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Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor

Title: Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor
Authors: Wei, GZ
Martin, KA
Xing, PY
Agrawal, R
Whiley, L
Wood, TK
Hejndorf, S
Ng, YZ
Low, JZY
Rossant, J
Nechanitzky, R
Holmes, E
Nicholson, JK
Tan, E-K
Matthews, PM
Pettersson, S
Item Type: Journal Article
Abstract: While modulatory effects of gut microbes on neurological phenotypes have been reported, the mechanisms remain largely unknown. Here, we demonstrate that indole, a tryptophan metabolite produced by tryptophanase-expressing gut microbes, elicits neurogenic effects in the adult mouse hippocampus. Neurogenesis is reduced in germ-free (GF) mice and in GF mice monocolonized with a single-gene tnaA knockout (KO) mutant Escherichia coli unable to produce indole. External administration of systemic indole increases adult neurogenesis in the dentate gyrus in these mouse models and in specific pathogen-free (SPF) control mice. Indole-treated mice display elevated synaptic markers postsynaptic density protein 95 and synaptophysin, suggesting synaptic maturation effects in vivo. By contrast, neurogenesis is not induced by indole in aryl hydrocarbon receptor KO (AhR−/−) mice or in ex vivo neurospheres derived from them. Neural progenitor cells exposed to indole exit the cell cycle, terminally differentiate, and mature into neurons that display longer and more branched neurites. These effects are not observed with kynurenine, another AhR ligand. The indole-AhR–mediated signaling pathway elevated the expression of β-catenin, Neurog2, and VEGF-α genes, thus identifying a molecular pathway connecting gut microbiota composition and their metabolic function to neurogenesis in the adult hippocampus. Our data have implications for the understanding of mechanisms of brain aging and for potential next-generation therapeutic opportunities.
Issue Date: 6-Jul-2021
Date of Acceptance: 1-Jan-2021
URI: http://hdl.handle.net/10044/1/90111
DOI: 10.1073/pnas.2021091118
ISSN: 0027-8424
Publisher: Proceedings of the National Academy of Sciences
Start Page: 1
End Page: 10
Journal / Book Title: Proceedings of the National Academy of Sciences
Volume: 118
Issue: 27
Copyright Statement: © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Publication Status: Published
Online Publication Date: 2021-07-01
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Department of Brain Sciences



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