肠道菌群对认知功能与阿尔茨海默病发病机制的影响

Alzheimer’s disease (AD), as the most common form of dementia among older individuals, has been recognized as a major public health concern in societies with an aging population. Despite much progress, the pathogenesis of AD remains to be elucidated and there are no available effective treatments that stop or reverse the progression of the disease. It has recently become evident that intestinal microbiota can greatly influence all aspects of physiology including gut–brain communication, brain function and even behaviour. And dysbiosis of intestinal microbiota has been suggested to associate with AD. However, no systematic study of relationship between intestinal microbiota and AD has been currently reported. This study is designed to performe pyrosequencing-based analysis of the 16S rRNA gene V3 region to analyze alteration of intestinal microbiota in AD model; investigate the effects of target bacteria on cognition of gnotobiotic mice, target bacteria sensitive antibiotic and probiotics on the cognitive deficits in AD model to definite the association between intestinal microbiota and AD, so as to offer microbiota-based approaches for mechanism research and clinical prevention and treatment of AD.

阿尔茨海默病（Alzheimer’s disease, AD）是老年人最常见的痴呆类型，随着全球老龄化和环境的恶化，发病形势异常严峻。但至今无有效的治疗药物，发病机制也不明确。近年来随着对“微生物-肠-脑”轴的研究，大量数据表明正常的肠道菌群对认知功能具有重要作用，而肠道菌群失调可能与AD的发病有关。但目前尚无对AD肠道菌群的系统研究，本项目拟应用16S rRNA测序分析AD模型肠道菌群的变化并结合文献筛选出目标差异菌；通过研究差异菌对无菌动物认知功能的影响，差异菌敏感的抗菌药或益生菌对AD模型认知功能的影响进一步明确肠道菌群与认知功能和AD发病的关系。希望为AD等认知相关疾病的机制研究和临床防治提供新线索。

阿尔茨海默病（Alzheimer’s disease, AD）是老年人最常见的痴呆类型，迄今无有效的治疗药物，发病机制也不明确。近年来大量数据表明肠道菌群失调可能与AD的发病有关。但目前尚无对AD肠道菌群的系统研究，本项目应用16S rRNA和宏基因组测序分析了不同年龄阶段AD模型肠道菌群的变化；通过粪菌移和益生菌植入无菌动物和AD/WT小鼠研究不同肠道菌群对认知功能的影响并初步探索其中机制；同时给予Cy3G干预AD模型小鼠观察对其认知功能和肠道菌群的影响。结果显示8-12月龄AD模型小鼠肠道菌群的α多样性显著降低；在门水平上，8-12月龄AD小鼠的Verrucomicrobia含量比同月龄WT小鼠大概增加6倍；在种水平上，产丁酸菌pullicaecorum在AD小鼠中明显减少；我们猜测AD模型肠道菌群的改变可能与Aβ在肠道沉积损伤肠道结构与屏障相关；生物信息学分析和对短链脂肪酸的检测结果均提示AD小鼠肠道菌群的变化可能影响碳水化合物、核苷酸和短链脂肪酸（如丁酸）的代谢。分别将WT粪菌、AD粪菌和益生菌移植入无菌小鼠体内均可改善无菌小鼠的认知功能，但三者间并无明显差异；而将WT、AD粪菌进行相互移植并不改变彼此的认知功能，这提示正常的肠道微生态对认知功能的维持具有重要作用，但是肠道菌群紊乱可能与AD的认知障碍并不存在直接相关性；另外粪菌/益生菌移植对无菌小鼠认知功能的改善可能与短链脂肪酸的增加及其神经递质的变化有关。对肠道菌群的调节可能是Cy3G对AD模型小鼠认知功能的潜在机制之一。以上结果初步明确了肠道菌群与认知功能和AD发病的关系，希望为AD等认知相关疾病的机制研究和临床防治提供线索。