Microbiome, Environment, and Parkinsons disease (MEP) PESTICIDE EXPOSURES AND THE GUT MICROBIOME IN PARKINSONS DISEASE

微生物组、环境和帕金森病 (MEP) 农药暴露以及帕金森病中的肠道微生物组

• 批准号: 10240329
• 负责人: Beate R Ritz
• 金额: $ 65.18万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10240329
• 关键词: Address; Affect; Age; Air Pollution; Animals; Area; Assessment tool; Behavior; Biological; Biological Models; Blood; Blood specimen; Brain; Brain Pathology; California; Chronic; Clinical; Clinical Data; Cognitive; Communities; Complement; Constipation; Cross-Sectional Studies; Data; Development; Diet; Digestive System Disorders; Disease; Disease Progression; Elderly; Enrollment; Enteric Nervous System; Environment; Environmental Exposure; Environmental Impact; Environmental Risk Factor; Etiology; Exposure to; Feces; Funding; Gastroparesis; Genes; Genetic; Geographic Information Systems; Health Personnel; Household; Human; Human Microbiome; Immune system; Impaired cognition; Inflammation; Intervention; Lewy Bodies; Life Style; Longitudinal Studies; Measures; Mediating; Medical; Metabolic Pathway; Metagenomics; Metals; Microbe; Motor; Nerve Degeneration; Nervous System Physiology; Neurodegenerative Disorders; Nutrient; Onset of illness; Parkinson Disease; Participant; Pathologic; Pathway interactions; Patients; Pesticides; Pharmaceutical Preparations; Phenotype; Physiology; Play; Population; Population Study; Prevention; Process; Public Policy; RNA, Ribosomal, 16S; Records; Regulation; Reporting; Research; Resources; Role; Sampling; Serum; Shotguns; Specificity; Susceptibility Gene; System; Testing; Time; Toxin; agricultural pesticide; alpha synuclein; base; cell motility; cohort; disease diagnosis; experience; experimental study; follow-up; gastrointestinal; gastrointestinal symptom; gene environment interaction; gut microbiome; gut microbiota; gut-brain axis; human microbiota; inflammatory disease of the intestine; insight; member; metabolomics; metagenome; microbiome; microbiome composition; microbiome research; microbiota; motor impairment; non-motor symptom; novel; parkinson' s disease registry; pesticide exposure; pesticide interaction; prevent; protein aggregation; recruit; rural environment; rural health network; sex; time use; tool; uptake

Abstract. The human microbiome has a major role in the uptake and handling of nutrients, medications, and toxins; and is of great immune system relevance. Evidence is mounting that it can affect aspects of neurologic function, brain activity, and behavior via the ‘gut-brain-axis’. New propositions are that environmental exposures such as pesticides, metals, and air pollution influence the microbiome and the human immune system and that the microbiome plays a role in Parkinson’s disease (PD). Here we propose the novel hypothesis that a) the microbiome is affected by chronic environmental exposures, specifically pesticides; and b) an altered gut microbiome composition or function contributes to the progression of neurodegeneration in PD. PD - a progressive neurodegenerative disease – has various non-motor symptoms including gastro-intestinal (GI) features such as constipation and gastroparesis. Its pathologic hallmarks, namely Lewy bodies and α-synuclein aggregates, have been found in the gut’s enteric nervous system of PD patients along with inflammation. The role of the gut microbiome in PD is underexplored and no study has addressed whether toxins influence neurodegeneration via the microbiome. We previously developed a resource to investigate long-term exposure to pesticides in humans, i.e. a geographic information system (GIS) model based on records from the California state pesticide use reporting (PUR) system. Capitalizing on our unique PUR exposure assessment tool and the Parkinson's Disease Susceptibility Genes and Pesticides Study (PEG; R01 ES-010544) resources, we have joined forces with Drs. Mayer and Jacob (UCLA Division of Digestive Diseases) - experts in brain-gut connection microbiome research - and propose to analyze the gut microbiome of 400 PD patients and 600 (200 age-matched household & 400 age-sex matched community) controls using 16S ribosomal RNA to assess relative abundance of microbiota. Specifically, we will assess composition and function (using the predicted metagenome) in pesticide exposed vs. non-exposed controls and PD patients of different progression phenotypes. We will newly enroll 200 new-onset, of these 100 medication naïve (MN) PD patients, to collect data on exposures, gut motility indicators, and fecal samples for metabolomics and culture based experiments (before and after starting PD medications); assess differences in relative abundances of microbes over time using 16S ribosomal RNA and shotgun metagenomics and conduct metabolomics (blood or stool) analyses for new onset PD patients (twice, longitudinally) and their household controls. We combine for this research our extensive expertise in pesticide exposure assessment and studying PD progression in community-based patients, an exceptionally well-characterized population living in a heavily pesticide exposed region, with the expertise of our UCLA GI team in brain-gut axis research and the resources of the UCLA microbiome core. Our resources provide a strong and efficient platform for addressing chronic environmental exposure to pesticides and their impacts on the gut microbiome and on neurodegeneration. This research will suggest novel pathways and prevention options for a growing elderly population with chronic environmental exposures.

抽象的。 人类微生物组在营养物质、药物和毒素的吸收和处理方面发挥着重要作用。并且是伟大的 免疫系统相关性。越来越多的证据表明它可以影响神经功能、大脑活动和 通过“肠脑轴”的行为。新的主张是，环境暴露如农药、金属和 空气污染影响微生物组和人体免疫系统，微生物组在 帕金森病（PD）。在这里，我们提出了一个新的假设：a) 微生物组受到慢性疾病的影响 环境暴露，特别是农药； b) 肠道微生物组组成或功能的改变有助于 PD 神经变性的进展。 PD——一种进行性神经退行性疾病——具有多种非运动障碍 症状包括胃肠 (GI) 特征，如便秘和胃轻瘫。其病理特征， 即路易体和α-突触核蛋白聚集体，已在帕金森病患者的肠道肠神经系统中发现 并伴有炎症。肠道微生物组在帕金森病中的作用尚未得到充分探索，也没有研究涉及 毒素是否通过微生物组影响神经退行性变。我们之前开发了一个资源来调查 人类长期接触农药，即基于记录的地理信息系统（GIS）模型 加利福尼亚州农药使用报告 (PUR) 系统。利用我们独特的 PUR 暴露评估工具和 帕金森病易感基因和农药研究（PEG；R01 ES-010544）资源，我们联手 与博士。 Mayer 和 Jacob（加州大学洛杉矶分校消化疾病部）——脑肠连接微生物组研究专家—— 并建议分析 400 名 PD 患者和 600 名（200 名年龄匹配的家庭和 400 名年龄-性别 匹配的群落）使用 16S 核糖体 RNA 来评估微生物群的相对丰度。具体来说，我们将 评估暴露农药与未暴露对照的组成和功能（使用预测的宏基因组） 不同进展表型的 PD 患者。我们将新招募 200 名新发患者，其中 100 名从未接受过药物治疗 (MN) PD 患者，收集有关暴露、肠道动力指标和粪便样本的数据，用于代谢组学和培养 基于实验（开始帕金森病药物治疗之前和之后）；评估微生物相对丰度的差异 随着时间的推移，使用 16S 核糖体 RNA 和鸟枪法宏基因组学并进行代谢组学（血液或粪便）分析 新发帕金森病患者（纵向两次）及其家庭对照。我们在这项研究中结合了我们广泛的 农药暴露评估和研究社区患者帕金森病进展方面的专业知识， 生活在农药严重暴露地区的具有明确特征的人群，凭借我们加州大学洛杉矶分校 GI 团队的专业知识 脑肠轴研究和加州大学洛杉矶分校微生物组核心资源。我们的资源提供了强大而高效的 解决长期环境接触农药及其对肠道微生物组和环境影响的平台 神经变性。这项研究将为不断增长的老年人口提出新的途径和预防方案 长期暴露在环境中。