抑郁症发病机制不清，申请者发现肠道微生组紊乱是其潜在新病因（Nature子刊Molecular Psychiatry 2016），被Cell、Nat Med及 Nat Neurosci等他引176次（ESI 高被引）；继而证实改变的抑郁肠道微生组具有特异性（Science子刊Science Advances 2018），现亟待明确致抑郁的关键菌株，肠-脑途径及脑分子机制。据此，以患者与抑郁模型一致富集的拟杆菌属（Bacteroides）及其激活肠-脑轴LPS/TLR4为主线，开展：①宏基因表型关联分析产LPS的Bacteroides候选菌株，将其接种无菌小鼠及梯度抗生素处理小鼠，结合菌株干预及表型分析鉴定出致抑郁关键菌株；②将菌株及其培养上清分别接种TLR4敲出的无菌及对照小鼠，采用病毒示踪及光电极技术解析关键脑区；③通过“菌株-TLR4-分子通路”三节点递进干预，揭示关键菌株致抑郁机制。

Depression is a debilitating mental disorder. However, its pathogenesis still remains unclear. We provided evidence that dysbiosis of the gut microbiome attributes to the onset of MDD, which was also cited by Cell、Nat Med、Nature Neuroscience et al. Recently, we further found that alternations of gut microbiome were relatively specific (Science Advance 2018). Now, it is required to identify the key microbial species, gut-brain pathway and molecular basis of depression. Here, based on the consistently changed Bacteroides in both depressive patients and animals , and its activation of LPS/TLR4 pathway, we sought to perform: (i) Using metagenomics method, we sought to identify the candidate gut microbiota attributed to produce the LPS. Then, we transplant the candidate bacterial strains into germ-free mice and SPF mice intervened with gradient antibiotics, and further perform the depressive behaviors analysis to identify the key strains. (ii)The strains and their culture supernatant were inoculated with germ-free TLR4 knockout and control mice, the virus tracing and photoelectric technology were used to identify the key brain region. (iii) By targeted intervention of gut microbiota, use of TLR4 knock-out germ-free mice, and regulation of molecular pathways, we sought to uncover how the special microbial species to produce depression.