Preview Cell Metabolism, deadline February 7th, 2020 Title Microbiome modulation of host's adaptive immunity through bile acid modification

International audienceThe microbiome is well-known to influence the immune response of the host. Song et al. now show that the microbiome modulates adaptive immunity in mice through formation of bile acid species acting on RORγ + regulatory T cells via the Vitamin D Receptor, thereby lowering the vulnerability for chemically-induced colitis Text The intestinal tract is populated by a diverse, dynamic and metabolically-active microbial flora, the microbiome. It is well-established that an imbalanced microbiome ("dysbiosis") contributes to onset and progression of diseases of the host, including cardiovascular disorders and inflammatory bowel disease (IBD), i.e., disorders associated with inflammation. Indeed, the microbiome modulates the immune system of the host through complex interactions in which metabolites produced by bacteria signal to intestinal epithelial cells and immune cells. A broad spectrum of metabolites is formed from diet components, such as short-chain fatty acids (SCFA), synthesized directly by bacteria, or produced by the host and modified by bacteria 1. Secondary bile acids (BA) belong to the last group. BA are increasingly recognized as important signaling molecules impacting on glucose, lipid and energy metabolism. BA exert these actions through activation of membrane-bound (G protein-coupled BA receptor 1 (GPBAR1/TGR5)) and nuclear receptors (Farnesoid-X-Receptor (FXR) and Vitamin D Receptor (VDR)) 2. BA activation of TGR5, FXR and VDR has been implicated in shaping innate immune responses 3. Song et al. 4 now report a role of BA and VDR in the adaptive immune system, particularly in the modulation of a specific population of FOXP3 + regulatory T (T reg) cells expressing the transcription factor RORγ (RORγ + T reg) that are present in the colonic lamina propria. The circulating BA pool consists of a mixture of primary and secondary BA with varying physico-chemical characteristics and signaling functions 2. Primary BA are synthesized from cholesterol in the liver and conjugated to either taurine of glycine prior to secretion into bile. After a meal, BA are expelled into the small intestine to facilitate fat absorption. BA are efficiently maintained within the enterohepatic circulation by ileal and hepatic transporter systems. A small fraction of BA escapes ileal absorption and enters the colon to interact with the microbiome. Bacteria alter BA in a sequential process that is initiated by deconjugation and followed by epimerization, dehydroxylation and/or oxidation of-OH groups, generating secondary BA. A part of these modified BA is reabsorbed from the colon, enabling them to exert signaling functions in the host. In general, more hydrophobi