Abstract

The increasing global burden of Parkinson’s disease (PD), termed the PD pandemic, is exceeding expectations related purely to population aging and is likely driven in part by lifestyle changes and environmental factors. Pesticides are well recognized risk factors for PD, supported by both epidemiological and experimental evidence, with multiple detrimental effects beyond dopaminergic neuron damage alone. The microbiome-gut-brain axis has gained much attention in recent years and is considered to be a significant contributor and driver of PD pathogenesis. In this narrative review, we first focus on how both pesticides and the microbiome may influence PD initiation and progression independently, describing pesticide-related central and peripheral neurotoxicity and microbiome-related local and systemic effects due to dysbiosis and microbial metabolites. We then depict the bidirectional interplay between pesticides and the microbiome in the context of PD, synthesizing current knowledge about pesticide-induced dysbiosis, microbiome-mediated alterations in pesticide availability, metabolism and toxicity, and complex systemic pesticide-microbiome-host interactions related to inflammatory and metabolic pathways, insulin resistance and other mechanisms. An overview of the unknowns follows, and the role of pesticide-microbiome interactions in the proposed body-/brain-first phenotypes of PD, the complexity of environmental exposures and gene-environment interactions is discussed. The final part deals with possible further steps for translation, consisting of recommendations on future pesticide use and research as well as an outline of promising preventive/therapeutic approaches targeted on strengthening or restoring a healthy gut microbiome, closing with a summary of current gaps and future perspectives in the field.

中文翻译：

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农药和微生物组-肠-脑轴：帕金森病发病机制的趋同途径

摘要

帕金森病 (PD) 日益增加的全球负担（称为帕金森病大流行）超出了纯粹与人口老龄化相关的预期，并且可能部分是由生活方式的变化和环境因素驱动的。农药是公认的帕金森病危险因素，得到流行病学和实验证据的支持，除了多巴胺能神经元损伤之外，农药还具有多种有害影响。近年来，微生物组-肠-脑轴受到广泛关注，被认为是帕金森病发病机制的重要贡献者和驱动因素。在这篇叙述性综述中，我们首先关注农药和微生物组如何独立影响帕金森病的发生和进展，描述农药相关的中枢和外周神经毒性以及由于菌群失调和微生物代谢物导致的微生物组相关的局部和全身影响。然后，我们描述了PD背景下农药与微生物组之间的双向相互作用，综合了有关农药引起的生态失调、微生物组介导的农药有效性、代谢和毒性的改变以及与炎症相关的复杂的系统性农药-微生物组-宿主相互作用的当前知识。以及代谢途径、胰岛素抵抗等机制。接下来是对未知因素的概述，并讨论了农药-微生物组相互作用在拟议的身体/大脑优先的帕金森病表型中的作用、环境暴露的复杂性以及基因-环境相互作用。最后一部分涉及可能的进一步翻译步骤，包括对未来农药使用和研究的建议，以及旨在加强或恢复健康肠道微生物群的有前景的预防/治疗方法的概述，最后总结了当前的差距和未来领域的观点。