Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis

• Published in: Nature (London) Vol. 577; no. 7790; pp. 410 - 415
• Main Authors: Song, Xinyang, Sun, Ximei, Oh, Sungwhan F., Wu, Meng, Zhang, Yanbo, Zheng, Wen, Geva-Zatorsky, Naama, Jupp, Ray, Mathis, Diane, Benoist, Christophe, Kasper, Dennis L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.01.2020; Nature Publishing Group
• Subjects: 13/31; 38; 38/22; 38/23; 38/39; 38/61; 38/77; 38/90; 38/91; 45/41; 45/44; 631/250/347; 631/326/2565/547; 64; 64/60; Adaptive systems; Animals; Bacteria; Bile; Bile acids; Bile Acids and Salts - chemistry; Bile Acids and Salts - metabolism; Chemical synthesis; Cholesterol; Colitis; Colon; Diet; Digestive system; Duodenum; Energy balance; Energy metabolism; Foxp3 protein; G protein-coupled receptors; Gastrointestinal Microbiome; Gastrointestinal tract; Genomics; Hepatocytes; Homeostasis; Hormones; Humanities and Social Sciences; Immune system; Immunology; Inflammation; Innate immunity; Intestinal microflora; Intestine; Intestines - immunology; Intestines - microbiology; Lipid metabolism; Lipids; Lymphatic system; Lymphocytes; Lymphocytes T; Metabolic pathways; Metabolism; Metabolites; Mice, Inbred C57BL; Microbiomes; Microbiota; Microorganisms; multidisciplinary; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology; Nuclear receptors; Population; Receptors; Restoration; Science; Science (multidisciplinary); Small intestine; Spleen; Symbionts; T-Lymphocytes, Regulatory - immunology; Transcription factors; Vitamins
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1865-0

The metabolic pathways encoded by the human gut microbiome constantly interact with host gene products through numerous bioactive molecules 1 . Primary bile acids (BAs) are synthesized within hepatocytes and released into the duodenum to facilitate absorption of lipids or fat-soluble vitamins 2 . Some BAs (approximately 5%) escape into the colon, where gut commensal bacteria convert them into various intestinal BAs 2 that are important hormones that regulate host cholesterol metabolism and energy balance via several nuclear receptors and/or G-protein-coupled receptors 3 , 4 . These receptors have pivotal roles in shaping host innate immune responses 1 , 5 . However, the effect of this host–microorganism 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 (T reg ) cells expressing the transcription factor RORγ. Genetic abolition of BA metabolic pathways in individual gut symbionts significantly decreases this T reg cell population. Restoration of the intestinal BA pool increases colonic RORγ +  T reg cell counts 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 immunological homeostasis via the resulting metabolites. Both dietary and microbial factors influence the composition of the gut bile acid pool, which in turn modulates the frequencies and functionalities of RORγ-expressing colonic FOXP3 + regulatory T cells, contributing to protection from inflammatory colitis.