Metabolite - sensing receptor Ffar2 regulates colonic group 3 innate lymphoid cells and gut immunity

Group 3 innate lymphoid cells (ILC3s) sense environmental signals that are critical for gut homeostasis and host defense. However, the metabolite-sensing G-protein-coupled receptors that regulate colonic ILC3s remain poorly understood. We found that colonic ILC3s expressed Ffar2, a microbial metabolite-sensing receptor, and that Ffar2 agonism promoted ILC3 expansion and function. Deletion of Ffar2 in ILC3s decreased their in situ proliferation and ILC3-derived IL-22 production, led to impaired gut epithelial function: altering mucus-associated proteins and antimicrobial peptides and increased susceptibility to colonic injury and bacterial infection. Ffar2 agonism influenced a CCR6+ ILC3 subset and enhanced ILC3 recruitment to colonic lymphoid tissues. Ffar2 agonism activated AKT signaling and increased ILC3-derived IL-22 via an AKT and STAT3 axis. Our findings demonstrate that Ffar2 regulates colonic ILC3 proliferation and function in a cell-intrinsic manner and identifies an ILC3-receptor signaling pathway regulating gut inflammatory tone and pathogen defense.