环境铅毒物导致儿童学习记忆下降和认知功能障碍，小胶质细胞炎性激活在其中起重要作用，肠道菌群的改变可导致小胶质细胞激活，而铅暴露造成肠道菌群失调，但这种失调和铅致小胶质细胞激活进而造成神经损伤之间的关系和作用机制尚不清楚。前期实验发现，铅暴露导致肠道菌群发生改变，激活脑部小胶质细胞，使TLR4蛋白表达升高，本研究拟利用粪菌移植的动物模型，采用16SrDNA高通量测序和液质联用技术检测肠道菌群及其代谢物，并结合细胞模型，采用免疫荧光、电生理和慢病毒转染等方法，对TLR4相关蛋白的丰度进行检测和调节，探讨肠道菌群及其代谢物改变导致的小胶质细胞活化在铅暴露造成学习记忆损伤和神经行为改变中的作用；揭示肠道菌群代谢物调控的TLR4相关蛋白改变是铅诱导小胶质细胞炎性激活的关键环节；阐明铅暴露诱导的肠道菌群及其代谢物改变与小胶质细胞TLR4相关蛋白之间的关系，为后期调控肠道菌群以防治铅神经损伤奠定基础。

Lead exposure induces impaired learning, memory and other cognitive behavior in children, in which the activation of microglial cells plays a vital role. The dysbiosis of microbiota has recently been recognized as a key step in activating microglia and generating pro-inflammatory factors. Both disruption of microbiota and TLR4 activation are closely associated with microglia activation. However, whether and how lead-induced microbiota dysbiosis results in microglia activation remains to be unraveled. In our preliminary studies, we found that lead induces microbiota dysbiosis and the expression of TLR4 is upregulated after lead exposure. In this project, we propose to investigate the changes of microbiota and its metabolites induced by lead exposure, and the relationship of these changes to neurobehavioral deficits using in vivo models. Next, we propose to investigate the role of lead-induced microbiota dysbiosis and TLR4 signaling dysregulation in microglial activation. We will further explore the association of microbiota metabolites and TLR4 activation induced by lead in microglia. Our investigation will not only reveal the role of microbiota dysbiosis and related microglia activation in lead-induced neurotoxicity, but also shed light on the prevention and protection of lead-induced neurotoxicity.