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

项目 1 - 阿尔茨海默氏病轨迹中肠道微生物组和相关代谢组的变化

• 批准号: 10017875
• 负责人: Rima F Kaddurah-Daouk
• 金额: $ 56.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017875
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Animal Disease Models; Behavioral; Bile Acids; Biochemical; Biochemical Process; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood specimen; Brain; Brain imaging; Branched-Chain Amino Acids; Catalogs; Categories; Chemicals; Cholesterol Homeostasis; Cognition; Cognitive; Cohort Studies; Communication; Communities; Data; Data Analyses; Data Set; Dementia; Deoxycholic Acid; Development; Diet; Disease; Disease Progression; Dopamine; Elderly; Environmental Exposure; Ethnic Origin; Etiology; FAIR principles; Failure; Feces; Functional disorder; Funding; Genes; Genetic; Health; Hepatic; Human; Human Microbiome; Immune; Impaired cognition; Informatics; Infrastructure; Knowledge; Life Style; Link; Lipids; Liver; Machine Learning; Medicine; Mental Depression; Mental disorders; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Metagenomics; Methodology; Microbe; Natural Immunity; Neurodegenerative Disorders; Neurotransmitters; Norepinephrine; Output; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Peripheral; Phagocytosis; Phenotype; Phospholipids; Play; Production; Research; Resources; Role; Sampling; Serotonin; Shotguns; Sleep; Sleep disturbances; Taxonomy; Viral; Vitamins; Volatile Fatty Acids; apolipoprotein E-4; cerebral atrophy; circadian; clinical center; cognitive change; cohort; cytotoxic; deep learning; depressive symptoms; disease phenotype; dysbiosis; effective therapy; endophenotype; gamma-Aminobutyric Acid; glucose metabolism; gut bacteria; gut microbiome; gut-brain axis; immune function; metabolome; metabolomics; microbial; microbiome; microbiome alteration; microbiome composition; mild cognitive impairment; motor disorder; neuroimaging; neuropsychiatric disorder; neuropsychiatric symptom; open data; prevent; repository; sex; small molecule; tau Proteins; tool

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.

摘要 – 项目 1：人类肠道微生物组、代谢组和 AD 表型 越来越多的证据将阿尔茨海默病 (AD) 描述为一种代谢性疾病，涉及多种疾病 确定的生化干扰包括遗传因素、肠道细菌、饮食、生活方式和环境暴露。 所有这些都会导致人类新陈代谢及其在疾病状态（包括 AD）中的失调。 代谢物，例如维生素、短链脂肪酸和神经递质（例如 GABA、多巴胺、 去甲肾上腺素、血清素）由肠道细菌产生，因此可以调节大脑功能。 大脑和肠道之间的生化通讯可能会导致神经退行性病变 最近，肠道在精神疾病中发挥着重要作用，包括抑郁症和神经退行性疾病。 Co-PI Mazmanian 进一步强调了微生物组在帕金森病病因学中的作用。 AD 患者大脑中微生物代谢物的不同特征表明，人类 微生物组改变肠道细菌的代谢输出，将潜在的缓解疾病的化学物质发送到肠道 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其作用。 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 为了实施这个项目，我们将建立在肠道和大脑之间的生化轴上。 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 和相关痴呆症中央存储库 (NCRAD)、国家 阿尔茨海默病协调中心 (NACC) 以及代谢组学、宏基因组学卓越中心、 在这个提案中，我们寻求：1）定义组合和功能。 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 与肠道微生物组成和功能相关，并将这些与大脑成像变化联系起来； 3）连接血液和大脑代谢组，以定义肠脑通讯的生化和免疫轴。 我们还将探讨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）。健康和疾病状态下大脑的代谢状态。 似乎依赖于受肠道代谢影响的外周代谢状态，因此，请理解。 外周和中枢代谢如何与 AD 失败相关并与之相关对于理解这一点至关重要 疾病发病机制并开发新的有效疗法来减缓或预防该疾病。