基于肠道菌群变化研究“醒脾解郁法”对抑郁症的效应机理

Depression has become a prominent social issue. The intestinal flora, known as the "second brain", provides a new perspective for the study of depression. Previous studies have proven that "Xingpi Jieyu method" is an effective treatment of depression from the aspects of liver and spleen. The hypothesis of this study is the variation in intestinal flora could be one of the effector mechanisms of "Xingpi Jieyu method" in the prevention and treatment of depression. Through clinical trials, observations of the "Xingpi Jieyu method" on the regulation of intestinal flora in patients with depression were first made. Subsequently, similar observations were performed on rat models of depression, developed using CUMS protocol. Concurrently, fecal microbiota transplantation from patients with depression, related to liver and spleen, to sterile rats was conducted to further validate the hypothesis.Finally, the Chinese medicine culture medium of fecal coliform bacteria in vitro was used to investigate the presence of a direct regulatory role of the "Xingpi Jieyu method" in the intestinal microflora activity in patients with depression. Generally, from organelle to molecular level, the exploration of the regulatory mechanism in the gut microbiota of the "Xingpi Jieyu method", in the prevention and treatment of depression, holds substantial theoretical significance and clinical guidance in providing scientific basis for TCM treatment of depression.

抑郁症已成为突出的社会问题，肠道菌群被称为“第二大脑”，为抑郁症的研究提供了新视角，前期研究证实“醒脾解郁法”是肝郁脾湿抑郁症的有效治法。本研究假说认为肠道菌群变化可能是“醒脾解郁法”防治抑郁症的效应机制之一。本课题拟通过临床试验，观察“醒脾解郁法”对肝郁脾湿抑郁症患者肠道菌群的调控作用；然后通过动物实验，采用CUMS法建立肝郁脾湿抑郁大鼠模型，观察“醒脾解郁法”对应激相关性抑郁大鼠肠道菌群失调的调控机理，同时采用肝郁脾湿抑郁症患者粪菌移植法对无菌大鼠造模，进一步验证肠道菌群失调是否可以直接导致大鼠抑郁样行为及“醒脾解郁法”的疗效机制；最后进行粪菌体外培养实验，以探究“醒脾解郁法”对肝郁脾湿抑郁症患者肠道菌群活性是否存在直接调控作用。以期从整体、器官、分子水平，探索“醒脾解郁法”是否可以通过调控肠道菌群微生态防治抑郁症，为抑郁症中医“肝脾同治”提供科学依据，具有重要的理论及临床指导意义。

抑郁症已成为突出的社会问题，肠道菌群被称为“第二大脑”，成为抑郁症研究和治疗的新靶点。前期研究证实“醒脾解郁法”是肝郁脾湿抑郁症的有效治法，肠道菌群变化可能是“醒脾解郁法”防治抑郁症的效应机制之一。本课题通过临床试验，观察“醒脾解郁法”对肝郁脾湿抑郁症患者肠道菌群的调控作用，结果显示，治疗6周后，试验组临床有效率为93.55%，显效率为70.97%，在HAMD、HAMA总分及中医证候气虚、气滞、痰湿方面疗效明显（P＜0.01）。其作用机制为降低患者血清LPS、D-乳酸、DAO、IL-6、TNF-α含量（P＜0.01），改善肠道菌群结构，降低致病菌水平。通过动物实验，采用CRS肝郁脾湿抑郁模型大鼠和抑郁菌群移植诱导无菌大鼠，研究“醒脾解郁法”对大鼠抑郁样行为和肠道菌群失调的作用机理，结果发现醒脾解郁方可增加CRS抑郁大鼠海马DA、NE、5-HT、GABA、BDNF水平含量（P<0.01），增加外周血ACTH、GCS、CRH含量（P<0.01），降低CORT、IL-1β、IL-6、TNF-α含量（P<0.01），增加IL-4、IL-10含量（P<0.01），保护结肠黏膜完整性，调节肠道菌群丰度及总体结构，减少致病菌，增加与代谢、免疫稳态相关的有益菌属水平；通过抑郁菌群移植可诱导无菌大鼠出现抑郁样行为，醒脾解郁方可改变肠道微生物多样性，并对致病菌及有益菌产生调节作用，提示肠道菌群为“醒脾解郁法”改善大鼠抑郁样行为的重要靶点。最后通过粪菌体外培养实验，探究“醒脾解郁法”对肝郁脾湿抑郁症患者肠道菌群活性是否存在直接调控作用，结果发现，醒脾解郁方可引起益生菌的富集（双歧杆菌和乳酸杆菌），参与代谢产物磷酸泛酸合成、脂质合成、糖代谢等。本课题从整体、器官、分子等多层次证实“醒脾解郁法”可直接作用于肠道菌群，为中医药学防治抑郁症提供新的有效方药，为抑郁症中医“肝脾同治”理论提供科学依据。