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

Feb 20, 2019Journal of proteome research

Gut Microbes Help Produce the Human Ah Receptor Activator 2,8-Dihydroxyquinoline

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Abstract

2,8-Dihydroxyquinoline (2,8-DHQ) exhibits full AHR agonist activity in human cell lines.

2,8-DHQ is identified as a species-specific AHR agonist that shows different activity levels in human and mouse cells.
Nanomolar concentrations of 2,8-DHQ significantly increase CYP1A1 expression and, when combined with cytokines, enhance IL6 expression.
Ligand binding studies confirm that 2,8-DHQ acts as a ligand for the human AHR.
Dihydroxyquinolines, including 2,8-DHQ, were found in human fecal samples, with concentrations between 0 and 3.4 pmol/mg.
In mice, the presence of DHQ in cecal contents relies on the microbiota.

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

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