Objective To explore the therapeutic effect and mechanism of Shouhui Tongbian Capsule (首荟通便胶囊, SHTB) on post-stroke depression (PSD) using a multi-omics strategy. Methods A mouse model of PSD was established by photochemical induction of stroke combined with chronic unpredictable mild stress (CUMS). Depressive-like behaviors were evaluated by behavioral tests, and neuronal and myelin sheath structures were assessed by histological analysis. A comprehensive approach integrating 16S rDNA sequencing of gut microbiota, metabolomics of feces and brain tissues, proteomics, neurotransmitter detection and Western blotting was employed to systematically elucidate the potential mechanism. Additionally, gut microbiota was depleted by antibiotics to verify whether the effect of SHTB is dependent on intestinal microbes. Results SHTB significantly improved depressive-like behaviors and neuronal morphology in PSD mice. 16S rDNA sequencing analysis showed that SHTB restored the balance of gut microbiota, characterized by an increase in beneficial genera (e.g., Enterococcus) and a decrease in pro-inflammatory genera (e.g., Oscillibacter, Erysipelotrichaceae). Metabolomic results indicated that SHTB could correct fatty acid metabolism disorders, particularly linoleic acid and arachidonic acid pathways, and reduce the levels of neuroinflammation-related metabolites. Proteomics and neurotransmitter detection further revealed that SHTB could restore the levels of serotonin (5-HT), γ-aminobutyric acid (GABA), dopamine (DA) and norepinephrine (NE) (P < 0.05), reduce the abnormal accumulation of glutamate (P < 0.05), and inhibit the excessive activation of TLR4/MyD88/NF-κB inflammatory pathway (P < 0.05). After depletion of gut microbiota by antibiotics, the above effects were significantly attenuated, indicating that the efficacy of SHTB was gut microbiota-dependent. Conclusion SHTB could restore the gut microbiota, repair the intestinal barrier, regulate fatty acid metabolism, inhibit TLR4/MyD88/NF-κB pathway-mediated peripheral and central inflammatory responses, and restore the balance of key neurotransmitters through a gut microbiota-dependent mechanism. This multi-dimensional improvement in the gut-brain axis function contributes to its anti-PSD and neuroprotective effects.

post-stroke depression  /  Shouhui Tongbian Capsule  /  gut microbiota  /  fatty acid metabolism  /  neuroinflammation  /  neurotransmitter imbalance  /  TLR4/MyD88/NF-κB pathway