrier function.