Impact of Alcohol Induced Intestinal Microbiota Dysbiosis in a Rodent Model of Alzheimers Disease

This project investigates the relationship between alcohol consumption and brain neurodegeneration in an Alzheimers Disease transgenic mouse model. Alzheimers disease is a devastating neurodegenerative disorder associated with aging. While genetics is important in the development of Alzheimers disease, environment and lifestyle contribute significantly to the development and progression of Alzheimers disease. One such lifestyle factor is alcohol consumption. Chronic alcohol consumption is associated with a greater risk of all types of dementia, especially Alzheimers disease. We investigated whether alcohol promotes Alzheimers disease via a mechanism involving proinflammatory alterations to the intestinal microbiota. Alcohol has numerous effects on the body including alterations in the intestinal microbiome and compelling evidence indicates that the intestinal microbiome can impact neuroinflammation as well as brain structure and function. Thus, this project examined whether alcohol can promote Alzheimers disease by a mechanism including intestinal microbiota dysbiosis which leads to microglial activation, neuroinflammation, brain pathology, and cognitive dysfunction. This was done through a 20 week alcohol consumption study in Alzheimers Disease transgenic mice and their respective wild typle control. The study began when mice were 10 weeks of age and continued until mice were 30 weeks of age, for a total duration of 20 weeks. When mice were 30 weeks of age, after 20 weeks of experimental manipulations, alcohol was removed for two weeks prior to initiating behavioral testing, to avoid any potential confounds of alcohol on behavioral performance, following the protocol in the previously published study, followed by tissue harvest at the of study. Stool was collected at two timepoints, the end of treatment, last week of alcohol consumption, and end of study, the night before tissue harvest. This experiment was conducted in both males and females, and each sex was examined separately.

本研究针对阿尔茨海默病（Alzheimer's Disease, AD）转基因小鼠模型，探究酒精摄入与大脑神经退行性病变之间的关联。阿尔茨海默病是一种与衰老相关的毁灭性神经退行性疾病。尽管遗传因素在阿尔茨海默病的发病过程中至关重要，但环境与生活方式对疾病的发生及进展同样具有显著贡献。其中一类生活方式影响因素即为酒精摄入。长期酒精摄入与各类痴呆症的发病风险升高存在关联，尤以阿尔茨海默病为甚。
本研究旨在探究酒精是否通过引发肠道菌群（intestinal microbiota）促炎性改变的通路，促进阿尔茨海默病的发生发展。酒精对机体具有多重调控效应，其中包括肠道菌群组成的改变；现有确凿证据表明，肠道菌群可对神经炎症（neuroinflammation）、大脑结构与功能产生显著影响。因此，本研究旨在验证酒精是否可通过引发肠道菌群失调（intestinal microbiota dysbiosis）的机制，进而诱导小胶质细胞（microglia）激活、神经炎症、脑病理损伤及认知功能障碍，最终促进阿尔茨海默病的进展。
本研究通过对阿尔茨海默病转基因小鼠及其对应野生型对照小鼠开展为期20周的酒精摄入实验完成上述验证。实验于小鼠10周龄时启动，持续至30周龄，总时长为20周。在小鼠达到30周龄、完成20周实验干预后，参照已发表研究的实验方案，我们在启动行为学测试前将酒精撤去2周，以避免酒精对行为学表现造成潜在混淆因素，随后在实验结束时采集组织样本。
我们在两个时间点采集粪便样本：一是干预结束时，即酒精摄入的最后一周；二是实验结束当日，即组织采集前一晚。本实验同时纳入雄性与雌性小鼠，并对两种性别分别开展独立分析。