Fermented Gastrodia elata Blume ameliorates CUMS-induced depression in mice: synergistic regulation of cAMP/BDNF/CREB signaling and gut microbiota-metabolite axis

• The anti-depressant effect of Armillaria gallica fermented GE was investigated. • The content of gastrodin was increased by 3.8 times after fermented by A. gallica. • FG could synergistic regulation of cAMP/BDNF/CREB signaling and gut microbiota-metabolite axis. • FG could be used as a functional food to improve depressive symptoms in the future. Depression is a common mental illness with prolonged periods of low mood that affects billions of people around the world. Gastrodia elata Blume (GE) has the potential value in treating nervous system disease. Nevertheless, the potential antidepressant effects and molecular mechanism of GE that fermented by Armillaria gallica (FG) remain unclear. The aim of this study is to investigate the anti-depressant-like effect and action mechanism of Armillaria gallica fermented Gastrodia elata Blume (FG). The results showed that the content of gastrodin (GAS) and p-hydroxybenzyl alcohol (HBA) were increased by 3.8 and 1 times after fermented by A. gallica . The administration of FG could significantly improve the depressant-like behavior and ameliorate neuronal damage and apoptosis by decreasing the levels of inflammatory factors via the "brain-gut" axis. Meantime, FG could improve the gut microbiota imbalance and increase the richness of beneficial bacteria, Muribaculaceae, Lactobacillus and Desulfovibrio . The serum metabolomics analysis showed that FG can regulate cAMP signaling pathway and tryptophan metabolic pathways to improve depressive symptoms. Notably, the Western blotting results confirmed that the FG could regulate the phosphorylation of CREB and ERK proteins, decrease the NMDAR1, NMDAR2A, and CaMKIIα proteins expression, and increase the NMDAR2B, PSD-95, and Syn1 expression to exerting the anti-depressant effect. In this study, a novel fermentation strategy that could improve the active ingredient content of GE has been developed with significantly anti-depressant-like effects, suggesting that FG could be used as a functional food to improve depressive symptoms in the future.