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

Jiabao Liu, Ainaz Malekoltojari, Anjana Asokakumar, Vimanda Chow, Linhao Li, Hao Li, Marina Grimaldi, Nathanlown Dang, Jhenielle Campbell, Holly Barrett, Jianxian Sun, William Navarre, Derek Wilson, Hongbing Wang, Sridhar Mani, Patrick Balaguer, Sayeepriyadarshini Anakk, Hui Peng () and Henry M. Krause ()
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Jiabao Liu: University of Toronto
Ainaz Malekoltojari: 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
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
Henry M. Krause: University of Toronto

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46559-3

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