肠脑轴调控在n-3 PUFA防治阿尔兹海默症中的作用与机制研究

Alzheimer’s disease (AD) is the challenging public health problem worldwide, and its pathogenesis mechanism and control measures require further investigation. Recent studies suggest that the gut microbiota dysfunction induced gut brain axis imbalance might play important role in the development and progression of AD. n-3 polyunsaturated fatty acids (PUFAs) are the critical nutrients in maintaining the structure and function of central neurons, yet its effects and mechanism on AD control remains uncertain. Based on our previous finding that the elevated endogenous n-3 PUFA could increase the abundances of intestinal Lactobacillus acidophilus and Bifidobacterium and decrease the systematic inflammatory responses, which have been identified to be actively involved in the AD improvement via the neuroendocrine, vagal nerve and immune system pathways of gut brain axis, we hereby propose and verify the hypothesis that n-3 PUFA can modulation the gut brain axis by improving the gut microbiota and subsequently ameliorate the development and progression of AD. Based on the population intervention and animal study, this project is designed to comprehensively evaluate the effects of n-3 PUFA enrichment on AD control targeted on gut brain axis, by using the techniques of high throughput sequencing, metagenomic function prediction, fat-1/AD model establishment, germ-free animal model validation and systematic biology analysis. Our study is of great significance in further clarifying the effects and mechanism of gut microbiota-gut brain axis remodeling on AD control, and also provides scientific evidence for the prevention and treatment of AD through the dietary management.

阿尔兹海默症（AD）是全球范围内的重大公共卫生问题。近期研究表明，肠道菌群紊乱引起的肠脑轴失调可能在AD发生发展中起重要作用。n-3 PUFA是维护神经元正常结构和功能的关键营养素，但其对AD的防治效应及机制尚不明确。结合我们前期发现内源性n-3 PUFA水平上升可增加乳酸杆菌及双歧杆菌水平并降低体内炎症，而该类效应可通过肠脑轴的神经内分泌途径、迷走神经途径和免疫途径综合影响AD的转归，本项目提出“n-3 PUFA可通过改善肠道菌群调节肠脑轴，进而对AD的发生发展起保护作用”的研究假说。通过高通量测序、宏基因组功能预测、fat-1/AD模型构建、无菌动物验证、系统生物学分析等手段，从人群研究和动物实验两个层面综合评价以肠脑轴为靶点的n-3 PUFA干预在AD防治中的作用。本项目有助于进一步揭示肠道菌群、肠脑轴与AD发生发展的关系及其分子机制，并为指导居民从膳食营养途径防治AD提供理论依据。

阿尔兹海默症（AD）是全球范围内重大的公共卫生问题。随着我国人口老龄化加剧，AD也为我国公共卫生带来的巨大的挑战。结合既往研究结果，我们推测n-3 多不饱和脂肪酸（n-3 PUFA）可能通过微生物-肠脑轴改善AD症状。我们使用AD模型小鼠APP/PS1和能自身合成n-3 PUFA的fat-1小鼠杂交，根据基因型分为以下四组：野生对照组（WT）、内源性合成n-3 PUFA组（Fat-1）、AD模型组（APPPS1）、fat-1/APPPS1双表达基因组（Fat-1/APPPS1）。.与APPPS1组相比，Fat-1/APPPS1组学习记忆能能显著改善，同时Aβ淀粉样蛋白沉积显著降低。内源性n-3 PUFA上升还显著重塑了肠道菌群，相比于APPPS1组，Fat-1/APPPS1组Bacteroidales_S24-7_group丰度显著升高，Faecalibaculum和Desulfovibrio丰度显著降低。此外，内源性n-3 PUFA上升也显著改善了肠屏障功能，减少了内毒素（LPS）入血，继而降低了中枢神经系统炎症和小胶质细胞极化。.通过广谱抗生素清除实验和菌群移植实验，我们证明了内源性n-3 PUFA通过内源性n-3 PUFA通过微生物-肠脑轴，改善肠道屏障，通过抑制小胶质细胞活化和调节抑制小胶质细胞极化转化，改善AD症状。