基于多维组学探究逍遥散低极性部位对CUMS模型大鼠的抗抑郁作用

Antidepressant-like effects of the petroleum ether fraction of Xiaoyaosan in the CUMS rat model of depression

研究逍遥散低极性部位对抑郁模型大鼠干预作用,从肠道菌群和代谢物角度探讨逍遥散低极性部位抗抑郁作用机制。所有动物实验均通过山西大学科学研究伦理审查委员会审查。采用慢性温和不可预知应激(CUMS)程序对大鼠进行造模,以逍遥散低极性部位及阳性药(文拉法辛)为干预药物,结合16S rRNA基因测序和LC-MS代谢组学分析方法,探究逍遥散低极性部位对CUMS大鼠盲肠内容物肠道菌群和代谢物的影响,并对肠道菌群与代谢物进行Pearson关联分析。结果显示,逍遥散低极性部位显著改善CUMS大鼠的抑郁样行为;回调CUMS大鼠海马脑源性神经营养因子(BDNF)水平。肠道微生物群分析显示:逍遥散低极性部位给药可以增加CUMS模型大鼠微生物群的多样性,显著回调CUMS模型大鼠肠道微生物中罗斯氏菌属(Rothia)、普雷沃氏菌属([Prevotella]),其主要与肠道炎症和短链脂肪酸的产生有关。代谢组学结果表明,盲肠内容物中鉴定出与抑郁症相关的20种生物标志物,逍遥散低极性部位干预后可回调17种,涉及的通路为亚油酸代谢、牛磺酸和亚牛磺酸代谢、初级胆汁酸生物合成、精氨酸和脯氨酸代谢。相关分析进一步表明,逍遥散低极性部位调节的肠道菌群与盲肠内容物代谢产物之间存在很强的相关性。综上,逍遥散低极性部位可能通过调节肠道菌群的组成及盲肠内容物的代谢物及通路发挥抗抑郁疗效,该研究为后续探索逍遥散低极性部位抗抑郁机制提供创新思路和实验依据。

This study aimed to investigate the effect of the petroleum ether fraction of Xiaoyaosan(XY-A)in a rat depression model with consideration of an underlying mechanism based on gut microbiota and metabolomics.All procedures involving animal treatment were approved according to the Committee on the Ethics of Animal Experiments of Shanxi University.A rat model was established using the chronic unpredictable mild stress(CUMS)procedure and XY-A and venlafaxine(positive control)were used as intervention drugs.Sequencing of the 16 S rRNA gene combined with LC-MS metabolomics was used to investigate the effects of XY-A on gut microbiota and metabolites in CUMS-induced depression,and Pearson correlation analysis was carried out on gut microbiota and metabolites.The results showed that XY-A significantly improved the depression-like behavior of CUMS rats and restored the level of brain-derived neurotrophic factor(BDNF)in the hippocampus.Gut microbiota analysis revealed that XY-A can increase the diversity of microbial species in CUMS rats and significantly restored the relative abundance of intestinal Rothia[Prevotella],with effects on intestinal inflammation and the production of short-chain fatty acids.Cecal content metabolomics identified twenty biomarkers that were altered by depression,whereas administration of XY-A ameliorated the changes in seventeen metabolites,with the most strongly affected metabolic pathways being linoleic acid metabolism,taurine and hypotaurine metabolism,primary bile acid biosynthesis,and arginine and proline metabolism.Correlation analysis further showed that there was a strong relationship between the gut microbiota and the cecal content metabolites.In summary,XY-A may exert antidepressant effects by regulating the composition of the gut microbiota and the metabolites and pathways of the cecum.The results provide a reference for the potential molecular mechanism of antidepressant action of XY-A.