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Human gut bacteria produce ΤΗ17-modulating bile acid metabolites

Author

Listed:
  • Donggi Paik

    (Harvard Medical School)

  • Lina Yao

    (Harvard Medical School)

  • Yancong Zhang

    (Broad Institute of MIT and Harvard
    Harvard T. H. Chan School of Public Health)

  • Sena Bae

    (Harvard T. H. Chan School of Public Health
    Harvard T. H. Chan School of Public Health)

  • Gabriel D. D’Agostino

    (Harvard Medical School)

  • Minghao Zhang

    (University of Oxford)

  • Eunha Kim

    (Harvard Medical School)

  • Eric A. Franzosa

    (Harvard T. H. Chan School of Public Health
    Harvard T. H. Chan School of Public Health)

  • Julian Avila-Pacheco

    (Broad Institute of MIT and Harvard)

  • Jordan E. Bisanz

    (University of California San Francisco)

  • Christopher K. Rakowski

    (Bucknell University)

  • Hera Vlamakis

    (Broad Institute of MIT and Harvard
    MIT)

  • Ramnik J. Xavier

    (Broad Institute of MIT and Harvard
    MIT
    Massachusetts General Hospital and Harvard Medical School
    Massachusetts General Hospital and Harvard Medical School)

  • Peter J. Turnbaugh

    (University of California San Francisco
    Chan Zuckerberg Biohub)

  • Randy S. Longman

    (Weill Cornell Medicine)

  • Michael R. Krout

    (Bucknell University)

  • Clary B. Clish

    (Broad Institute of MIT and Harvard)

  • Fraydoon Rastinejad

    (University of Oxford)

  • Curtis Huttenhower

    (Broad Institute of MIT and Harvard
    Harvard T. H. Chan School of Public Health
    Harvard T. H. Chan School of Public Health)

  • Jun R. Huh

    (Harvard Medical School
    Harvard Medical School and Brigham and Women’s Hospital)

  • A. Sloan Devlin

    (Harvard Medical School)

Abstract

The microbiota modulates gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17A (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. Although it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown, and it was unclear whether 3-oxoLCA and other immunomodulatory bile acids are associated with inflammatory pathologies in humans. Here we identify human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Similar to 3-oxoLCA, isoLCA suppressed TH17 cell differentiation by inhibiting retinoic acid receptor-related orphan nuclear receptor-γt, a key TH17-cell-promoting transcription factor. The levels of both 3-oxoLCA and isoLCA and the 3α-hydroxysteroid dehydrogenase genes that are required for their biosynthesis were significantly reduced in patients with inflammatory bowel disease. Moreover, the levels of these bile acids were inversely correlated with the expression of TH17-cell-associated genes. Overall, our data suggest that bacterially produced bile acids inhibit TH17 cell function, an activity that may be relevant to the pathophysiology of inflammatory disorders such as inflammatory bowel disease.

Suggested Citation

  • Donggi Paik & Lina Yao & Yancong Zhang & Sena Bae & Gabriel D. D’Agostino & Minghao Zhang & Eunha Kim & Eric A. Franzosa & Julian Avila-Pacheco & Jordan E. Bisanz & Christopher K. Rakowski & Hera Vlam, 2022. "Human gut bacteria produce ΤΗ17-modulating bile acid metabolites," Nature, Nature, vol. 603(7903), pages 907-912, March.
    • Handle: RePEc:nat:nature:v:603:y:2022:i:7903:d:10.1038_s41586-022-04480-z
    DOI: 10.1038/s41586-022-04480-z
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    Cited by:

    1. Peng Zhang & Xinying Li & Jinyuan Liang & Yuanwen Zheng & Yao Tong & Jing Shen & Yatai Chen & Penghu Han & Shuzheng Chu & Ruirui Liu & Mengqi Zheng & Yunjiao Zhai & Xiaolong Tang & Cuijuan Zhang & Hui, 2025. "Chenodeoxycholic acid modulates cholestatic niche through FXR/Myc/P-selectin axis in liver endothelial cells," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    2. Ethan A. Older & Jian Zhang & Zachary E. Ferris & Dan Xue & Zheng Zhong & Mary K. Mitchell & Michael Madden & Yuzhen Wang & Hexin Chen & Prakash Nagarkatti & Mitzi Nagarkatti & Daping Fan & Melissa El, 2024. "Biosynthetic enzyme analysis identifies a protective role for TLR4-acting gut microbial sulfonolipids in inflammatory bowel disease," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Xusheng Zhang & Xintong Gao & Zhen Liu & Fei Shao & Dou Yu & Min Zhao & Xiwen Qin & Shuo Wang, 2024. "Microbiota regulates the TET1-mediated DNA hydroxymethylation program in innate lymphoid cell differentiation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Guanqun Li & Liwei Liu & Tianqi Lu & Yuhang Sui & Can Zhang & Yongwei Wang & Tao Zhang & Yu Xie & Peng Xiao & Zhongjie Zhao & Chundong Cheng & Jisheng Hu & Hongze Chen & Dongbo Xue & Hua Chen & Gang W, 2023. "Gut microbiota aggravates neutrophil extracellular traps-induced pancreatic injury in hypertriglyceridemic pancreatitis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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