基于无菌小鼠研究肠道微生物紊乱所致抑郁的代谢通路及其调控代谢酶

Depression is an environment and gene interact affected mental disorder with high suicide rate. However, its pahogenesis still remains unclear. Gut microbiota is the most abundant external environment in human body. We firstly reported that depression is associated with disturbance of gut microbiota. Recent 16S rRNA sequence analysis of fresh fecal, as well as colonization of germ-free mice with fecal sample from depression patients resulted in depressive behavioral, put further evidence to this hypothesis. .Herein, we use the aforementioned germ-free mice model to uncover the underlying metabolic mechanism of depression in perspective of gut-brain axis. (1) Both targeted and untargeted metabolomic methods will be used to uncover the potential perturbed metabolic pathways and key enzymes. Moreover the meta-transcriptome analysis of fecal samples from the depressed and control mice will be also performed. Integration of the obtained information, the key “gut-brain” metabolite pathways can be uncovered; (2) Colonization of germ free mice with metabolite supernatant obtained from depressed and control mice will be used to validate the core pathway; (3)To validate the biological function of the key enzyme in mice brain with activation/ deactivation method of antidepressant in mice.

抑郁症是一种环境与基因交互影响的复杂精神疾病。肠道微生物是人体最大、最直接的外环境，成为现今解析疾病机制新的热点与前沿。前期课题组率先在国际上报道抑郁症伴有肠道微生物源的代谢物紊乱；近期通过粪便16S rRNA测序证实抑郁症伴有肠道微生物紊乱，且将抑郁症患者粪便灌胃植入无菌小鼠诱导出抑郁样行为。.据此，本课题拟以粪便转植无菌抑郁小鼠为载体，以肠-脑轴为主线，研究微生物紊乱所致抑郁的代谢通路及其调控代谢酶。主要开展以下工作：（1）整合靶向/非靶向代谢组学研究优势，开展“肠-脑”两个水平的动态代谢分析，结合粪便宏转录信息，发现微生物紊乱所致抑郁的“肠-脑”代谢通路；（2）提取抑郁和对照小鼠粪便代谢上清灌胃于无菌小鼠，结合行为分析，靶向验证 “肠-脑”核心通路；（3）采用药物激活或抑制脑内代谢通路的代谢酶，结合行为分析，验证其生物学功能。

抑郁症是一种环境与基因交互影响的复杂精神疾病。肠道微生物是人体最大、最直接的外环境。本课题以粪便转植无菌抑郁小鼠为载体，以肠-脑轴为主线，整合靶向/非靶向代谢组学研究优势，开展“肠-脑”两个水平的动态代谢分析，结合粪便宏转录信息，发现微生物紊乱所致抑郁的“肠-脑”代谢通路。该成果发表在Nature子刊Mol Psychiatry (Zheng Peng et al. Mol Psychiatry 2016a； IF=13.34)，被新英格兰Journal Watch评为2016年“Practice-changing Articles ”、仅1年即被Cell、Nature Neuroscience等他引100余次.