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

项目摘要 2型糖尿病（T2 D）的患病率正在稳步上升，这突出了了解糖尿病的关键需求。 这种情况的病因。随着T2 D的急剧上升，长期使用杀虫剂和除草剂也 RoundUp是美国使用最多的除草剂。作为草甘膦， RoundUp针对植物中发现的莽草酸途径，但不是哺乳动物，草甘膦被认为是安全的 供人类使用。然而，我们的初步数据显示，即使在相当于美国可接受日剂量的剂量下， 摄入，长期草甘膦暴露损害小鼠的口服葡萄糖耐量。与哺乳动物细胞不同， 一些肠道细菌利用莽草酸途径，我们实验室和其他实验室的数据表明， 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， 至少部分由宿主内源性化合物（包括胆汁酸）的细菌修饰介导。初级 在肝脏中产生的胆汁酸通过肠道细菌生物转化为次级胆汁酸种类， 参与葡萄糖稳态的信号分子。我的初步数据显示慢性草甘膦 小鼠中的暴露与次级胆汁酸减少相关，可能是由于肠道微生物组引起的 运动一样的由于次级胆汁酸主要激动G-蛋白偶联胆汁酸受体1（Gpbar 1，也称为 作为TGR 5），并且TGR 5激活对葡萄糖耐量有益，这是合理的，草甘膦介导的转变 在肠道微生物组中，通过修饰胆汁酸和TGR 5信号传导影响葡萄糖稳态。这 将在以下目标中检验假设：1）确定草甘膦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是影响所必需的; 2）确定 草甘膦如何改变肝肠胆汁酸的体内平衡，以及TGR 5是否介导草甘膦对 葡萄糖耐量。该奖学金将提供转基因小鼠群体维护，鸟枪 宏基因组测序和分析，胆汁酸定量，以及合作机会 通过参加会议，与该领域经验丰富的科学家和专业发展， 介绍。Frank Duca博士的实验室和亚利桑那大学为此提供了极好的环境 研究，可访问亚利桑那大学斯蒂尔儿童研究中心的微生物组核心 生物技术设施，以及药理学和毒理学领域的研究人员的知识， 新陈代谢.

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.