肠道微生态在脑老化认知功能减退中的作用及机制研究

Normal brain aging is accompanied by cognitive decline, and the mechanisms are complex and unclear. Gut microbiome may have critical effects on structures， functions of brain and neurodegenerative processes and diseases. Studies have shown that gut microbiome of the elderly was significantly different from that of the adult, which may affect health level and disease of susceptibility in elderly populations. Studies have reported the effects of gut microbiome on learning and memory，but it is based on the special animal model. And no report to systematically observe the effect of gut microbiome on cognitive decline in the normal aging animal model. In this study, 1. Bi-directional fecal microbiome transplantion (FMT) of aged and adult rats would be carried out, to observe the cognitive behavior by operating conditioning and Y maze; to observe different brain regions and function connection by fMRI; to observe synapse and dendritic spines by electron microscopy and Golgi staining; to observe the expression of BDNF, NMDAR1 and GR by western blot; Aged rats were treated with probiotics and antibiotics，to observe the cognitive behavior; 2. To detect oxidative stress in brain after FMT, to explore if gut microbiome have the role through oxidative stress mechanism; 3. GF drosophila were fed with different bacterial strain and then were observed cognitive behavior, to discover the bacteria affecting cognition. The present study may provide new evidence for the occurrence and mechanism of cognitive decline in normal aging.

脑老化最重要的特征是认知功能减退，机制复杂且不明。研究发现老年人群的肠道微生态发生显著改变，可能影响老年人的健康水平和疾病发生。已有报道利用特殊动物模型观察肠道微生态对学习记忆的影响，但尚无利用正常衰老动物系统观察肠道菌群影响老化认知功能减退的报道。为明确肠道微生态对老化认知功能的影响，本项目采用正常衰老大鼠及老年与年轻鼠交叉粪菌移植的动物模型，通过宏基因组测序、操作条件反射、fMRI成像、生化测定、电镜、免疫组化、果蝇观察等技术，观察老年鼠及经过交叉粪菌移植的年轻（或老年）鼠的肠道菌群和认知功能，包括认知行为、脑区及功能连接、突触包括树突棘、重要信号分子改变等；为探讨肠道微生态影响老化认知功能的可能机制，检测老年鼠及粪菌移植鼠脑组织氧化应激反应的改变；通过给无菌果蝇喂养老年与年轻鼠差异菌并检测认知行为，筛选与老化认知功能减退相关的菌株。本项目可能为老化认知功能减退发生及机制提供新的证据。

老年大鼠认知功能减退，同时肠道菌群与年轻大鼠有明显差异。但是肠道菌群在脑老化认知减退中的作用及机制并不明确。本课题通过交叉粪菌移植，将老年大鼠的粪菌移植给年轻大鼠，在改变了肠道菌群的同时年轻大鼠出现认知功能减退；内侧前额叶和海马功能活动下降；突触结构改变及突触素表达减少；树突棘密度减小；某些重要的信号分子如BDNF、NR1表达减少，AGE/RAGE表达增加。表明老年的肠道菌群可引起年轻大鼠脑老化认知减退。氧化应激和炎症是脑老化的重要机制。老年的肠道菌群引起年轻大鼠循环和脑内氧化应激和炎症水平增加。将年轻大鼠的肠道菌群移植给老年大鼠，老年大鼠的肠道菌群改变，盲肠、血清及脑内代谢物发生改变，认知功能得到改善。我们的研究首次证实肠道微生态在脑老化认知功能减退中发挥重要作用。肠道菌群可能通过代谢途径影响氧化应激和炎症水平在脑老化认知功能减退中发挥作用。本课题已在Aging-US发表文章1篇（影响因子5.682，他引频次32），在北大中文核心期刊发表文章1篇，申请实用新型专利2项。培养博士研究生3名，硕士研究生1名。