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 积累证据角色阿尔茨海默氏病（AD）是一种代谢性疾病，有几个 确定的生化扰动。遗传因素，肠道细菌，饮食，生活方式和环境暴露 所有这些都导致人类代谢及其在包括AD在内的疾病状态的失调。许多生物活性 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，因此可以调节脑功能。双向 大脑与肠道之间的生化交流可能有助于神经退行性和 精神疾病，包括抑郁症和神经退行性疾病。最近，肠道的角色 Co-Pi Mazmanian强调了帕金森氏病病因的微生物组。此外，我们显示 AD患者大脑中微生物代谢产物的不同特征，表明对人类的变化 微生物组改变了肠道细菌的代谢输出，以将潜在的疾病改良化学物质发送到 可能导致病理生理学的大脑。在此提案中，我们寻求更深入的了解 AD发病机理中的肠道微生物组，并使用强大的宏基因组学和代谢组学工具来定义 肠道和大脑之间通信的生化轴。为了实施这个项目，我们将基于大型 计划和既定基础设施包括：美国肠道项目和人类微生物项目 （由Co-Pi Knight领导），AD代谢组学财团（由Co-Pi Kaddurah-Daouk领导），AD研究 中心（ADRCS），全国性的AD和相关痴呆症（NCRAD）国家集中式存储库，国家 阿尔茨海默氏症协调中心（NACC），以及代谢组学，宏基因组学的卓越中心， 信息，机器和深度学习。在此提案中，我们寻求：1）定义构图和功能 跨AD阶段的肠道微生物组的变化； 2）定义血液和粪便的代谢组差异 与肠道微生物组组成和功能有关，并将其与认知和脑成像变化联系起来；和 3）连接血液和脑代谢组，以定义肠道通信的生化和免疫轴。 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）。健康和疾病中大脑的代谢状态 似乎依赖于外周代谢状态，其肠道代谢受到影响。因此，理解 外围和中央代谢与AD失败的联系以及与AD失败相关的如何对理解至关重要 疾病发病机理以及开发新的有效疗法以减缓或预防疾病。