Dihydromyricetin Alleviates Reserpine-Induced Depression by Modulating the Microbiota–Gut–Brain Axis

Abstract

Abstract Dihydromyricetin (DMY) is a natural flavonoid with neuroprotective and antidepressant potential, but its role in the microbiota–gut–brain axis remains unclear. Using a reserpine-induced depression rat model, we integrated behavioral, inflammatory, histological, microbiota, metabolomic, and fecal microbiota transplantation (FMT) analyses. DMY alleviated anhedonia, behavioral despair, and cognitive dysfunction, reduced circulating pro-inflammatory cytokines and hippocampal neuronal damage, and increased brain-derived neurotrophic factor expression. DMY also restored gut microbial diversity and composition and partially normalized bile acid and short-chain fatty acid profiles. Notably, FMT from DMY-treated donors reproduced antidepressant-like behavioral effects and restored key microbial metabolites. These findings suggest that DMY may alleviate depression-like phenotypes through coordinated regulation of gut microbiota, microbial metabolites, and neuroinflammatory responses, supporting its potential as a dietary strategy for depression management.