Chen Yue-Yue, Lu Yu-Ting, Wang Yi-di, Ding Na-Na, Huang Ze-Xiang, Hu Jing-Bo, Tong Jia-Xi, Zhang Ying-Ren, Deng Li-Juan, Luo Xiang, Hao Wen-Zhi, Chen Jia-Xu
Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine, School of Traditional Chinese Medicine; Jiangmen Traditional Chinese Medicine Hospital of Jinan University, Jinan University, Guangzhou 510632, China.
Guangdong Second Provincial General Hospital, Integrated Chinese and Western Medicine Postdoctoral research station, School of Medicine, Jinan University, Guangzhou 510632, China.
Phytomedicine. 2025 Sep;145:157078. doi: 10.1016/j.phymed.2025.157078. Epub 2025 Jul 13.
Post-stroke depression (PSD) represents the most prevalent complication of stroke and has been reported to be associated with an imbalance in the gut microbiota. Clinically, Xiaoyaosan (XYS) alleviates depressive symptoms in patients with PSD. However, the existing literature does not provide sufficient evidence to ascertain whether XYS can alleviate these symptoms by modulating gut microbiota.
This study aims to investigate the potential mechanism of XYS to improve depression-like behavior in mice with PSD by regulating intestinal flora and microbial metabolism.
The authors assessed the effect of XYS on the behaviour of PSD mice and evaluated the effects of XYS on structure and metabolism of gut microbiota, the protein expression levels of P2X7 and NLRP3, and associated inflammatory factors in PSD mice. In addition, by performing faecal microbiota transplantation (FMT) on PSD mice with faecal bacteria treated with XYS, the authors further clarified the relationship between intestinal flora disorder, the onset of PSD, and the intervention effect of XYS.
To investigate the ameliorative effect of XYS on behavioural abnormalities and clarify the important role of intestinal flora regulation in the improvement of PSD by XYS in diseased mice, the authors employed various methodologies, including the PSD model, behavioural tests, haematoxylin and eosin staining, ultrastructural morphology, enzyme-linked immunosorbent assay, western blotting, 16S rRNA sequencing, metabolomic analyses, and FMT.
Oral administration of XYS effectively alleviated depression-like behaviours in PSD mice and repaired the damaged colonic mucosa. XYS inhibited inflammatory factors in serum and hippocampus and regulated the protein expression levels of P2X7 and NLRP3 in the colon and hippocampus of PSD mice. Moreover, XYS restored the gut microbiota and modulated intestinal metabolites in PSD mice. It effectively reduced the abundances of microbes including Ligullacoccus, Streptococcus, and Staphylococcus, while significantly increased the abundances of microbes including Faecalibaculum, Allobaculum, and Monolobus. Furthermore, XYS effectively regulated intestinal metabolites such as methylparaben, valproic acid (Depakene), and disulfiram. More importantly, faecal transplants from the PSD models reproduced depression-like behaviours in normal mice, while XYS-FMT effectively alleviated depression-like behaviours in PSD mice.
Our findings indicate that XYS improves depression-like behaviours in mice with PSD by modulating the gut microbiota and microbial metabolism, and regulating the P2X7R/NLRP3 inflammasome.
中风后抑郁症（PSD）是中风最常见的并发症，据报道与肠道微生物群失衡有关。临床上，逍遥散（XYS）可缓解PSD患者的抑郁症状。然而，现有文献没有提供足够的证据来确定XYS是否能通过调节肠道微生物群来缓解这些症状。
本研究旨在探讨XYS通过调节肠道菌群和微生物代谢改善PSD小鼠抑郁样行为的潜在机制。
作者评估了XYS对PSD小鼠行为的影响，并评估了XYS对PSD小鼠肠道微生物群的结构和代谢、P2X7和NLRP3的蛋白表达水平以及相关炎症因子的影响。此外，通过对用XYS处理过的粪便细菌的PSD小鼠进行粪便微生物群移植（FMT），作者进一步阐明了肠道菌群紊乱、PSD的发病机制以及XYS的干预效果之间的关系。
为了研究XYS对行为异常的改善作用，并阐明肠道菌群调节在患病小鼠中XYS改善PSD中的重要作用，作者采用了多种方法，包括PSD模型、行为测试、苏木精和伊红染色、超微结构形态学、酶联免疫吸附测定、蛋白质印迹法、16S rRNA测序、代谢组学分析和FMT。
口服XYS可有效缓解PSD小鼠的抑郁样行为，并修复受损的结肠黏膜。XYS抑制血清和海马中的炎症因子，并调节PSD小鼠结肠和海马中P2X7和NLRP3的蛋白表达水平。此外，XYS恢复了PSD小鼠的肠道微生物群并调节了肠道代谢产物。它有效降低了包括 Ligullacoccus、链球菌和葡萄球菌在内的微生物丰度，同时显著增加了包括粪杆菌属、别杆菌属和单叶菌属在内的微生物丰度。此外，XYS有效调节了对羟基苯甲酸甲酯、丙戊酸（德巴金）和双硫仑等肠道代谢产物。更重要的是，来自PSD模型的粪便移植在正常小鼠中重现了抑郁样行为 while XYS-FMT有效缓解了PSD小鼠的抑郁样行为。
我们的研究结果表明，XYS通过调节肠道微生物群和微生物代谢以及调节P2X7R/NLRP3炎性小体来改善PSD小鼠的抑郁样行为。
