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Bile acid metabolites control TH17 and Treg cell differentiation
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Abstract
Bile acids are abundant in the mammalian gut, where they undergo bacteria-mediated transformation to generate a large pool of bioactive molecules. Although bile acids are known to affect host metabolism, cancer progression and innate immunity, it is unknown whether they affect adaptive immune cells such as T helper cells that express IL-17a (T H 17 cells) or regulatory T cells (T reg cells). Here we screen a library of bile acid metabolites and identify two distinct derivatives of lithocholic acid (LCA), 3-oxoLCA and isoalloLCA, as T cell regulators in mice. 3-OxoLCA inhibited the differentiation of T H 17 cells by directly binding to the key transcription factor retinoid-related orphan receptor-γt (RORγt) and isoalloLCA increased the differentiation of T reg cells through the production of mitochondrial reactive oxygen species (mitoROS), which led to increased expression of FOXP3. The isoalloLCA-mediated enhancement of T reg cell differentiation required an intronic Foxp3 enhancer, the conserved noncoding sequence (CNS) 3; this represents a mode of action distinct from that of previously identified metabolites that increase T reg cell differentiation, which require CNS1. The administration of 3-oxoLCA and isoalloLCA to mice reduced T H 17 cell differentiation and increased T reg cell differentiation, respectively, in the intestinal lamina propria. Our data suggest mechanisms through which bile acid metabolites control host immune responses, by directly modulating the balance of T H 17 and T reg cells.
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“Nevertheless, it is noteworthy that certain secondary BAs serve significant biological functions, including the regulation of host metabolism, immunity, and resistance against intestinal pathogen expansion.21,360–364”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [363]
In the citing paper
“On the other hand, certain secondary BAs exert anti-inflammatory effects by stimulating Treg cell differentiation and inhibiting TH17 cell differentiation.361,363,364,702,710”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [363]
In the citing paper
“Hence, in humans BACH2 might be an important regulator of homeostatic Th17 cells that could be exploited for the treatment of human autoimmune diseases.”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [60]
In the citing paper
“multiple single-nucleotide polymorphisms (SNPs) in the BACH2 locus are associated with human autoimmune diseases and a protective allele for MS disease correlates with an increase of BACH2 expression in CD4+ T cells”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [60]
In the citing paper
“by integrating single-cell ATAC-seq and single-cell RNA-seq, we generated a regulatory network across npTh17, pTh17, and Th1 cells”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [60]
In the citing paper
“Predicted regulators of the non-pathogenic- and general- Th17 program included RORγt, ETS1, BACH2, FOSL2, and RBPJ.”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [60]
In the citing paper
“The network predicted the pathogenic Th17- and Th1- program to be regulated by the transcription factors ATF3, BHLHE40, FOS, NR4A1, EOMES, and T-BET.”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [60]
In the citing paper
“We validated BACH2 as a novel regulator of Th17 pathogenicity that promoted immunomodulatory programs and restrained pro-inflammatory Th1-like programs in Th17 cells.”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [60]
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Wang, X., Weng, Y. Z., Geng, S., Wang, C., Jin, C., Shi, L., & Jin, Y. (2023) · Food and Chemical Toxicology · doi:10.1016/j.fct.2023.113657 · Cited by 20
Grosicki, G. J., Pugh, J. N., Wosinska, L., Quilter, K., Mattimoe, D., Allen, J. M., Joyce, S. A., O’Sullivan, Ó., & Close, G. L. (2023) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00024.2023 · Cited by 20
Gut microbiota regulate migration of lymphocytes from gut to lung
Ni, S., Yuan, X., Cao, Q., Chen, Y., Peng, X., Lin, J., Li, Y., Ma, W., Gao, S., & Chen, D. (2023) · Microbial Pathogenesis · doi:10.1016/j.micpath.2023.106311 · Cited by 24
Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy
Nenkov, M., Shi, Y. H., Ma, Y., Gaßler, N., & Chen, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010006 · Cited by 23
Hernández-Rocha, C., Borowski, K., Turpin, W., Filice, M., Nayeri, S., Garay, J. A. R., Stempak, J. M., & Silverberg, M. S. (2021) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjab096 · Cited by 20
Zhou, M., Liu, W., Zhang, J., & Sun, N. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.794754 · Cited by 18
Bile acid‐activated receptors in innate and adaptive immunity: targeted drugs and biological agents
Cheung, K. C. P., Ma, J., Loiola, R. A., Chen, X., & Jia, W. P. (2023) · European Journal of Immunology · doi:10.1002/eji.202250299 · Cited by 22
Systematic identification of secondary bile acid production genes in global microbiome
Yang, Y., Gao, W., Zhu, R., Tao, L., Chen, W., Zhu, X., Shen, M., Xu, T., Zhao, T., Zhang, X., et al. (2024) · mSystems · doi:10.1128/msystems.00817-24 · Cited by 22
From Microbes to Metabolites: Advances in Gut Microbiome Research in Type 1 Diabetes
Blok, L. C. H. M., Hanssen, N. M. J., Nieuwdorp, M., & Rampanelli, E. (2025) · Metabolites · doi:10.3390/metabo15020138 · Cited by 21
Interaction between gut microbiota and T cell immunity in colorectal cancer
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Liu, C., Yang, Y., Guo, S., Cao, Y., Wang, L., & Wu, C. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.07.033 · Cited by 23
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Bai, Y., Zhao, T., Gao, M. M., Zou, Y., & Lei, X. (2022) · Biochemistry · doi:10.1021/acs.biochem.2c00264 · Cited by 19
Zhang, H., Guan, W., Li, L., Guo, D., Zhang, X., Guan, J., Luo, R., Zheng, S., Fu, J., Cheng, Y., et al. (2022) · BMC Veterinary Research · doi:10.1186/s12917-022-03483-2 · Cited by 19
Akkermansia and its metabolites play key roles in the treatment of campylobacteriosis in mice
Jiang, L., Yuan, C., Ye, W., Huang, Q., Chen, Z., Wu, W., & Qian, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1061627 · Cited by 19
Interactions of Nanomaterials with Gut Microbiota and Their Applications in Cancer Therapy
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Metadata
- Authors
- Hang, S., Paik, D., Yao, L., Kim, E., Trinath, J., Lu, J., Ha, S., Nelson, B. N., Kelly, S. P., Wu, L., Zheng, Y., Longman, R. S., Rastinejad, F., Devlin, A. S., Krout, M. R., Fischbach, M. A., Littman, D. R., & Huh, J. R.
- Affiliations
- Harvard University (US)
- Birla Institute of Technology and Science - Hyderabad Campus (IN)
- Bucknell University (US)
- New York University (US)
- Salk Institute for Biological Studies (US)
- Weill Cornell Medicine (US)
- University of Oxford (GB)
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Fischbach, Michael A.
- Littman, Dan R.
- Huh, Jun R.
- ORCID
- Venue
- Nature
- Published
- 2019-11-27
- Volume
- 576
- Issue
- 7785
- Pages
- 143-148
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6949019
- OpenAlex
- W2990182987
- Cited by
- 1,457
- References
- 59
- Citations by year
- 2026: 274 · 2025: 287 · 2024: 260 · 2023: 207 · 2022: 174 · 2021: 158 · 2020: 94 · 2019: 3
- FWCI
- 43.07
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-02-25)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Wellcome Trust (210664/Z/18/Z)
- National Institute of Allergy and Infectious Diseases (R01AI107027, R01AI080885)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK103358, R01DK114252, R01DK110559, P30DK034854)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- bile acid metabolites, lithocholic acid, Th17 cell differentiation, regulatory T cells, RORγt, Foxp3, mitochondrial reactive oxygen species, gut microbiota, intestinal lamina propria, IL-17A, T cell regulation
- MeSH terms
- Animals, Cell Differentiation, Lithocholic Acid, Mice, Inbred C57BL, Reactive Oxygen Species, T-Lymphocytes, Regulatory, Mice, Forkhead Transcription Factors, Th17 Cells
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