Microbial bile acid metabolites modulate gut RORγ+ Treg cell homeostasis

The human gut microbiome encompasses the collection of microbial genomes in the intestines. The metabolic pathways encoded by this allied gene pool constantly interact with host gene products through numerous bioactive molecules. Primary bile acids (BAs) are synthesized within hepatocytes through cholesterol catabolism, and—in response to dietary stimuli—released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins. A small portion of BAs (~5%) escape into the colon where gut commensal bacteria convert them into a variety of intestinal BAs which are considered important hormones regulating host cholesterol metabolism and energy balance via several nuclear receptors or G protein–coupled receptors. These receptors have been shown to play pivotal roles in shaping host innate immune responses. However, the impact of this host–microbe biliary network on the adaptive immune system remains poorly characterized. Here we report that both dietary and microbial factors influence the composition of the gut BA pool and modulate an important population of colonic Foxp3+ Tregs expressing the transcriptional factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this Treg population. Microbial BA metabolites modulate colonic RORγ Tregs and gut inflammation via BA nuclear receptors. Restoration of intestinal BA pool increases colonic RORγ Treg levels and ameliorates host susceptibility to inflammatory colitis. Thus, a pan-genomic interaction in the biliary network between hosts and their bacterial symbionts can control host immunologic homeostasis via the resulting metabolites.