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Gut Microbial Catabolites of Tryptophan Are Ligands and Agonists of the Aryl Hydrocarbon Receptor: A Detailed Characterization
B. Vyhlídalová, K. Krasulová, P. Pečinková, A. Marcalíková, R. Vrzal, L. Zemánková, J. Vančo, Z. Trávníček, J. Vondráček, M. Karasová, S. Mani, Z. Dvořák
Language English Country Switzerland
Document type Journal Article
Grant support
20-00449S
Grantová Agentura České Republiky
PrF-2020-006
Univerzita Palackého v Olomouci
RVO 68081707
Akademie Věd České Republiky
P30CA013330
NIH HHS - United States
P30DK020541
NIH HHS - United States
CA127231
NIH HHS - United States
CA161879
NIH HHS - United States
PR160167
U.S. Department of Defense
R43DK105694
U.S. Department of Defense
P30DK041296
U.S. Department of Defense
362520
Crohn's and Colitis Foundation of America
NLK
Free Medical Journals
from 2000
Freely Accessible Science Journals
from 2000
PubMed Central
from 2007
Europe PubMed Central
from 2007
ProQuest Central
from 2000-03-01
Open Access Digital Library
from 2000-01-01
Open Access Digital Library
from 2007-01-01
Health & Medicine (ProQuest)
from 2000-03-01
ROAD: Directory of Open Access Scholarly Resources
from 2000
PubMed
32283770
DOI
10.3390/ijms21072614
Knihovny.cz E-resources
- MeSH
- Cytochrome P-450 CYP1A1 genetics MeSH
- Gene Expression MeSH
- Indoles MeSH
- Humans MeSH
- Ligands MeSH
- Metabolic Networks and Pathways MeSH
- Protein Multimerization MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Promoter Regions, Genetic MeSH
- Receptors, Aryl Hydrocarbon agonists metabolism MeSH
- Genes, Reporter MeSH
- Gastrointestinal Microbiome * drug effects MeSH
- Basic Helix-Loop-Helix Transcription Factors agonists metabolism MeSH
- Tryptophan metabolism MeSH
- Protein Binding MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
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 CYP1A1 mRNA in 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.
References provided by Crossref.org
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- $a Vyhlídalová, Barbora $u Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic
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- $a 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 CYP1A1 mRNA in 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.
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