基于“微生物-肠-脑”轴研究针刺治疗抑郁症的代谢通路及其调控代谢酶

Major depressive disorder (MDD) is a socially detrimental psychiatric disorder, both genes and environment can have an impact on it. Intestinal microbial is the largest and most direct external environment. our group first found that intestinal microbial disorders was a new cause of MDD. The results was focused on by Cell and Nature Review. In 2016, clinical practice guidelines of American Academy of Internal Medicine pointed out that acupuncture was an effective treatment of depression, the research of the mechanism needed to be carried out immediately. Recent studies have shown that acupuncture can regulate intestinal microbial. In this study, based on acupuncture treatment of depression model, the intestinal-brain axis as the main line, we explore the metabolic pathways and metabolic enzymes on the treatment of depression. (1) Based on the metabolomics research platform, this study integrates the results of both targeted and non-targeted metabolomics to carry out the intestinal-brain metabolic analysis, combining with fecal transcription information to discover intestinal- brain metabolic pathway and the key metabolic enzymes. (2) We use the feces supernatant of chronic unpredicted mild stress (CUMS) group, acupuncture treatment of CUMS group and control group mice to gavage the germ-free (GF) mice. Through the analysis of fecal supernatant and brain tissue of GF mice, combining with behavioral analysis, target the intestinal-brain metabolic pathway. (3) We use drugs to activate or inhibit the metabolic enzymes of brain metabolism pathway, combining with behavioral analysis, to verify biological function. Finally, we reveal the mechanism and provide a theoretical basis for the extensive application of acupuncture on the treatment of depression.

抑郁症是一种基因与环境交互影响的重大精神疾病。肠道微生物是人体最大、最直接的外环境，课题组率先发现肠道微生物紊乱是抑郁症新的病因，成果被Cell, Nature Review重点评述。2016年美国内科学会临床实践指南指出，针刺是抑郁症的有效治疗方式，亟待阐明其机制。鉴于针刺可调节肠道微生物，我们拟以肠-脑轴为研究主线，探索针刺治疗抑郁症代谢通路及代谢酶:⑴联合采用靶向/非靶向代谢组方法，开展“肠-脑”两个水平的代谢分析，结合粪便宏转录信息，筛选针刺治疗抑郁症所致的“肠-脑”代谢通路及代谢酶；⑵将慢性不可预见性温和刺激(CUMS）组、针刺干预CUMS组与对照组小鼠粪便植入无菌小鼠，采集粪便上清及脑组织，结合抑郁行为学分析，靶向验证“肠-脑”核心通路；⑶采用药物激活或抑制脑内代谢通路的关键酶，结合抑郁行为分析，验证其生物学功能。最终为揭示针刺治疗抑郁症的相关机制及其广泛应用提供理论依据。

抑郁症是基因与外环境交互影响的重大精神疾病。针刺在抑郁症的治疗中具有疗效好且副作用小的优势。本课题以针刺治疗CUMS抑郁大鼠模型为载体，“微生物-肠-脑”轴为主线，开展靶向与非靶向结合的代谢组学策略，并进行动态代谢组学与肠道微生物多样性研究，整合针刺治疗抑郁症过程中粪便与脑代谢通路，发现针刺治疗抑郁症对“肠-脑”的调节作用。

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