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Reciprocal interactions between metabolism and immunity

Intestinal microbial communities play a key role in mammalian physiology. Yet, the microbiome stands out as a formidable challenge to the immune system: How can we host trillions of bacteria without mounting an inflammatory response? Commensal microbes shape T cell differentiation into multiple specialized subsets, including immunosuppressive regulatory T (Treg) cells. Peripherally generated Treg (pTreg) cells induced during microbial colonization restrain innate and adaptive immune responses against commensals, preserve intestinal health, and maintain a niche for bacteria living close to the epithelium. The signals and mechanisms mediating pTreg cell differentiation in response to microbial colonization are not yet fully understood. Host genetics and environmental factors impact the composition of the microbiota, suggesting that immunoregulatory cues likely arise from ubiquitously present molecules. We discovered that the microbial metabolites secondary bile acids and short-chain fatty acids facilitate the differentiation of pTreg cells via distinct, non-overlapping mechanisms. In addition, we found that changes in secondary bile acids and in bile acid-sensing pathways during inflammation shape effector T cell responses. Our findings suggest that bacterial metabolites are key molecules governing T cell biology at the steady state and during immune responses, further supporting the notion that T cells and gut microbes partake in intimate reciprocal interactions.