Indole microbial intestinal metabolites expand the repertoire of ligands and agonists of the human pregnane X receptor
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
33002526
DOI
10.1016/j.toxlet.2020.09.015
PII: S0378-4274(20)30425-2
Knihovny.cz E-resources
- Keywords
- Indole metabolites, Intestinal health, Microbial catabolism, Pregnane X receptor,
- MeSH
- Cytochrome P-450 CYP3A genetics metabolism MeSH
- Indoles metabolism MeSH
- Cells, Cultured MeSH
- Indoleacetic Acids metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Cell Line, Tumor MeSH
- ATP Binding Cassette Transporter, Subfamily B genetics metabolism MeSH
- Pregnane X Receptor agonists genetics MeSH
- Genes, Reporter MeSH
- Gastrointestinal Microbiome * MeSH
- Intestinal Mucosa * metabolism microbiology MeSH
- Transfection MeSH
- Tryptophan metabolism MeSH
- Protein Binding MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- ABCB1 protein, human MeSH Browser
- CYP3A4 protein, human MeSH Browser
- Cytochrome P-450 CYP3A MeSH
- indole MeSH Browser
- indoleacetamide MeSH Browser
- Indoles MeSH
- Indoleacetic Acids MeSH
- Ligands MeSH
- ATP Binding Cassette Transporter, Subfamily B MeSH
- Pregnane X Receptor MeSH
- Tryptophan MeSH
The interplays between the metabolic products of intestinal microbiota and the host signaling through xenobiotic receptors, including pregnane X receptor (PXR), are of growing interest, in the context of intestinal health and disease. A distinct class of microbial catabolites is formed from dietary tryptophan, having the indole scaffold in their core structure, which is a biologically active entity. In the current study, we examined a series of ten tryptophan microbial catabolites for their interactions with PXR signaling. Utilizing a reporter gene assay, we identified indole (IND) and indole-3-acetamide (IAD) as PXR agonists. IND and IAD induced PXR-regulated genes CYP3A4 and MDR1 in human intestinal cancer cells. Using time-resolved fluorescence resonance energy transfer, we show that IND (IC50 292 μM) and IAD (IC50 10 μM) are orthosteric ligands of PXR. Binding of PXR in its DNA response elements was enhanced by IND and IAD, as revealed by chromatin immunoprecipitation assay. We demonstrate that tryptophan microbial intestinal metabolites IND and IAD are ligands and agonists of human PXR. These findings are of particular importance in understanding the roles of microbial catabolites in human physiology and pathophysiology. Furthermore, these results are seminal in expanding potential drug repertoire through microbial metabolic mimicry.
References provided by Crossref.org
Mixture Effects of Tryptophan Intestinal Microbial Metabolites on Aryl Hydrocarbon Receptor Activity
Bacterial Indole as a Multifunctional Regulator of Klebsiella oxytoca Complex Enterotoxicity
