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

摘要-项目1：人体肠道微生物组、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，有几种 发现了生化干扰。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的新陈代谢及其在疾病状态下的失调，包括阿尔茨海默病。许多生物活性 代谢物，如维生素、短链脂肪酸和神经递质(如GABA、多巴胺、 去甲肾上腺素(5-羟色胺)是由肠道细菌产生的，因此可以调节大脑功能。双向 大脑和肠道之间的生化交流可能有助于神经退行性变和 精神疾病，包括抑郁症和神经退行性疾病。最近，一个角色的肠子 Co-Pi Mazmanian强调了微生物组在帕金森病病因学中的作用。此外，我们还展示了 AD患者脑内微生物代谢产物的不同特征，表明人类 微生物组改变肠道细菌的代谢输出，将潜在的疾病修饰性化学物质输送到 可能对病理生理学有贡献的大脑。在这项建议中，我们寻求更深入地了解 肠道微生物组在AD发病机制中的作用，并使用强大的元基因组学和代谢组学工具来定义 肠道和大脑之间的生物化学轴。为了实施这个项目，我们将建立在大型 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 (由Co-Pi Knight领导)，AD代谢组学联盟(由Co-Pi Kaddurah-Daouk领导)，AD Research 中心(ADRC)、国家AD和相关痴呆中央资料库(NCRAD)、国家 阿尔茨海默氏症协调中心(NACC)，以及代谢组学、元基因组学、 信息学、机器和深度学习。在本提案中，我们试图：1)定义组成和功能 阿尔茨海默病不同阶段肠道微生物群的变化；2)确定血液和粪便中代谢组的差异 与肠道微生物群的组成和功能有关，并将其与认知和脑成像变化联系起来；以及 3)连接血液和大脑代谢物，确定肠脑通讯的生化和免疫轴。 我们还将探索肠道微生物群在神经精神症状发展中的作用(例如， 抑郁表型和睡眠障碍)。大脑在健康和疾病中的代谢状态 似乎依赖于受肠道新陈代谢影响的外周代谢状态。因此，理解 外周和中枢新陈代谢是如何与阿尔茨海默病的失败联系在一起的，这对于理解 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.