A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1

Wei Li; Saiyu Hang; Yuan Fang; Sena Bae; Yancong Zhang; Minghao Zhang; Gang Wang; Megan D McCurry; Munhyung Bae; Donggi Paik; Eric A Franzosa; Fraydoon Rastinejad; Curtis Huttenhower; Lina Yao; A Sloan Devlin; Jun R Huh

doi:10.1016/j.chom.2021.07.013

A bacterial bile acid metabolite modulates T_reg activity through the nuclear hormone receptor NR4A1

Cell Host Microbe. 2021 Sep 8;29(9):1366-1377.e9. doi: 10.1016/j.chom.2021.07.013. Epub 2021 Aug 19.

Authors

Wei Li¹, Saiyu Hang², Yuan Fang³, Sena Bae⁴, Yancong Zhang⁵, Minghao Zhang⁶, Gang Wang², Megan D McCurry¹, Munhyung Bae¹, Donggi Paik², Eric A Franzosa⁷, Fraydoon Rastinejad⁶, Curtis Huttenhower⁸, Lina Yao⁹, A Sloan Devlin¹⁰, Jun R Huh¹¹

Affiliations

¹ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
² Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
⁴ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
⁵ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁷ Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: lina_yao@hms.harvard.edu.
¹⁰ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: sloan_devlin@hms.harvard.edu.
¹¹ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: jun_huh@hms.harvard.edu.

Abstract

Bile acids act as signaling molecules that regulate immune homeostasis, including the differentiation of CD4⁺ T cells into distinct T cell subsets. The bile acid metabolite isoallolithocholic acid (isoalloLCA) enhances the differentiation of anti-inflammatory regulatory T cells (T_reg cells) by facilitating the formation of a permissive chromatin structure in the promoter region of the transcription factor forkhead box P3 (Foxp3). Here, we identify gut bacteria that synthesize isoalloLCA from 3-oxolithocholic acid and uncover a gene cluster responsible for the conversion in members of the abundant human gut bacterial phylum Bacteroidetes. We also show that the nuclear hormone receptor NR4A1 is required for the effect of isoalloLCA on T_reg cells. Moreover, the levels of isoalloLCA and its biosynthetic genes are significantly reduced in patients with inflammatory bowel diseases, suggesting that isoalloLCA and its bacterial producers may play a critical role in maintaining immune homeostasis in humans.

Keywords: T cells; bile acids; human microbiome; inflammatory bowel disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Bacteroidetes / metabolism*
Bile Acids and Salts / metabolism*
Cell Differentiation / physiology
Chromatin / metabolism
Forkhead Transcription Factors / genetics
Humans
Inflammatory Bowel Diseases / pathology
Multigene Family / genetics
Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
Phenanthrenes / metabolism*
Promoter Regions, Genetic / genetics
Signal Transduction / physiology
T-Lymphocyte Subsets / cytology
T-Lymphocyte Subsets / immunology
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology*

Substances

Bile Acids and Salts
Chromatin
FOXP3 protein, human
Forkhead Transcription Factors
NR4A1 protein, human
Nuclear Receptor Subfamily 4, Group A, Member 1
Phenanthrenes
isoallolithocholic acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding