目的 采用多组学策略探讨首荟通便胶囊（Shouhui Tongbian Capsule，SHTB）对卒中后抑郁（post-stroke depression，PSD）的治疗效果及其作用机制。方法 通过光化学诱导脑卒中联合慢性不可预见性温和应激（chronic unpredictable mild stress，CUMS）建立PSD小鼠模型。通过行为学测试评价抑郁样行为，并通过组织学分析评估神经元和髓鞘结构。综合运用肠道菌群16S rDNA测序、粪便和脑组织代谢组学、蛋白组学、神经递质检测及Western blotting等方法，系统解析其潜在机制。此外，通过抗生素清除肠道菌群，以验证SHTB的作用是否依赖于肠道微生物。结果 SHTB能显著改善PSD小鼠的抑郁样行为及神经元形态。16S rDNA测序分析结果显示，SHTB可恢复肠道菌群平衡，表现为有益菌属（如肠球菌属Enterococcus）的增加以及促炎菌属（如颤螺菌属Oscillibacter、丹毒丝菌科Erysipelotrichaceae）的减少。代谢组学结果表明，SHTB可纠正脂肪酸代谢紊乱，特别是亚油酸和花生四烯酸通路，并降低神经炎症相关代谢物水平。蛋白组学和神经递质检测进一步揭示，SHTB能够恢复5-羟色胺（5-hydroxytryptamine，5-HT）、γ-氨基丁酸（γ-aminobutyric acid，GABA）、多巴胺（dopamine，DA）和去甲肾上腺素（norepinephrine，NE）水平（P＜0.05），并减少谷氨酸的异常累积（P＜0.05），同时抑制TLR4/MyD88/NF-κB炎症通路的过度激活（P＜0.05）。在抗生素清除肠道菌群后，上述效应均显著减弱，表明SHTB的功效具有肠道菌群依赖性。结论 SHTB能通过肠道菌群依赖性的方式，重塑肠道菌群、修复肠道屏障、调控脂肪酸代谢、抑制TLR4/MyD88/NF-κB通路介导的外周及中枢炎症反应、并恢复关键神经递质平衡，多维度改善肠-脑轴功能，从而发挥抗PSD及神经保护作用。

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.

R285.5

山东省自然科学基金资助项目(ZR2022LZY021)