The gut microbiome and glyphosate neurotoxicity

肠道微生物组和草甘膦的神经毒性

• 批准号: 10229481
• 负责人: Kun Lu
• 金额: $ 7.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-06 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229481
• 关键词: 16S ribosomal RNA sequencing; Address; Adverse effects; Affect; Amino Acid Neurotransmitters; Aromatic Amino Acids; Brain; Cessation of life; Colon; DNA; Data; Dose; Exposure to; Feces; Foundations; Future; Genes; Genome; Health; Herbicides; Homeostasis; Human; Human Microbiome; Liver; Mammals; Maps; Metabolic; Metabolism; Metagenomics; Methods; Modeling; Mus; Neurotransmitters; Organ; Pathway interactions; Pesticides; Phenotype; Plants; Public Health; Recording of previous events; Regulation; Research; Rodent; Role; Roundup; Serum; Shotguns; System; Testing; Time; Toxic effect; Transplantation; Urine; Water; Xenobiotics; Zebrafish; base; design; expectation; exposed human population; frontier; glyphosate; gut bacteria; gut microbiome; gut microbiota; human disease; inorganic phosphate; metabolome; metabolomics; metagenome; microbiome; microbiome alteration; microbiome composition; microbiota transplantation; monoamine; neurobehavioral; neurobehavioral disorder; neurotoxicity; neurotoxicology; novel; relating to nervous system; shikimate

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.

抽象的 该应用解决了神经毒理学领域的一个重大空白，即肠道微生物组的作用。微生物组 人体肠道的功能通过其在多种宿主中的关键作用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。肠道微生物组很容易受到外部因素的影响这一事实提出了 关于异生素对肠道微生物群的作用的问题。基于草甘膦的除草剂，例如 农达是全球使用最广泛的农药。草甘膦作用于植物中的莽草酸途径 通过抑制 5-烯醇丙酮莽草酸-3-磷酸合酶 (EPSPS)，从而破坏 芳香族氨基酸，导致植物死亡。由于哺乳动物中不存在莽草酸途径，因此 人们普遍认为草甘膦对人类是安全的。然而，草甘膦的副作用包括 对哺乳动物的神经毒性已有充分记录。特别重要的是，许多具有重要功能的肠道 啮齿动物和人类的细菌确实具有莽草酸途径，这突出表明草甘膦可能会干扰 肠道微生物组和相关的莽草酸途径改变芳香氨基酸、前体的稳态 单胺类神经递质。值得注意的是，神经行为障碍通常以失调为特征 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，特别是与人体暴露相关的剂量，在很大程度上尚未被探索 然而。这一特定应用的目的是确定草甘膦对肠道干扰的影响 微生物组以及草甘膦破坏的微生物组在引起宿主神经毒性中的作用。我们将 通过首先表征肠道微生物组谱的变化，分三个阶段解决问题 16S rRNA 测序，然后使用鸟枪法宏基因组学和代谢组学绘制代谢变化图。 最后，我们将定义草甘膦扰乱肠道微生物组如何导致代谢组、莽草酸和 通过微生物组移植研究相关途径、神经递质和神经行为表型。我们的 拟议的研究意义重大，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。当这个项目完成后，我们的 期望这些结果将为未来的研究奠定基础，旨在扩大我们的理解 草甘膦神经毒性以及肠道微生物组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频繁的除草剂。