The Ability of Glyphosate to Impair Metabolic Homeostasis Via the Gut Microbiome and Metabolites

草甘膦通过肠道微生物组和代谢物损害代谢稳态的能力

• 批准号: 10707920
• 负责人: Frank Anthony Duca
• 金额: $ 34.36万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707920
• 关键词: Adult; Affect; Agriculture; Antibiotics; Bacteria; Bile Acids; Chemicals; Chlorinated Hydrocarbons; Chronic; Complex; Coupled; Data; Development; Diabetes Mellitus; Disease; Dose; Economic Burden; Elderly; Environment; Environmental Exposure; Environmental Impact; Enzymes; Exhibits; Exposure to; Female; Genetic; Germ-Free; Glucose; Goals; Health; Herbicides; High Fat Diet; Homeostasis; Human; Impairment; Incidence; Industry; Insecticides; Intestines; Knockout Mice; Life; Link; Malignant Neoplasms; Mammalian Cell; Mammals; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Pesticides; Physiological; Plants; Play; Prevalence; Rattus; Receptor Activation; Receptor Signaling; Regulation; Research; Rodent; Role; Roundup; Safety; Signal Pathway; Signal Transduction; Small Intestines; Testing; Time; United States; Weaning; Weight Gain; Work; antagonist; bacterial metabolism; bile acid metabolism; blood glucose regulation; environmental chemical; environmental chemical exposure; glyphosate; gut microbiome; gut microbiota; impaired glucose tolerance; insight; male; microbial; microbiota; obesity development; obesity risk; obesity treatment; receptor; shikimate; social; targeted treatment

PROJECT SUMMARY The prevalence of obesity and diabetes continue to rise unabated in the United States, creating a grave social and economic burden. Although development of these diseases is multi-faceted and complex, there is accumulating evidence for the impact of environmental chemical exposures on metabolic homeostasis. Currently, glyphosate is the most commonly used herbicide in the United States, however, to date, no studies have ever assessed whether glyphosate exposure impacts the development of obesity and diabetes. Thus, the long-term goal of this project is to better understand how recent and current pesticide usage can impact long-term metabolic homeostasis. Glyphosate targets the shikimate pathway found in plants, and not mammals, leading to the assumption of its general safety. However, glyphosate can also target bacteria, and glyphosate exposure results in an altered gut microbiome profile. Despite the fact that previous pesticides are associated with metabolic disease, and that glyphosate is known to alter the gut microbiota which can impact energy and glucose homeostasis, no study has ever examined whether exposure to glyphosate can result in development of obesity and/or diabetes. One of the main roles of the gut microbiota is bile acid metabolism, and studies suggest that alterations in bile acid signaling represent a plausible link between the gut microbiota and regulation of metabolic homeostasis via changes in Farnesoid X receptor (FXR) signaling. These facts, coupled with our preliminary data, led to the hypothesis that exposure to glyphosate shifts the gut microbiome, leading to altered intestinal bile acid signaling that contributes to impairments in energy and glucose homeostasis. This hypothesis will be tested in 3 aims: 1) assess if exposure to glyphosate during different developmental timepoints promotes metabolic dysfunction in male and female mice on a chow or high-fat diet, 2) determine the role of the gut microbiome in the effects of glyphosate exposure on metabolic homeostasis, and 3) identify the impact of altered bile acid signaling via glyphosate exposure in impaired metabolic homeostasis. The proposed study will be the first ever to provide mechanistic insight of the effects of glyphosate exposure on metabolic homeostasis. This proposal will provide valuable data leading to further research examining how environmental pesticide usage can affect human health, and possibly identify microbial targets to offset the detrimental effects of environmental chemical use.

项目概要 在美国，肥胖和糖尿病的患病率继续有增无减， 造成严重的社会和经济负担。尽管这些疾病的发生 环境影响是多方面且复杂的，越来越多的证据表明 化学物质暴露对代谢稳态的影响。目前最常用的是草甘膦 然而，迄今为止，还没有研究评估美国是否使用过除草剂 接触草甘膦会影响肥胖和糖尿病的发生。因此，长期 该项目的目标是更好地了解最近和当前农药的使用如何影响 长期代谢稳态。 草甘膦针对植物中发现的莽草酸途径，而不是哺乳动物，导致 对其总体安全性的假设。然而，草甘膦也可以针对细菌，并且 接触草甘膦会导致肠道微生物组特征改变。尽管事实上 以前的农药与代谢性疾病有关，而草甘膦已知 改变肠道微生物群，从而影响能量和葡萄糖稳态，目前还没有研究表明 检查接触草甘膦是否会导致肥胖和/或 糖尿病。肠道微生物群的主要作用之一是胆汁酸代谢，研究 表明胆汁酸信号的改变代表了肠道之间的合理联系 微生物群和通过 Farnesoid X 受体变化调节代谢稳态 (FXR) 信令。这些事实，加上我们的初步数据，得出了这样的假设： 接触草甘膦会改变肠道微生物群，导致肠道胆汁酸改变 导致能量和葡萄糖稳态受损的信号传导。这个假设 将测试 3 个目标：1) 评估在不同发育阶段是否接触草甘膦 时间点会促进吃食物或高脂肪饮食的雄性和雌性小鼠的代谢功能障碍， 2) 确定肠道微生物组在草甘膦暴露对代谢影响中的作用 体内平衡，3) 确定草甘膦暴露改变胆汁酸信号的影响 代谢稳态受损。拟议的研究将是有史以来第一个提供 草甘膦暴露对代谢稳态影响的机制见解。这 该提案将提供有价值的数据，从而进一步研究环境如何 农药的使用会影响人类健康，并可能确定微生物目标来抵消农药的影响 环境化学品使用的有害影响。