柴胡疏肝散抗抑郁作用的新机制—胆汁酸调节的肠道菌群轮廓及吸收成分基础

Depression is the leading cause of human disability and suicide. Clinical effects of Western medicine is limited, whereas, traditional Chinese medicine has the advantage of “multi-target” effects and low toxicity. We inspired by the theory of traditional Chinese medicine-“Gan Dan Xiang Yi”, and proposed innovative approach to investigate new mechanism for the antidepressant effect of Chaihu-Shugan-San (CSS) based on "bile acid- regulated gut microbiota". CSS increased total bile acids concentrations in the serum of mice with depression in Chinese syndrome-Gan Qi Yu Jie, and the transcriptional level of rate-limiting enzyme in bile acid synthetic pathway in livers of these mice, however, feeding non-absorbing bile acid binding resins (cholestyramine) significantly reduced the antidepressant effect of CSS. Bile acid regulate the outline gut flora, and the gut flora modulate the pathological processes of depression. Therefore, this project intends to use molecular biology techniques, liquid chromatography-mass spectrometry, and in vivo/vitro experiment on three different level with whole, cellular and molecular aspects to investigate: does CSS treat depression in Chinese syndrome-Gan Qi Yu Jie by changing bile acid homeostasis and regulate gut microbiota; how CSS increase bile acid synthesis, does this effect relate to FXR-fgf15/shp pathway, and what are the absorbed compounds related to this effect; difference of bile acids concentrations in the serum and gut microbiota between mice and patients in the preliminary diagnosis with depression in Chinese syndrome-Gan Qi Yu Jie to tell species differences; All these work aims to clarify whether the influence of bile acids to antidepressant effects of CSS mediate by gut microbiota and the related absorbing components, to explore new ways to study the molecular mechanism of antidepressant treatment with CSS, and its potential of clinical transformation.

抑郁症是导致人类致残的头号杀手和自杀的主要原因。西医治疗有限，中医中药以其“多靶点”效应和低毒副作用取得了满意疗效。我们受中医肝胆相依理论启发，创新性提出基于“胆汁酸调节肠道菌群轮廓”研究柴胡疏肝散（CSS）抗抑郁作用的新机制。我们发现CSS可增加抑郁症肝气郁结证型小鼠血中总胆汁酸含量和胆酸合成限速酶转录，肠胆汁酸减少可明显减弱CSS抗抑郁作用。胆汁酸调节肠道菌群，肠道菌群影响抑郁症病理过程。故本项目拟用分子生物学和液质联用等技术，从整体、细胞和分子水平考察：CSS是否通过改变胆汁酸稳态，调节肠道菌群，治疗肝气郁结证型抑郁症；CSS增加胆汁酸合成是否通过FXR-fgf15/shp通路实现及相关吸收成分；初诊肝气郁结证型抑郁症患者胆汁酸含量及肠道菌群与模型动物差异；以明确胆汁酸对CSS抗抑郁作用的影响是否由肠道菌群轮廓介导及相关吸收成分，探索CSS抗抑郁治疗分子机制研究的新途径及其临床转化。

抑郁是造成失能寿命损失年的主要原因且诊治率普遍较低。研究表明，肠道菌群在抑郁症的发病及治疗中起到重要作用，而胆汁酸是调节肠道菌群的重要内源性小分子物质，故本课题的研究重点是胆汁酸-肠道菌之间的对话出错是否影响柴胡疏肝散抗抑郁疗效。结果显示，1）主动调节胆汁酸可以影响柴胡疏肝散的抗抑郁疗效，表现为经典的抑郁行为学指标糖水消耗以及强迫游泳的主动和被动应对时间改变；2）主动调节胆汁酸可以改变柴胡疏肝散影响的肠道菌群；3）肠道内胆汁酸减少造成的柴胡疏肝散的药效减弱被药物调节的肠道菌灌胃改善，并且过滤掉菌群后的粪便移植的改善作用消失，提示胆汁酸与肠道菌群之间的交互作用是柴胡疏肝散调节的靶点。同时，柴胡具有高生物活性而低生物利用度的特点，我们在体外将人的肠道菌与方剂中的君药柴胡提取物共孵育，观察到肠道菌对药物的生物转化途径，发现肠道菌对柴胡的主要代谢为脱糖和脱水，并且对肠道菌群的种类和量有影响，提示肠道菌与药物也存在直接的相互作用。本项目已发表标注基金资助相关论文6篇，其中SCI论文6篇，申请专利1项，出版相关中文专著1部，获奖励1项。已培养硕士3名。本研究为中药复方治疗抑郁症及其机制研究提供新的思路。