Abstract

The aryl hydrocarbon receptor (AHR) is a major regulator of immune function within the gastrointestinal tract. Resident microbiota are capable of influencing AHR-dependent signaling pathways via production of an array of bioactive molecules that act as AHR agonists, such as indole or indole-3-Aldehyde. Bacteria produce a number of quinoline derivatives, of which some function as quorum-sensing molecules. Thus, we screened relevant hydroxyquinoline derivatives for AHR activity using AHR responsive reporter cell lines. 2,8-Dihydroxyquinoline (2,8-DHQ) was identified as a species-specific AHR agonist that exhibits full AHR agonist activity in human cell lines, but only induces modest AHR activity in mouse cells. Additional dihydroxylated quinolines tested failed to activate the human AHR. Nanomolar concentrations of 2,8-DHQ significantly induced CYP1A1 expression and, upon cotreatment with cytokines, synergistically induced IL6 expression. Ligand binding competition studies subsequently confirmed 2,8-DHQ to be a human AHR ligand. Several dihydroxyquinolines were detected in human fecal samples, with concentrations of 2,8-DHQ ranging between 0 and 3.4 pmol/mg feces. Additionally, in mice the microbiota was necessary for the presence of DHQ in cecal contents. These results suggest that microbiota-derived 2,8-DHQ would contribute to AHR activation in the human gut, and thus participate in the protective and homeostatic effects observed with gastrointestinal AHR activation.

Original languageEnglish (US)
Pages (from-to)1715-1724
Number of pages10
JournalJournal of Proteome Research
Volume18
Issue number4
DOIs
StatePublished - Apr 5 2019

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Aryl Hydrocarbon Receptors
Microbiota
Metabolism
Hydroxyquinolines
Chemical activation
Cells
2,8-dihydroxyquinoline
Quinolines
Ligands
Derivatives
Cell Line
Quorum Sensing
Cytochrome P-450 CYP1A1
Molecules
Human Activities
Feces
Gastrointestinal Tract
Interleukin-6
Bacteria
Cytokines

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Chemistry(all)

Cite this

@article{8de5064768f947d0b781ffc51f18bbc2,
title = "Microbiota Metabolism Promotes Synthesis of the Human Ah Receptor Agonist 2,8-Dihydroxyquinoline",
abstract = "The aryl hydrocarbon receptor (AHR) is a major regulator of immune function within the gastrointestinal tract. Resident microbiota are capable of influencing AHR-dependent signaling pathways via production of an array of bioactive molecules that act as AHR agonists, such as indole or indole-3-Aldehyde. Bacteria produce a number of quinoline derivatives, of which some function as quorum-sensing molecules. Thus, we screened relevant hydroxyquinoline derivatives for AHR activity using AHR responsive reporter cell lines. 2,8-Dihydroxyquinoline (2,8-DHQ) was identified as a species-specific AHR agonist that exhibits full AHR agonist activity in human cell lines, but only induces modest AHR activity in mouse cells. Additional dihydroxylated quinolines tested failed to activate the human AHR. Nanomolar concentrations of 2,8-DHQ significantly induced CYP1A1 expression and, upon cotreatment with cytokines, synergistically induced IL6 expression. Ligand binding competition studies subsequently confirmed 2,8-DHQ to be a human AHR ligand. Several dihydroxyquinolines were detected in human fecal samples, with concentrations of 2,8-DHQ ranging between 0 and 3.4 pmol/mg feces. Additionally, in mice the microbiota was necessary for the presence of DHQ in cecal contents. These results suggest that microbiota-derived 2,8-DHQ would contribute to AHR activation in the human gut, and thus participate in the protective and homeostatic effects observed with gastrointestinal AHR activation.",
author = "Hubbard, {Troy D.} and Qing Liu and Murray, {Iain Alexander} and Fangcong Dong and Charles Miller and Smith, {Philip B.} and Krishne Gowda and Lin, {Jyh ming} and Shantu Amin and Patterson, {Andrew David} and Perdew, {Gary H.}",
year = "2019",
month = "4",
day = "5",
doi = "10.1021/acs.jproteome.8b00946",
language = "English (US)",
volume = "18",
pages = "1715--1724",
journal = "Journal of Proteome Research",
issn = "1535-3893",
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TY - JOUR

T1 - Microbiota Metabolism Promotes Synthesis of the Human Ah Receptor Agonist 2,8-Dihydroxyquinoline

AU - Hubbard, Troy D.

AU - Liu, Qing

AU - Murray, Iain Alexander

AU - Dong, Fangcong

AU - Miller, Charles

AU - Smith, Philip B.

AU - Gowda, Krishne

AU - Lin, Jyh ming

AU - Amin, Shantu

AU - Patterson, Andrew David

AU - Perdew, Gary H.

PY - 2019/4/5

Y1 - 2019/4/5

N2 - The aryl hydrocarbon receptor (AHR) is a major regulator of immune function within the gastrointestinal tract. Resident microbiota are capable of influencing AHR-dependent signaling pathways via production of an array of bioactive molecules that act as AHR agonists, such as indole or indole-3-Aldehyde. Bacteria produce a number of quinoline derivatives, of which some function as quorum-sensing molecules. Thus, we screened relevant hydroxyquinoline derivatives for AHR activity using AHR responsive reporter cell lines. 2,8-Dihydroxyquinoline (2,8-DHQ) was identified as a species-specific AHR agonist that exhibits full AHR agonist activity in human cell lines, but only induces modest AHR activity in mouse cells. Additional dihydroxylated quinolines tested failed to activate the human AHR. Nanomolar concentrations of 2,8-DHQ significantly induced CYP1A1 expression and, upon cotreatment with cytokines, synergistically induced IL6 expression. Ligand binding competition studies subsequently confirmed 2,8-DHQ to be a human AHR ligand. Several dihydroxyquinolines were detected in human fecal samples, with concentrations of 2,8-DHQ ranging between 0 and 3.4 pmol/mg feces. Additionally, in mice the microbiota was necessary for the presence of DHQ in cecal contents. These results suggest that microbiota-derived 2,8-DHQ would contribute to AHR activation in the human gut, and thus participate in the protective and homeostatic effects observed with gastrointestinal AHR activation.

AB - The aryl hydrocarbon receptor (AHR) is a major regulator of immune function within the gastrointestinal tract. Resident microbiota are capable of influencing AHR-dependent signaling pathways via production of an array of bioactive molecules that act as AHR agonists, such as indole or indole-3-Aldehyde. Bacteria produce a number of quinoline derivatives, of which some function as quorum-sensing molecules. Thus, we screened relevant hydroxyquinoline derivatives for AHR activity using AHR responsive reporter cell lines. 2,8-Dihydroxyquinoline (2,8-DHQ) was identified as a species-specific AHR agonist that exhibits full AHR agonist activity in human cell lines, but only induces modest AHR activity in mouse cells. Additional dihydroxylated quinolines tested failed to activate the human AHR. Nanomolar concentrations of 2,8-DHQ significantly induced CYP1A1 expression and, upon cotreatment with cytokines, synergistically induced IL6 expression. Ligand binding competition studies subsequently confirmed 2,8-DHQ to be a human AHR ligand. Several dihydroxyquinolines were detected in human fecal samples, with concentrations of 2,8-DHQ ranging between 0 and 3.4 pmol/mg feces. Additionally, in mice the microbiota was necessary for the presence of DHQ in cecal contents. These results suggest that microbiota-derived 2,8-DHQ would contribute to AHR activation in the human gut, and thus participate in the protective and homeostatic effects observed with gastrointestinal AHR activation.

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U2 - 10.1021/acs.jproteome.8b00946

DO - 10.1021/acs.jproteome.8b00946

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JO - Journal of Proteome Research

JF - Journal of Proteome Research

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