Depression is increasingly recognized as a disorder driven by complex interactions among the gut microbiota, host metabolism, and neuroplasticity. In this study, we demonstrated that Hericium erinaceus extract (HEE) alleviates depressive-like behaviors in corticosterone (CORT)-induced mice by orchestrating a novel microbiota–metabolite–brain signaling cascade. HEE intervention reversed CORT-induced disruptions in amino acid homeostasis, notably normalizing serum glutamate and proline levels. Simultaneously, HEE remodeled gut microbiota composition, suppressing the overgrowth of Bacteroides associated with glutamate dysregulation. Fecal microbiota transplantation (FMT) experiments confirmed the causative role of HEE-modulated microbiota in alleviating depressive symptoms. At the neurochemical level, HEE significantly restored 5-hydroxytryptamine (5-HT) levels and reactivated the BDNF/TrkB/CREB signaling axis in the hippocampus and BV2 microglial cells. Mechanistically, our findings suggest HEE as a potent natural agent capable of reprogramming the Bacteroides –glutamate–BDNF/TrkB/CREB axis to promote neuroprotection and emotional resilience. This work provides new insight into gut–brain axis interventions and highlights the therapeutic potential of HEE in depression management.
Gong et al. (Sun,) studied this question.