Microbial Bile Acid Metabolites Modulate Gut RORγ+ Regulatory T Cell Homeostasis

Abstract

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules1. Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins2. Some BAs (~5%) escape into the colon, where gut commensal bacteria convert them into a variety of intestinal BAs2 that are important hormones regulating host cholesterol metabolism and energy balance via several nuclear receptors and/or G protein–coupled receptors3,4. These receptors play pivotal roles in shaping host innate immune responses1,5. 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+ regulatory T cells (Tregs) expressing the transcriptional factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this Treg population. Restoration of the intestinal BA pool increases colonic RORγ+ Treg levels and ameliorates host susceptibility to inflammatory colitis via BA nuclear receptors. Thus, a pan-genomic biliary network interaction between hosts and their bacterial symbionts can control host immunologic homeostasis via the resulting metabolites.