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

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。

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.