抑郁障碍是重大精神疾病，机制不清；申请者发现肠道微生组紊乱是其新病因（Nature子刊Mol Psychiatry 2016），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30余次；现亟待明确其致病菌株及致抑郁机制。据此，拟以人源化抑郁小鼠肠-脑肽聚糖（PGN）-TLR2激活为桥梁, 在“肠”明确产生PGN的关键菌株，在“脑”明确PGN-TLR2激活的通路及致抑郁机制：(1)采用宏基因表型关联分析，挖掘产生PGN的微生物菌属；发现PGN-TLR2激活信号通路及其致抑郁机制；(2)抗生素/选择性培养干预产生PGN的菌属，挖掘产生PGN亚类菌株；将其接种TLR2 KO无菌小鼠，并干预信号通路，实现“菌株-TLR2-信号通路”三节点递进干预，证实关键菌株及致抑郁机制。

Major depressive disorder (MDD) is a debilitating mental disorder. However, its pahogenesis still remains unclear. We for the first time found provid evidence that disturbed gut microbiota attribute to the onset of MDD, which was designated as Practice-changing Articles in 2016 by NEJM Journal Watch. Moreover, this novel finding was also highlighted by Cell、Nature Neuroscience et al. Here, based on the higher levels of peptidoglycan (PGN) and toll-like receptors 2 (TLR2), we sought to uncover the key microbial species and underlying molecular basis of depression: (i) Using metagenomics method, we sought to identify the key gut microbiota attributed to produce the PGN in the humanized depressive model, and uncover the signal pathways and molecular basis involved in activity of PGN- PGN; (ii) By targeted intervention of gut microbiota generating PGN using antibiotic, use of TLR2 knock-out germ-free mice, and regulation of signal pathways, we sought to identify the special microbial species to produce PGN, and uncover the key molecular mechanisms and therapic targeters in depression.