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

抽象的。 人体微生物组在营养素、药物和毒素的摄取和处理中起着重要作用; 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， 行为通过“肠脑轴”。新的主张是，环境暴露，如农药，金属， 空气污染影响微生物组和人体免疫系统，微生物组在其中发挥作用。 帕金森病（PD）。在这里，我们提出了一个新的假设，即a）微生物组受到慢性 环境暴露，特别是农药;和B）改变的肠道微生物组组成或功能有助于 帕金森病神经退行性变的进展PD --一种进行性神经退行性疾病--具有各种非运动性疾病， 症状包括胃肠道（GI）特征，如便秘和胃轻瘫。它的病理特征， 即Lewy小体和α-突触核蛋白聚集体，已在PD患者的肠道肠神经系统中发现 沿着炎症。肠道微生物组在PD中的作用尚未得到充分研究，也没有研究涉及 毒素是否通过微生物组影响神经变性。我们以前开发了一个资源来调查 人类长期接触农药的情况，即基于 加州州农药使用报告系统。利用我们独特的PUR暴露评估工具， 帕金森病易感基因和农药研究（PEG; R 01 ES-010544）资源，我们已经联手 Mayer博士和Jacob博士（UCLA消化疾病部门）-脑肠道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）的肠道微生物组 匹配的社区）对照，使用16 S核糖体RNA来评估微生物群的相对丰度。具体来说，我们将 评估农药暴露与非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。我们将新入组200例新发患者，其中100例未经药物治疗 (MN)PD患者，收集暴露数据、肠道动力指标和粪便样本，用于代谢组学和培养 基于实验（开始PD药物治疗前后）;评估微生物相对丰度的差异 随着时间的推移，使用16 S核糖体RNA和鸟枪宏基因组学进行代谢组学（血液或粪便）分析， 新发PD患者（两次，纵向）及其家庭对照。我们联合收割机为这项研究结合了我们广泛的 在农药暴露评估和研究社区患者PD进展方面的专业知识， 生活在农药严重暴露地区的特征良好的人群，我们的UCLA 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。我们的资源提供了一个强大而高效的 解决长期环境接触农药及其对肠道微生物组和 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选择 长期暴露在环境中

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.