WenDan Decoction activates neuronal autophagy in the hippocampus via the gut-brain axis to improve depressive-like behavior in HFD mice

BACKGROUND: High-fat diet (HFD) is implicated in depression pathogenesis. WenDan Decoction (WDD), a classical traditional Chinese medicine formula, shows promise for metabolic and psychiatric disorders, but its precise mechanisms require elucidation. METHODS: The chemical constituents of WDD were characterized by UPLC-MS/MS. The antidepressant effects of WDD in HFD mice were evaluated through behavioral tests, ELISA, and histopathology. Gut-brain axis mechanisms were investigated via 16S rRNA sequencing, untargeted metabolomics, network pharmacology, Nissl staining, transmission electron microscopy, Western blot, and RT-qPCR. Validation was performed through antibiotic depletion, fecal microbiota transplantation (FMT), and exogenous prostaglandin F2α (PGF2α) supplementation experiments. RESULTS: WDD administration significantly ameliorated depressive-like behaviors of HFD mice with relatively low hepatorenal toxicity. It restored intestinal mucosal integrity, mitigated inflammation, re-established gut microbial homeostasis and subsequently regulated arachidonic acid metabolism. Correlation analysis revealed that the strongest negative association between the differential microbiota Lactobacillus murinus and the arachidonic acid metabolite PGF2α. WDD attenuated blood-brain barrier disruption by diminishing pro-inflammatory metabolites, suppressed PI3K/AKT/mTOR pathway, and restored autophagic flux, thereby rescuing neuronal ultrastructural and functional impairments. The application of PI3K agonists reversed the effective regulation of WDD. Crucially, FMT experiments further confirmed that the gut microbiota and metabolite PGF2α are essential for WDD's antidepressant effects. CONCLUSION: WDD ameliorates depressive-like behaviors in HFD mice by modulating the gut microbiota and metabolism to suppress PI3K/AKT/mTOR pathway activation and restore autophagic flux. This study provides crucial mechanistic insights into WDD's effects against depression.