Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells

• Published in: Nature (London) Vol. 581; no. 7809; pp. 475 - 479
• Main Authors: Campbell, Clarissa, McKenney, Peter T., Konstantinovsky, Daniel, Isaeva, Olga I., Schizas, Michail, Verter, Jacob, Mai, Cheryl, Jin, Wen-Bing, Guo, Chun-Jun, Violante, Sara, Ramos, Ruben J., Cross, Justin R., Kadaveru, Krishna, Hambor, John, Rudensky, Alexander Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2020; Nature Publishing Group
• Subjects: 38/91; 631/250/347; 631/326/2565/2134; 82/58; Ablation; Acids; Amino Acid Sequence; Anaerobic bacteria; Analysis; Animals; Antigens; Bacteria; Bacteria - metabolism; Bacteroides - metabolism; Bile; Bile acid metabolism; Bile acids; Bile Acids and Salts - chemistry; Bile Acids and Salts - metabolism; Biological activity; CD4 antigen; Cell differentiation; Cell growth; Chemical properties; Colon - microbiology; Conserved sequence; Consortia; Cytokines; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Differentiation; Female; Fermentation; Foxp3 protein; Gastrointestinal Microbiome; Humanities and Social Sciences; Immune system; Immunoregulation; Immunostimulation; Immunosuppressive agents; In vivo methods and tests; Influence; Intestine; Kinases; Lymphocytes; Lymphocytes T; Male; Mammals; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Microbial Consortia; Microorganisms; multidisciplinary; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Oxidation; Physiology; Receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Science; Science (multidisciplinary); T cell proliferation; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; Tumor necrosis factor-TNF; United States
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-2193-0

Intestinal health relies on the immunosuppressive activity of CD4 + regulatory T (T reg ) cells 1 . Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1) 2 – 4 . Products of microbial fermentation including butyrate facilitate the generation of peripherally induced T reg (pT reg ) cells 5 – 7 , indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids 8 with a range of physiological functions 9 . Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pT reg cells. We found that the secondary bile acid 3β-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of T reg cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing T reg cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation. The secondary bile acid 3β-hydroxy-deoxycholic (isodeoxycholic) acid, produced by gut bacteria, promotes the generation of colonic extrathymic regulatory T cells, whose immunosuppressive activities are known to be essential for intestinal health.