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: 10872374
• 负责人: Beate R Ritz
• 金额: $ 14.82万
• 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/10872374
• 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; cell motility; cohort; disease diagnosis; experience; experimental study; follow-up; gastrointestinal; gastrointestinal symptom; gene environment interaction; gut inflammation; gut microbiome; gut microbiota; gut-brain axis; human microbiota; 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，药物和毒素的摄取和处理中具有重要作用。而且很棒 免疫系统相关性。有证据表明，它可以影响神经功能，大脑活动和 通过“肠道轴”行为。新主张是，环境暴露，例如农药，金属和 空气污染影响微生物组和人类免疫系统，微生物组在 帕金森氏病（PD）。在这里，我们提出了一个新的假设，即a）微生物组受慢性的影响 环境暴露，特别是农药； b）改变的肠道微生物组组成或功能有助于 在PD中神经退行性的进展。 PD - 进行性神经退行性疾病 - 具有各种非运动 包括胃肠道（GI）特征在内的症状，例如便秘和胃轻瘫。它的病理标志， 即Lewy身体和α-突触核蛋白聚集体已在PD患者的肠道神经系统中发现 以及炎症。肠道微生物组在PD中的作用尚未得到充实，并且没有研究 毒素是否通过微生物组影响神经退行性。我们以前开发了一种资源来调查 长期接触人类农药，即基于来自地理信息系统的地理信息系统（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 帕金森氏病敏感性基因和农药研究（PEG; R01 ES-010544）资源，我们已经联手了 与博士。 Mayer and Jacob（UCLA消化疾病分部） - 脑形连接微生物组研究专家 - 和分析400例PD患者和600名肠道微生物组的建议（200个年龄匹配的家庭和400个年龄性别 使用16S核糖体RNA来评估微生物群的相对丰度的匹配社区）对照。具体来说，我们会的 评估农药暴露与非暴露对照和非暴露对照的组成和功能（使用预测的元基因组） 不同进展表型的PD患者。我们将新招收200种新的，这100种药物很幼稚 （MN）PD患者，收集有关代谢组学和培养的暴露，肠运动指标和粪便样品的数据 基于实验（开始PD药物之前和之后）；评估微生物相对丰度的差异 随着时间的流逝，使用16S核糖体RNA和shot弹枪宏基因组学并进行代谢组学（血液或粪便）分析 新发作PD患者（两次，纵向）及其家庭控制。我们为这项研究结合了我们的广泛 在基于社区的患者中，农药暴露评估和研究PD进展方面的专业知识，这是一个异常的 居住在农药暴露的地区的特征良好的人口，我们的UCLA GI团队的专业知识 大脑轴轴研究和UCLA微生物组核心的资源。我们的资源提供了强大而有效的 解决慢性环境暴露于农药的平台及其对肠道微生物组的影响 神经变性。这项研究将为增长的老年人群提供新的途径和预防选择 慢性环境暴露。

项目成果

Stochastic Epigenetic Mutations Influence Parkinson's Disease Risk, Progression, and Mortality.

• DOI: 10.3233/jpd-212834
• 发表时间: 2022
• 期刊: JOURNAL OF PARKINSONS DISEASE
• 影响因子: 5.2
• 作者: Chen, Gary K.;Yan, Qi;Paul, Kimberly C.;Kusters, Cynthia D. J.;Folle, Aline Duarte;Furlong, Melissa;Keener, Adrienne;Bronstein, Jeff;Horvath, Steve;Ritz, Beate
• 通讯作者: Ritz, Beate

Epigenetic mutation load is weakly correlated with epigenetic age acceleration.

• DOI: 10.18632/aging.103950
• 发表时间: 2020-09-29
• 期刊: Aging
• 作者: Yan Q;Paul KC;Lu AT;Kusters C;Binder AM;Horvath S;Ritz B
• 通讯作者: Ritz B

Air Pollution and the Risk of Parkinson's Disease: A Review.

• DOI: 10.1002/mds.28922
• 发表时间: 2022-05
• 期刊: MOVEMENT DISORDERS
• 影响因子: 8.6
• 作者: Murata, Hiromi;Barnhill, Lisa M.;Bronstein, Jeff M.
• 通讯作者: Bronstein, Jeff M.

Ethnicity and Parkinson's Disease: Motor and Nonmotor Features and Disease Progression in Latino Patients Living in Rural California.

• DOI: 10.1093/gerona/glad016
• 发表时间: 2023-07-08
• 期刊: JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
• 影响因子: 5.1
• 作者: Folle, Aline Duarte;Flores, Marie E. S.;Kusters, Cynthia;Paul, Kimberly C.;Del Rosario, Irish;Zhang, Keren;Ruiz, Cristina;Castro, Emily;Bronstein, Jeff;Ritz, Beate;Keener, Adrienne M.
• 通讯作者: Keener, Adrienne M.

α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson's disease from multiple system atrophy.

• DOI: 10.1007/s00401-021-02324-0
• 发表时间: 2021-09
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Dutta S;Hornung S;Kruayatidee A;Maina KN;Del Rosario I;Paul KC;Wong DY;Duarte Folle A;Markovic D;Palma JA;Serrano GE;Adler CH;Perlman SL;Poon WW;Kang UJ;Alcalay RN;Sklerov M;Gylys KH;Kaufmann H;Fogel BL;Bronstein JM;Ritz B;Bitan G
• 通讯作者: Bitan G