Abstract
Background and purposeAlthough a large collection of data has shown that ginsenosides, the major active ingredients from Ginseng, have neuroprotective and anti-depressant effect, the mechanism of action is incompletely understood. This study aims to elucidate the antidepressant mechanism of ginsenoside Rg1 (Rg1), a poorly absorbed ginsenoside, from the perspective of gut microbe to brain signaling. MethodsA mouse model of depression was induced by unpredictable mild stress (UMS). Behavioral and neurochemical tests were conducted to evaluate the effect and mechanism of Rg1 on depressive behavior. Non-target and target metabolomics were performed to identify the signaling metabolites underlying the antidepressant efficacy of Rg1. Gut microbial structure was analyzed by 16S rRNA sequencing and the potential functional strains associated with Rg1 action were investigated by in vitro bacterial culture. Chemical intervention was used to explore the mechanism of Rg1 and signaling metabolite. ResultsRg1 improved UMS-induced despair, anxiety-like and social avoidance behaviors in mice, which were accompanied by increased hypothalamic oxytocin secretion and restored neural proliferation in the hippocampus. Metabolomic analysis of the gut-brain axis revealed that Rg1 increased the concentration of serum and brain indole-3-acetic acid (IAA), a bacterial metabolite that was partially attributed to the enrichment of Lactobacillus murinus in the gut microbiome. Oral supplementation of IAA mimicked the anti-depressant action of Rg1, while oxytocin receptor antagonist abrogated the anti-depressant effects of both Rg1 and IAA. ConclusionOur work provides a new gut-to-brain signaling mechanism for the antidepressant effects of Rg1. In particular, Rg1 enriches the abundance of Lactobacillus murinus, which in turn increases the level of brain IAA and potentiates hypothalamic oxytocin signal. These findings suggest a promising pathway for producing antidepressant effects through gut-brain crosstalk.
Published Version
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