The gut microbiome and glyphosate neurotoxicity

摘要 这项应用解决了神经毒理学中的一个重大空白，即肠道微生物组的作用。微生物群 人类肠道疾病通过其在多种宿主中的关键作用而对人类健康产生深远的影响。 相关功能。越来越多的证据表明，肠道菌群失调对 各种人类疾病。肠道微生物群很容易受到外部因素的影响，这一事实引发了 关于外源生物对肠道微生物区系作用的问题。基于草甘膦的除草剂，如 农达是世界上使用最广泛的杀虫剂。草甘膦作用于植物中的莽草酸途径 通过抑制5-烯丙酮基莽草酸-3-磷酸合成酶(EPSPS)，从而扰乱 芳香氨基酸，导致植物死亡。由于莽草酸途径在哺乳动物中不存在，所以它是 人们普遍认为草甘膦在人体内是安全的。然而，草甘膦的不良反应包括 哺乳动物的神经毒性，已经有了很好的文献记载。尤其重要的是，许多功能上重要的肠道 啮齿动物和人类的细菌确实有莽草酸途径，强调草甘膦可能扰乱 肠道微生物组和相关的莽草酸途径改变芳香氨基酸前体的动态平衡 单胺类神经递质。值得注意的是，神经行为障碍的特征通常是调节失调。 芳香氨基酸和神经递质途径。然而，肠道之间的功能相互作用 微生物组和草甘膦的暴露，特别是与人体暴露有关的剂量，在很大程度上是未被探索的。 现在还不行。这一特殊应用的目的是确定草甘膦对肠道干扰的影响 微生物组和草甘膦破坏的微生物组在引发宿主神经毒性中的作用。我们会 将问题分为三个阶段，首先用特征描述肠道微生物组的变化 16S rRNA测序，然后用鸟枪式元基因组学和代谢组学绘制代谢改变图谱。 最后，我们将定义草甘膦扰动的肠道微生物群如何引起代谢组、莽草酸和 微生物组移植的相关途径、神经递质和神经行为表型。我们的 拟议的研究具有重要意义，代表了草甘膦研究的新前沿，因为我们专注于肠道 微生物组扰动作为其神经毒性的新机制。在这个项目完成时，它是我们的 期望这些结果将为今后旨在扩大我们对 草甘膦的神经毒性和肠道微生物群在接触草甘膦引起的人类疾病中的作用 历史上使用最广泛和最广泛的除草剂。

ABSTRACT This application addresses a significant gap in neurotoxicology, i.e. the role of gut microbiome. The microbiome of the human intestinal tract has a profound effect on human health through its key role in a wide range of host- related functions. Mounting evidence indicates that dysregulated gut microflora contribute significantly to a variety of human diseases. The fact that the gut microbiome can be readily affected by external factors raises questions regarding the role of xenobiotics on intestinal microflora. Glyphosate-based herbicides, such as Roundup, are the most widely used pesticides worldwide. Glyphosate acts on the shikimate pathway in plants through inhibiting 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), which disrupts the synthesis of aromatic amino acids, leading to plant death. Since the shikimate pathway does not exist in mammals, it is generally believed that glyphosate would be safe in humans. However, glyphosate adverse effects, including neurotoxicity, in mammals has been well documented. Of particular importance, many functionally important gut bacteria of rodents and humans do have the shikimate pathway, highlighting that glyphosate may perturb the gut microbiome and associated shikimate pathway to alter the homeostasis of aromatic amino acids, precursors of monoamine neurotransmitters. Of note, neurobehavioral disorders are often characterized with dysregulated aromatic amino acids and neurotransmitter pathways. However, the functional interaction between the gut microbiome and glyphosate exposure, especially at doses relevant to human exposure, is largely unexplored yet. The objective of this particular application is to define the impact of glyphosate on disturbing the gut microbiome and the role of glyphosate-disrupted microbiome in provoking neurotoxicity in the host. We will approach the problems in three stages by first characterizing the changes in the gut microbiome profiles with 16S rRNA sequencing, and then using shotgun metagenomics and metabolomics to map metabolic alterations. Lastly, we will define how glyphosate-perturbed gut microbiome causatively alters metabolome, shikimate and relevant pathways, neurotransmitters and neurobehavioral phenotypes via microbiome transplantation. Our proposed study is significant and represents a new frontier in glyphosate research because we focus on gut microbiome perturbation as a novel mechanism of its neurotoxicity. At the completion of this project, it is our expectation that these results will lay a foundation for future studies aiming at expanding our understanding of glyphosate neurotoxicity and the role of gut microbiome in human diseases caused by exposure to glyphosate, the most widely and heavily used herbicide in history.