2. Academic Validation
  3. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells

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

  • Nature. 2020 May;581(7809):475-479. doi: 10.1038/s41586-020-2193-0.
Clarissa Campbell # 1,  Peter T McKenney # 2 3,  Daniel Konstantinovsky 4,  Olga I Isaeva 5 6,  Michail Schizas 2,  Jacob Verter 2,  Cheryl Mai 7,  Wen-Bing Jin 8,  Chun-Jun Guo 8,  Sara Violante 9,  Ruben J Ramos 9,  Justin R Cross 9,  Krishna Kadaveru 3,  John Hambor 3,  Alexander Y Rudensky 10 11 12 13
Affiliations

Affiliations

  • 1 Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. campbec2@mskcc.org.
  • 2 Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 SHINE Program, Research Beyond Borders, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
  • 4 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  • 5 Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia.
  • 6 BostonGene LLC, Lincoln, MA, USA.
  • 7 Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.
  • 8 Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College, Cornell University, New York, NY, USA.
  • 9 Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10 Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rudenska@mskcc.org.
  • 11 BostonGene LLC, Lincoln, MA, USA. rudenska@mskcc.org.
  • 12 Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College, Cornell University, New York, NY, USA. rudenska@mskcc.org.
  • 13 Howard Hughes Medical Institute and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA. rudenska@mskcc.org.
  • # Contributed equally.
PMID: 32461639 DOI: 10.1038/s41586-020-2193-0
Abstract

Intestinal health relies on the immunosuppressive activity of CD4+ regulatory T (Treg) cells1. 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 Treg (pTreg) cells5-7, 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 Steroids8 with a range of physiological functions9. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pTreg 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 Treg 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 Treg cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.

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