以肽聚糖-TLR2激活为桥梁解析致抑郁的肠道微生物菌株及机制

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.

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。

抑郁障碍是一种基因与环境交互影响的重大精神疾病，发病机制学说众多，主要有单胺类神经递质失衡、神经发生障碍、氧化应激障碍以及免疫调节紊乱等；申请者发现肠道微生组紊乱是其新病因，现亟待明确其致病菌株及致抑郁机制。据此，课题组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。我们通过依托构建的多中心抑郁障碍临床队列，整合分析了肠道微生物结构和功能紊乱与疾病严重程度、预后、疗效的关联。运用WGCNA，MGS等算法，挖掘PGN相关的9种拟杆菌属在抑郁症中的一致性的改变，并发现微生物源的谷氨酸、色氨酸及苯丙氨酸代谢通路紊乱,这可能与抑郁发病机制有关。随后，通过将抑郁症与精神分裂症（SCZ）进行比较，发现仅有15.3%微生物一致性上调、而构建“人源化”SCZ小鼠诱导出显著的精神分裂样行为和抑郁样行为抵抗，同时伴有谷氨酸-GABA代谢障碍。此外，基于前期构建的非人灵长类抑郁模型，发现抑郁样猴主要伴拟杆菌科紊乱；“肠-脑”轴宏基因及代谢表征加权共表达网络分析（WGCNA）显示，其可调控“肠-脑”轴甘油磷脂代谢参与抑郁行为的发生。我们的结果为抑郁症诊治提供全新靶点，拓展了微生物调控抑郁症发生发展的机制假说。