Presented by: Eunyoung Chun
Gut microbial metabolites such as short-chain fatty acids (SCFAs) are increasingly recognized for shaping gut homeostasis and intestinal immunity. These metabolites directly activate a subset of G-protein-coupled receptors (GPCRs), termed the metabolite-sensing GPCRs. Engagement of GPCRs by microbial metabolites influences mucosal homeostasis and epithelial barrier integrity that are driven by interactions between mucosal immune cells, epithelial cell subsets, and the microbiota. Group 3 innate lymphoid cells (ILC3s) are critical innate sentinels that orchestrate mucosal homeostasis and host defense. ILC3s are highly enriched in the gut and sense a multitude of environmental signals derived from microbiota, diet, or host nervous and circadian systems. Diet-derived or host-derived signal that regulates ILC3s have been identified, yet, how microbial metabolites affect ILC3 expansion and function remain unknown.
In this study, we show that colonic ILC3s sense SCFAs via a metabolite-sensing GPCR, Ffar2 (GPR43). Ffar2 agonism by acetate and propionate selectively promotes ILC3 proliferation and IL-22 production which is essential for intestinal barrier immunity. Indeed, Ffar2-deficient ILC3s dampen the epithelial barrier through decreased antimicrobial peptide and mucin production and consequently, increase susceptibility to colonic inflammation and enteric bacterial infection. Mechanistically, Ffar2 regulates ILC3-derived IL-22 production through activation of AKT and STAT3 or partially ERK and STAT3 signal pathways.
Collectively, our findings shed light on how diet and microbiota control gut homeostasis and mucosal immunity via regulating ILC3 biology and open up the new therapeutic possibilities of metabolite-sensing receptors for the treatment of intestinal diseases such as inflammatory bowel diseases.
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