Cited by 306Gut microbiota and healthT-cell and B-cell ImmunologyDrug Transport and Resistance Mechanisms

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

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Li, Wei, Hang, Saiyu, Fang, Yuan, Bae, Sena, Zhang, Yancong, Zhang, Minghao, Wang, Gang, McCurry, Megan D., Bae, Munhyung, Paik, Donggi, Franzosa, Eric A., Rastinejad, Fraydoon, Huttenhower, Curtis, Yao, Lina, Devlin, A. Sloan, Huh, Jun R.·2021·Cell Host & Microbe

DOI 10.1016/j.chom.2021.07.013PMC PMC9064000

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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.

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Authors: Li, W., Hang, S., Fang, Y., Bae, S., Zhang, Y., Zhang, M., Wang, G., McCurry, M. D., Bae, M., Paik, D., Franzosa, E. A., Rastinejad, F., Huttenhower, C., Yao, L., Devlin, A. S., & Huh, J. R.
Affiliations: Harvard University (US)
Broad Institute (US)
University of Oxford (GB)
Brigham and Women's Hospital (US)
Corresponding author: Yao, Lina
Devlin, A. Sloan
Huh, Jun R.
ORCID: Li, Wei
Hang, Saiyu
Fang, Yuan
Zhang, Yancong
Wang, Gang
McCurry, Megan D.
Bae, Munhyung
Paik, Donggi
Franzosa, Eric A.
Rastinejad, Fraydoon
Huttenhower, Curtis
Devlin, A. Sloan
Huh, Jun R.
Venue: Cell Host & Microbe
Publisher: Elsevier BV
Published: 2021-09
Volume: 29
Issue: 9
Pages: 1366-1377.e9
ISSN: 1931-3128 (ISSN-L)
DOI: 10.1016/j.chom.2021.07.013
PMC: PMC9064000
OpenAlex: W3193797930
Cited by: 306
References: 81
Citations by year: 2026: 70 · 2025: 74 · 2024: 68 · 2023: 40 · 2022: 48 · 2021: 6
FWCI: 12.70
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 373 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell Host & Microbe (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (R01 DK110559, MIRA R35 GM128618)
Harvard Medical School
Seres Therapeutics
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: bile acid metabolites, regulatory T cells, Foxp3, Nur77, nuclear receptors, gut microbiota, Bacteroidetes, inflammatory bowel disease, immune homeostasis, CD4+ T cell differentiation, chromatin structure
MeSH terms: Bile Acids and Salts, Cell Differentiation, Chromatin, Multigene Family, Humans, Phenanthrenes, Promoter Regions, Genetic, Inflammatory Bowel Diseases, Signal Transduction, T-Lymphocyte Subsets, Bacteroidetes, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Nuclear Receptor Subfamily 4, Group A, Member 1

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

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