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

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.

How Microbes Affect Depression: Underlying Mechanisms via the Gut–Brain Axis and the Modulating Role of Probiotics

“…Recently, Wei et al investigated the effect of indole, a tryptophan metabolite of colonic microbiota, on hippocampal neurogenesis, and showed that the neurogenic effect was mediated by the aryl hydrocarbon receptor (AhR) [142]. In that study, however, another AhR ligand, kynurenine, did not induce neurogenesis, suggesting ligand specificity in the AhR-mediated regulation of neurogenesis.…”

Targeting Aryl Hydrocarbon Receptor Signaling Enhances Type I Interferon-Independent Resistance to Herpes Simplex Virus

“…Indeed, it can be inferred that AHR may influence viral infection through impacting IRF-3 independent of IFN. Interestingly, gut and skin microbes regulate neurogenesis and skin barrier function via AHR signaling in mice based on mice lacking AHR having neurogenesis dysfunction and being more liable to infection ( 31 , 32 ), suggesting the existence of an opposite role of this receptor when infected with different microorganisms.…”

The Future Potential of Biosensors to Investigate the Gut-Brain Axis

“…Other studies in mice under chronic mild stress observed that indole production correlated with changes in mice behavior (Mir et al, 2020), while overproduction of indoleinduced anxiety-like behavior in rats (Jaglin et al, 2018). In contrast, studies in mice have shown that indole stimulation of the AhR regulates neurogenesis in the adult hippocampus, a critical step in recovering from depression (Wei et al, 2021). Thus, maintenance of indole levels appears critical for proper gutbrain axis regulation (Jaglin et al, 2018;Mir et al, 2020).…”