TY - JOUR
T1 - Diindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands
AU - Liu, Jiabao
AU - Malekoltojari, Ainaz
AU - Asokakumar, Anjana
AU - Chow, Vimanda
AU - Li, Linhao
AU - Li, Hao
AU - Grimaldi, Marina
AU - Dang, Nathanlown
AU - Campbell, Jhenielle
AU - Barrett, Holly
AU - Sun, Jianxian
AU - Navarre, William
AU - Wilson, Derek
AU - Wang, Hongbing
AU - Mani, Sridhar
AU - Balaguer, Patrick
AU - Anakk, Sayeepriyadarshini
AU - Peng, Hui
AU - Krause, Henry M.
N1 - We thank K.Doty of the Histology laboratory, UIUC for assistance in setting up experiments, and X.Wang for providing human gut microbe extracts. J.L. was supported by a Charles H. Best Postdoctoral Fellowship and Precision Medicine Initiative (PRiME) Fellowship. The work was supported by a Canadian Institutes of Health Research (PJT-186117) to H.M.K., a New Frontiers in Research Fund grant (NRFRE-2019-00901) to H.M.K. and H.P., National Institutes of Health grants (R01CA222469) to S.M., (R01DK113080) to S.A., (R01CA262084) to L.L. and (R21AA02852) to H.W., an American Cancer Society grant (RSGACS132640) to S.A., a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grants (RGPIN480432, and CRDPJ597036) to D.J.W. and an Agence Nationale de la Recherche SYNERACT grant to P. B. Infrastructure support was also provided by the Canada Foundation for Innovation, Ontario Research Fund, and NSERC Research Tools and Instrument grants.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-024-46559-3
DO - 10.1038/s41467-024-46559-3
M3 - Article
C2 - 38519460
AN - SCOPUS:85188462649
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2563
ER -