Project 1 - Changes in Gut Microbiome and related Metabolome Across Trajectory of Alzheimer's Disease

摘要-项目1：人类肠道微生物组、代谢组和AD表型 越来越多的证据表明阿尔茨海默病（AD）是一种代谢紊乱， 生化干扰已确认遗传因素、肠道细菌、饮食、生活方式和环境暴露 所有这些都有助于人类代谢及其在疾病状态（包括AD）中的失调。许多生物活性 代谢物如维生素、短链脂肪酸，和神经递质（例如，伽马氨基丁酸多巴胺 去甲肾上腺素5-羟色胺）由肠道细菌产生，因此可以调节大脑功能。双向 大脑和肠道之间的生物化学通讯可能导致神经退行性疾病， 精神疾病，包括抑郁症和神经变性疾病。最近，肠道的作用 Co-PI Mazmanian强调了微生物组在帕金森病病因学中的作用。此外，我们显示 AD患者大脑中微生物代谢产物的独特特征，表明人类的变化 微生物组改变肠道细菌的代谢产物，将潜在的疾病修饰化学物质送入肠道， 可能有助于病理生理学的大脑。在本提案中，我们寻求更深入地了解 AD发病机制中的肠道微生物组，并使用强大的宏基因组学和代谢组学工具来定义 肠道和大脑之间的生化交流轴。为了实施这个项目，我们将建立在大 倡议和已建立的基础设施，包括：美国肠道项目和人类微生物组项目 (led由Co-PI Knight领导）、AD代谢组学联盟（由Co-PI Kaddurah-Daouk领导）、AD研究 国家AD和相关痴呆症集中储存库（NCRAD），国家 阿尔茨海默氏症协调中心（NACC），以及代谢组学，宏基因组学， 信息学、机器和深度学习。在这个建议中，我们寻求：1）定义成分和功能 AD各阶段肠道微生物组的变化; 2）定义血液和粪便中的代谢组差异 与肠道微生物组组成和功能相关，并将其与认知和脑成像变化联系起来; 3)连接血液和大脑代谢组，以定义肠-脑通信的生化和免疫轴。 我们还将探索肠道微生物组在神经精神症状发展中的作用（例如， 抑郁表型和睡眠障碍）。健康和疾病时大脑的代谢状态 似乎依赖于外周代谢状态，并受到肠道代谢的影响。因此，理解 外周和中枢代谢如何与AD的失败联系在一起， 研究疾病的发病机制，并开发新的有效疗法来减缓或预防疾病。

ABSTRACT – Project 1: Human Gut Microbiome, Metabolome and AD Phenotypes Accumulating evidence characterizes Alzheimer’s disease (AD) as a metabolic disorder with several biochemical perturbations identified. Genetic factors, gut bacteria, diet, lifestyle, and environmental exposures all contribute to human metabolism and its dysregulation in disease states including AD. Many bioactive metabolites, such as vitamins, short-chain fatty acids, and neurotransmitters (e.g., GABA, dopamine, norepinephrine serotonin), are produced by the gut bacteria and thus can modulate brain function. Bidirectional biochemical communication between the brain and the gut may contribute to neurodegenerative and psychiatric diseases including depression and neurodegenerative diseases. Recently, a role for the gut microbiome in the etiology of Parkinson’s disease was highlighted by Co-PI Mazmanian. Further, we show distinct profiles in microbial metabolites in brains of AD patients, suggesting that changes to the human microbiome alter the metabolic output of gut bacteria to send potentially disease-modifying chemicals into the brain that may contribute to pathophysiology. In this proposal, we seek a deeper understanding of the role of the gut microbiome in AD pathogenesis and use powerful metagenomics and metabolomics tools to define biochemical axis of communication between the gut and brain. To implement this project we will build on large initiatives and established infrastructures including: The American Gut Project and Human Microbiome Project (led by Co-PI Knight), the AD Metabolomics Consortium (led by Co-PI Kaddurah-Daouk), AD Research Centers (ADRCs), National Centralized Repository for AD and Related Dementias (NCRAD), The National Alzheimer’s Coordinating Center (NACC), and centers of excellence in metabolomics, metagenomics, informatics, machine and deep learning. In this proposal we seek to: 1) define compositional and functional changes in the gut microbiome across stages of AD; 2) define metabolome differences in blood and feces related to gut microbiome composition and function and link these to cognitive and brain imaging changes; and 3) connect blood and brain metabolomes to define biochemical and immune axes of gut-brain communication. We will also explore the role of the gut microbiome in the development of neuropsychiatric symptoms (e.g., depressive phenotypes and sleep disturbances). The metabolic state of the brain in health and in disease seems dependent on peripheral metabolic states with influences from gut metabolism. Hence, understanding how peripheral and central metabolism is connected and linked to failures in AD is critical to the understanding of disease pathogenesis and for development of new effective therapies to slow or prevent the disease.