肠道菌群调控阿尔茨海默病认知功能的血流动力学机制及其超声影像评估

Alzheimer's disease (AD) has become a serious health care issue in our country, while there is still no effective intervention. New methods for AD prevention and treatment are imperatively needed. Previous studies found that the cerebral blood flow (CBF) reduction may be the initiating factors of abnormal accumulation of amyloid-β peptides, which is the key pathological characteristic of AD. Interventions that can improve brain perfusion are likely to be a new treatment for AD. Microbiota is associated with brain metabolism and cerebrovascular atherosclerosis in AD, which can significantly influence CBF. Previously, we found modulation on gut microbiota could effectively reverse the cardio and cerebrovascular impairment caused by adverse factors. We also found significantly decreases in Anaerostipes and Lactobacillus in AD patients. In current proposed project, we will further identify the characteristic species by microbiota analysis and try to confirm the relationship between the specific species，CBF and cognitive functions in clinical AD patients by ultrasound imaging. Then, corresponding microbiota intervention using the selected species will be made in AD model mouse. The small-animal ultrasound and PET imaging are used to evaluated the intervention effect on CBF. The brain amyloid-β peptides and cognitive function were also assessed. This project is aimed to elaborate the hemodynamic mechanism of the cognitive function modulation in Alzheimer’s disease by microbiota, and provide new method for AD prevention and treatment.

阿尔茨海默病(Alzheimer's disease, AD)已成为我国严重的医疗卫生问题，目前仍无切实有效的干预手段，亟需提出防治新思路。研究发现脑血流受损可能是引起脑Aβ蛋白异常堆积这一AD关键病理改变的始动因素，并有望成为新的干预途径。肠道菌群能够通过影响AD脑代谢水平和脑血管硬化程度，显著影响AD脑血流。申请人前期发现菌群调整能有效对抗不利因素引起的心脑血管损伤；并针对AD菌群初筛分析发现其产丁酸菌属和乳酸菌属显著减少。本项目拟在此基础上，通过进一步菌群分析明确特征菌种，结合超声成像AD脑血流动力学评估及认知功能评价，在临床样本中确立菌种和AD脑血流及认知功能的关系；进而对小鼠模型进行相应菌种干预，通过小动物超声及PET成像观察其对改善AD小鼠脑血流、脑组织Aβ水平及认知功能的作用。本研究有望阐明肠道菌群调控AD认知功能的血流动力学机制，并为AD防治提供菌群干预新思路。

阿尔茨海默病(Alzheimer's disease, AD)已成为我国严重的医疗卫生问题，目前仍无切实有效的干预手段，亟需提出防治新思路。研究发现脑血流受损可能是引起脑Aβ蛋白异常堆积这一AD关键病理改变的始动因素，并有望成为新的干预途径。肠道菌群能够通过影响AD脑代谢水平和脑血管硬化程度，显著影响AD脑血流。本项目通过菌群分析明确特征菌种，结合超声成像AD脑血流动力学评估及认知功能评价，确立丁酸菌和AD脑血流及认知功能的关系；进而对小鼠模型进行丁酸梭菌干预，为保证菌群干预的有效性，构建了MPN-MUC2（MM2）系统对丁酸梭菌进行封装，显著提高了菌群定植率；干预后通过小动物超声成像、荧光染色和行为学实验，发现其有效改善了AD 小鼠血管功能、脑血流量和认知功能得到改善，且用MM2 封装后在降低灌菌频次时也能达到高频次未封装灌菌干预的效果，进一步说明经MM2 封装增加了细菌在肠道的定植率；通过菌群分析，发现丁酸梭菌干预改善AD的机制主要是干预后AD小鼠的肠道微生物多样性增加，产丁酸的特征菌种显著增加，代谢物和血液中的丁酸含量增加，血管组织炎症反应降低和内皮功能的改善，脑血流改善，脑组织 Aβ 水平和神经炎症反应显著降低。本研究阐明了肠道菌群调控AD认知功能的血流动力学机制，构建及验证了MM2系统菌群移植干预对AD小鼠脑血流和认知功能的有效性，为AD防治提供了菌群干预新思路。