Project 3 - Mechanistic studies on role of gut microbiome in models for Alzheimer's disease

摘要-项目3 来自环境的感官和分子信号影响大脑活动，并帮助塑造心理或 身体反应。胃肠道（GI）代表了我们周围分子世界的最大门户 我们，并发送信号，旅行到身体的所有器官，影响他们的功能，包括大脑。 用于肠-脑通信的管道包括肠道中产生的代谢物等， 激活肠神经系统（ENS）并通过迷走神经发出信号，或者分子甚至可以到达 大脑通过体循环然而，人们对细胞和分子生物学知之甚少。 连接肠道和大脑的机制进一步说，如果来自肠道的复杂信号流 调节大脑活动，也许由于环境的改变而引起的变化可能导致大脑活动的偏离。 健康人类与众多的常驻微生物物种有着密切的、终生的联系， 被称为微生物组，它代表了许多疾病中潜在的强大环境因素。肠道 细菌调节营养和新陈代谢，协调免疫系统的发育和功能。 系统有趣的是，肠道微生物组的群落结构和组成在神经系统中发生了改变。 焦虑、抑郁、自闭症谱系障碍（ASD）、精神分裂症、帕金森病等病症 (PD)和阿尔茨海默病（AD）。这些变化是疾病的结果还是 仍然完全未知。区分相关性和因果关系的研究既具有挑战性， 在人类中是不合理的。因此，我们建议研究人类微生物组在以下方面的功能贡献： 新的AD小鼠模型，以测试从肠道到大脑的微生物信号的假设， 促进神经免疫激活、病理学和神经变性的症状。虽然基础和临床 研究正在迅速确定AD的病理生理学，但大多数病例的原因仍不清楚。因此，在本发明中， 即使是最好的药物，相对无效或有严重的副作用，也只能解决症状 并且不改变疾病。我们提供了开创性的证据，表明肠道微生物组是一个关键因素， 使用小鼠模型研究AD的病理学，为疾病病因学提供了全新的视角。解开 肠道-微生物组-大脑的联系有望改变神经科学， 可能是阿尔茨海默病的革命性诊断和治疗方法。

ABSTRACT – PROJECT 3 Sensory and molecular signals from the environment influence brain activity and help shape psychological or physical responses. The gastrointestinal (GI) tract represents our largest portal to the molecular world around us, and sends signals that travel to all organs of the body that impact their function, including the brain. Conduits used for gut-to-brain communication include, among others, metabolites produced in the gut that may activate the enteric nervous system (ENS) and signal via the vagus nerve, or molecules may even reach the brain through systemic circulation. However, there is remarkably little known about the cellular and molecular mechanisms that connect the gut to the brain. Further, if indeed the flow of complex signals from the gut modulates brain activity, perhaps changes due to altered environments may result in deviations from brain health. Humans share an intimate and life-long association with multitudes of resident microbial species, known as the microbiome, which represents a potentially strong environmental factor in may diseases. Gut bacteria regulate nutrition and metabolism, and orchestrate the development and function of the immune system. Intriguingly, the community structure and composition of the gut microbiome is altered in neurologic conditions such as anxiety, depression, autism spectrum disorder (ASD), schizophrenia, Parkinson’s disease (PD) and Alzheimer’s disease (AD). Whether these changes are a consequence of disease or a contributor remain entirely unknown. Studies that distinguish correlation from causation are both challenging and unjustified in humans. Thus, we propose to study the functional contributions of the human microbiome in novel mouse models of AD to test the hypothesis that microbial signals that travel from the gut to the brain promote neuroimmune activation, pathology, and symptoms of neurodegeneration. While basic and clinical research is rapidly defining the pathophysiology of AD, the cause(s) of most cases remain unknown. Thus, even the best medicines, which are relatively ineffective or have severe side effects, only address symptoms and are not disease-modifying. We provide seminal evidence that the gut microbiome is a key contributor to the pathology of AD using mouse models, offering entirely novel perspectives into disease etiology. Unraveling gut-microbiome-brain connections holds the promise of transforming the neurosciences and revealing potentially revolutionary diagnostics and treatments for Alzheimer’s disease.