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A bacterial bile acid metabolite modulates Treg activity through the nuclear hormone receptor NR4A1
Open accessPublished version of a preprint
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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“Because NUR77 was shown to be required for isoalloLCA–induced FOXP3 expression in CD4+ T cells (32),”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [32]
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Metadata
- 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
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2021-09
- Volume
- 29
- Issue
- 9
- Pages
- 1366-1377.e9
- ISSN
- 1931-3128 (ISSN-L)
- 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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