Glyphosate impairs glucose homeostasis via gut microbiome induced alterations to bile acid signaling

草甘膦通过肠道微生物组诱导的胆汁酸信号改变损害葡萄糖稳态

• 批准号: 10749326
• 负责人: Rachel Meyer
• 金额: $ 4.53万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749326
• 关键词: Acute; Agonist; Agriculture; Antibiotics; Arizona; Bacteria; Bile Acids; Child; Chronic; Collaborations; Coupled; Data; Development; Diabetes Mellitus; Diagnosis; Dose; Environment; Environmental Risk Factor; Enzymes; Etiology; Exposure to; Fellowship; Female; Functional disorder; GPBAR1 gene; GTP-Binding Proteins; Genetic; Germ-Free; Glucose Intolerance; Gnotobiotic; Goals; Health; Herbicides; Homeostasis; Human; Impairment; Incidence; Insecticides; Intake; Intestines; Knockout Mice; Knowledge; Lithocholic Acid; Liver; Maintenance; Mammalian Cell; Mammals; Mediating; Metabolic Biotransformation; Metabolic Diseases; Metabolism; Metagenomics; Modification; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peptides; Pharmacology and Toxicology; Plants; Play; Population; Prevalence; Production; Receptor Signaling; Research; Research Personnel; Research Project Grants; Role; Roundup; Scientist; Shotguns; Signal Pathway; Signal Transduction; Signaling Molecule; Small Intestines; Testing; Training; Transgenic Mice; United States; Universities; blood glucose regulation; drinking water; dysbiosis; experience; glucagon-like peptide 1; glucose tolerance; glyphosate; gut bacteria; gut microbiome; gut microbiota; impaired glucose tolerance; improved; insight; insulin tolerance; male; metabolome; metagenomic sequencing; microbiome; oral glucose tolerance; prevent; proglucagon; receptor; shikimate; symposium

PROJECT SUMMARY The prevalence of type 2 diabetes (T2D) is steadily increasing, highlighting a critical need to understand the etiology of this condition. In line with the dramatic rise in T2D, chronic insecticide and herbicide use has also increased, with RoundUp being the most applied herbicide in the US. As glyphosate, the active ingredient in RoundUp, targets the shikimate pathway in found in plants, but not mammals, glyphosate is proposed to be safe for human use. However, our preliminary data show that, even at a dose equivalent to the US Acceptable Daily Intake, chronic glyphosate exposure impairs oral glucose tolerance in mice. Unlike mammalian cells, several species of gut bacteria utilize the shikimate pathway, and data from our lab and others indicates that chronic glyphosate exposure alters the gut microbiome. It is now well-known that the gut microbiome impacts host health, mediated at least in part by bacterial modification of host endogenous compounds, including bile acids. Primary bile acids, produced in the liver, are biotransformed into secondary bile acid species by gut bacteria and act as signaling molecules involved in glucose homeostasis. My preliminary data shows that chronic glyphosate exposure in mice is associated with a decrease in secondary bile acids, likely occurring due to gut microbiome shifts. As secondary bile acids primarily agonize the G-protein coupled bile acid receptor 1 (Gpbar1, also known as TGR5), and TGR5 activation is beneficial for glucose tolerance, it is plausible that glyphosate-mediated shifts in the gut microbiome impact glucose homeostasis via modification of bile acids and TGR5 signaling. This hypothesis will be tested in the following Aims: 1) Determine the impact of glyphosate exposure on glucose tolerance and the gut microbiome and determine if the gut microbiome is necessary for the effects; 2) Determine how glyphosate alters enterohepatic bile acid homeostasis and if TGR5 mediates the effects of glyphosate on glucose tolerance. This fellowship will provide training in transgenic mouse colony maintenance, shotgun metagenomic sequencing and analyses, and bile acid quantification, as well as opportunities for collaboration with experienced scientists in the field and professional development through conference attendance and presentations. The lab of Dr. Frank Duca and the University of Arizona provide an excellent environment for this research, with access to the Microbiome Core at the Steele Children’s Research Center, the University of Arizona Gnotobiotic Facility, as well as knowledge from researchers in the fields of pharmacology and toxicology and metabolism.

项目摘要 2型糖尿病（T2D）的患病率正在稳步增长，强调了了解 这种情况的病因。与T2D的急剧上升相符，慢性杀虫剂和除草剂的使用也有 增加，综述是美国最涂抹的除草剂。作为糖磷酸盐，活性成分 综述，针对植物中发现但没有哺乳动物的光滑途径，提议糖酸是安全的 用于人类使用。但是，我们的初步数据表明，即使在相当于美国可接受的每日剂量 摄入，慢性糖酸暴露会损害小鼠的口服葡萄糖耐受性。与哺乳动物细胞不同，有几个 肠道细菌的种类利用了光滑途径，我们实验室的数据表明慢性 草甘膦暴露改变了肠道微生物组。现在众所周知，肠道微生物组影响宿主健康， 至少部分是通过细菌修饰宿主内源性化合物（包括胆汁酸）介导的。基本的 肝脏在肝脏中产生的胆汁酸被肠道细菌生物转化为二级胆汁酸物种，并充当 与葡萄糖稳态有关的信号分子。我的初步数据表明慢性糖酸盐 小鼠的暴露与次级胆汁酸的降低有关，可能是由于肠道微生物组而发生的 转移。随着二级胆汁酸的一级苦恼G蛋白偶联的胆汁酸受体1（GPBAR1，也已知 作为TGR5），TGR5激活对葡萄糖耐量有益，因此草甘膦介导的移位是合理的 在肠道微生物组中，通过修饰胆汁酸和TGR5信号传导影响葡萄糖稳态。这 假设将在以下目的中进行检验：1）确定糖苷暴露对葡萄糖的影响 耐受性和肠道微生物组，并确定肠道微生物组是否对效果是必需的； 2）确定 草甘膦如何改变肠肝胆酸稳态，如果TGR5介导草甘膦对 葡萄糖耐受性。该奖学金将提供转基因老鼠菌落维护的培训，shot弹枪 元基因组测序和分析以及胆汁酸定量以及协作的机会 与该领域的经验丰富的科学家和专业发展，通过会议出席 演讲。弗兰克·杜卡（Frank Duca）博士和亚利桑那大学的实验室为此提供了一个绝佳的环境 研究，随着亚利桑那大学Steele儿童研究中心的微生物组核心 gnotobiotic设施以及药理学和毒理学领域的研究人员的知识以及 代谢。