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

抽象的。 人类微生物群在营养、药物和毒素的吸收和处理中起着重要作用； 免疫系统的相关性。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，如杀虫剂，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 帕金森氏病(PD)。在这里，我们提出了一个新的假设：a)微生物群受到慢性疾病的影响 环境暴露，特别是杀虫剂；以及b)肠道微生物群组成或功能发生变化 帕金森病患者神经退行性变的进展。帕金森病是一种进行性神经退行性疾病，有各种非运动性疾病 症状包括胃肠(GI)特征，如便秘和胃瘫。它的病理特征， 在PD患者的肠道神经系统中发现了路易小体和α-突触核蛋白聚集体 伴随着炎症。肠道微生物群在帕金森病中的作用还没有得到充分的探讨，也没有研究涉及到 毒素是否通过微生物群影响神经退化。我们之前开发了一个资源来调查 人类长期接触杀虫剂，即基于来自 加利福尼亚州农药使用报告系统。充分利用我们独特的PUR暴露评估工具和 帕金森氏病易感基因和农药研究(聚乙二醇；R01 ES-010544)资源，我们已经联合起来 与迈耶博士和雅各布博士(加州大学洛杉矶分校消化科)--大脑-肠道连接微生物组研究的专家-- 并建议对400例PD患者和600(200个年龄匹配家庭和400个年龄性别)的肠道微生物群进行分析 配对社区)对照使用16S核糖体RNA来评估微生物区系的相对丰度。具体来说，我们将 (使用预测的元基因组)评估接触农药与未接触农药的对照组的成分和功能 不同进展表型的帕金森病患者。我们将新招收200名新发病者，在这100种药物中天真 (M)帕金森病患者，收集有关暴露、肠道动力指标和粪便样本的数据，以进行代谢组学和培养 基础实验(开始服用PD药物前后)；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和鸟枪式元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。我们为这项研究结合了我们广泛的 在以社区为基础的患者中进行农药暴露评估和研究帕金森病进展的专业知识，是一个例外 在加州大学洛杉矶分校GI团队的专业知识下，生活在农药重度暴露地区的特征良好的人口 脑-肠轴研究和加州大学洛杉矶分校微生物核心的资源。我们的资源提供了强大而高效的 解决环境中长期接触杀虫剂及其对肠道微生物群等的影响的平台 神经退行性变。这项研究将为不断增长的老年人口提供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.