Journal article
Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor
Proceedings of the National Academy of Sciences, Vol.118(27), Art. e2021091118
2021
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.
Details
- Title
- Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor
- Authors/Creators
- G.Z. Wei (Author/Creator) - Nanyang Technological UniversityK.A. Martin (Author/Creator) - Nanyang Technological UniversityP.Y. Xing (Author/Creator) - Nanyang Technological UniversityR. Agrawal (Author/Creator) - Nanyang Technological UniversityL. Whiley (Author/Creator) - Murdoch UniversityT.K. Wood (Author/Creator) - Pennsylvania State UniversityS. Hejndorf (Author/Creator) - Karolinska InstitutetY.Z. Ng (Author/Creator) - Nanyang Technological UniversityJ.Z.Y. Low (Author/Creator) - Nanyang Technological UniversityJ. Rossant (Author/Creator) - Program in Developmental and Stem Cell Biology, Peter Gilgan Centre for Research and Learning, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.R. Nechanitzky (Author/Creator) - Princess Margaret Cancer CentreE. Holmes (Author/Creator) - Imperial College LondonJ.K. Nicholson (Author/Creator) - Imperial College LondonE-K Tan (Author/Creator)P.M. Matthews (Author/Creator) - Imperial College LondonS. Pettersson (Author/Creator) - Nanyang Technological University
- Publication Details
- Proceedings of the National Academy of Sciences, Vol.118(27), Art. e2021091118
- Publisher
- National Academy of Sciences
- Identifiers
- 991005543161807891
- Copyright
- © 2021 The Authors.
- Murdoch Affiliation
- Australian National Phenome Centre; Health Futures Institute
- Language
- English
- Resource Type
- Journal article
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- Citation topics
- 1 Clinical & Life Sciences
- 1.120 Inflammatory Bowel Diseases & Infections
- 1.120.384 Gut Microbiota
- Web Of Science research areas
- Neurosciences
- ESI research areas
- Neuroscience & Behavior