Indole microbial intestinal metabolites expand the repertoire of ligands and agonists of the human pregnane X receptor

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F20%3A73602167" target="_blank" >RIV/61989592:15310/20:73602167 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0378427420304252" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0378427420304252</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.toxlet.2020.09.015" target="_blank" >10.1016/j.toxlet.2020.09.015</a>

Result language

angličtina

Original language name

Indole microbial intestinal metabolites expand the repertoire of ligands and agonists of the human pregnane X receptor

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30108 - Toxicology

Project

<a href="/en/project/GA20-00449S" target="_blank" >GA20-00449S: Microbial catabolites of tryptophan as modulators of intestinal health via aryl hydrocarbon receptor</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

TOXICOLOGY LETTERS

ISSN

0378-4274

e-ISSN

—

Volume of the periodical

334

Issue of the periodical within the volume

NOV

Country of publishing house

IE - IRELAND

Number of pages

7

Pages from-to

87-93

UT code for WoS article

000580902700012

EID of the result in the Scopus database

2-s2.0-85091942520