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Diindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands

Author

Listed:
  • Jiabao Liu

    (University of Toronto)

  • Ainaz Malekoltojari

    (University of Toronto
    University of Toronto)

  • Anjana Asokakumar

    (University of Illinois Urbana-Champaign)

  • Vimanda Chow

    (York University)

  • Linhao Li

    (University of Maryland School of Pharmacy)

  • Hao Li

    (Department of Molecular Pharmacology; Department of Genetics; Department of Medicine; Albert Einstein College of Medicine)

  • Marina Grimaldi

    (Université Montpellier, Institut régional du Cancer de Montpellier (ICM))

  • Nathanlown Dang

    (University of Illinois Urbana-Champaign)

  • Jhenielle Campbell

    (University of Toronto)

  • Holly Barrett

    (University of Toronto)

  • Jianxian Sun

    (University of Toronto
    University of Toronto)

  • William Navarre

    (University of Toronto)

  • Derek Wilson

    (York University)

  • Hongbing Wang

    (University of Maryland School of Pharmacy)

  • Sridhar Mani

    (Department of Molecular Pharmacology; Department of Genetics; Department of Medicine; Albert Einstein College of Medicine)

  • Patrick Balaguer

    (Université Montpellier, Institut régional du Cancer de Montpellier (ICM))

  • Sayeepriyadarshini Anakk

    (University of Illinois Urbana-Champaign)

  • Hui Peng

    (University of Toronto
    University of Toronto)

  • Henry M. Krause

    (University of Toronto
    University of Toronto)

Abstract

Numerous studies have demonstrated the correlation between human gut bacteria and host physiology, mediated primarily via nuclear receptors (NRs). Despite this body of work, the systematic identification and characterization of microbe-derived ligands that regulate NRs remain a considerable challenge. In this study, we discover a series of diindole molecules produced from commensal bacteria metabolites that act as specific agonists for the orphan constitutive androstane receptor (CAR). Using various biophysical analyses we show that their nanomolar affinities are comparable to those of synthetic CAR agonists, and that they can activate both rodent and human CAR orthologues, which established synthetic agonists cannot. We also find that the diindoles, diindolylmethane (DIM) and diindolylethane (DIE) selectively up-regulate bona fide CAR target genes in primary human hepatocytes and mouse liver without causing significant side effects. These findings provide new insights into the complex interplay between the gut microbiome and host physiology, as well as new tools for disease treatment.

Suggested Citation

  • Jiabao Liu & Ainaz Malekoltojari & Anjana Asokakumar & Vimanda Chow & Linhao Li & Hao Li & Marina Grimaldi & Nathanlown Dang & Jhenielle Campbell & Holly Barrett & Jianxian Sun & William Navarre & Der, 2024. "Diindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46559-3
    DOI: 10.1038/s41467-024-46559-3
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    References listed on IDEAS

    as
    1. Vanessa Delfosse & Béatrice Dendele & Tiphaine Huet & Marina Grimaldi & Abdelhay Boulahtouf & Sabine Gerbal-Chaloin & Bertrand Beucher & Dominique Roecklin & Christina Muller & Roger Rahmani & Vincent, 2015. "Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    2. Bingning Dong & Ju-Seog Lee & Yun-Yong Park & Feng Yang & Ganyu Xu & Wendong Huang & Milton J. Finegold & David D. Moore, 2015. "Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    3. Ping Wei & Jun Zhang & Margarete Egan-Hafley & Shuguang Liang & David D. Moore, 2000. "The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism," Nature, Nature, vol. 407(6806), pages 920-923, October.
    4. Barry M. Forman & Iphigenia Tzameli & Hueng-Sik Choi & Jasmine Chen & Devendranath Simha & Wongi Seol & Ronald M. Evans & David D. Moore, 1998. "Androstane metabolites bind to and deactivate the nuclear receptor CAR-β," Nature, Nature, vol. 395(6702), pages 612-615, October.
    5. Mei Lan Chen & Xiangsheng Huang & Hongtao Wang & Courtney Hegner & Yujin Liu & Jinsai Shang & Amber Eliason & Huitian Diao & HaJeung Park & Blake Frey & Guohui Wang & Sarah A. Mosure & Laura A. Solt &, 2021. "CAR directs T cell adaptation to bile acids in the small intestine," Nature, Nature, vol. 593(7857), pages 147-151, May.
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