Gut microbial catabolites of tryptophan are ligands and agonists of the aryl hydrocarbon receptor: A detailed characterization

Barbora Vyhlídalová, Kristýna Krasulová, Petra Pečinková, Adéla Marcalíková, Radim Vrzal, Lenka Zemánková, Jan Vančo, Zdenĕk Trávníček, Jan Vondráček, Martina Karasová, Sridhar Mani, Zdenĕk Dvořák

Research output: Contribution to journalArticle

Abstract

We examined the effects of gut microbial catabolites of tryptophan on the aryl hydrocarbon receptor (AhR). Using a reporter gene assay, we show that all studied catabolites are low-potency agonists of human AhR. The efficacy of catabolites differed substantially, comprising agonists with no or low (i3-propionate, i3-acetate, i3-lactate, i3-aldehyde), medium (i3-ethanol, i3-acrylate, skatole, tryptamine), and high (indole, i3-acetamide, i3-pyruvate) efficacies. We displayed ligand-selective antagonist activities by i3-pyruvate, i3-aldehyde, indole, skatole, and tryptamine. Ligand binding assay identified low affinity (skatole, i3-pyruvate, and i3-acetamide) and very low affinity (i3-acrylate, i3-ethanol, indole) ligands of the murine AhR. Indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, and i3-acetamide induced CYP1A1mRNAin intestinal LS180 and HT-29 cells, but not in the AhR-knockout HT-29 variant. We observed a similar CYP1A1 induction pattern in primary human hepatocytes. The most AhR-active catabolites (indole, skatole, tryptamine, i3-pyruvate, i3-acrylate, i3-acetamide) elicited nuclear translocation of the AhR, followed by a formation of AhR-ARNT heterodimer and enhanced binding of the AhR to the CYP1A1 gene promoter. Collectively, we comprehensively characterized the interactions of gut microbial tryptophan catabolites with the AhR, which may expand the current understanding of their potential roles in intestinal health and disease.

Original languageEnglish (US)
Article number2614
JournalInternational Journal of Molecular Sciences
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2020

Keywords

  • Hydrocarbon receptor
  • Indoles
  • Microbiome
  • Tryptophan

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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  • Cite this

    Vyhlídalová, B., Krasulová, K., Pečinková, P., Marcalíková, A., Vrzal, R., Zemánková, L., Vančo, J., Trávníček, Z., Vondráček, J., Karasová, M., Mani, S., & Dvořák, Z. (2020). Gut microbial catabolites of tryptophan are ligands and agonists of the aryl hydrocarbon receptor: A detailed characterization. International Journal of Molecular Sciences, 21(7), [2614]. https://doi.org/10.3390/ijms21072614