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

项目总结 2型糖尿病(T2D)的患病率正在稳步上升，这突显了了解 这种情况的病因学。随着T2D的急剧上升，慢性杀虫剂和除草剂的使用也 增加，农达是美国应用最多的除草剂。作为草甘膦，草甘膦的活性成分 草甘膦在植物中发现，而不是在哺乳动物中发现，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，即使在相当于美国每日可接受的剂量的情况下， 摄入，慢性草甘膦暴露会损害小鼠的口服葡萄糖耐量。与哺乳动物细胞不同，有几个 各种肠道细菌利用莽草酸途径，来自我们实验室和其他实验室的数据表明，慢性 接触草甘膦会改变肠道微生物群。现在众所周知，肠道微生物群影响宿主健康， 至少部分通过细菌修饰宿主内源化合物，包括胆汁酸。主要 在肝脏中产生的胆汁酸被肠道细菌生物转化为次级胆汁酸种类，并起到 参与葡萄糖动态平衡的信号分子。我的初步数据显示慢性草甘膦 小鼠的暴露与次级胆汁酸的减少有关，这可能是由于肠道微生物群引起的 轮班。由于次级胆汁酸主要刺激G蛋白偶联的胆汁酸受体1(Gpbar1，也称为 由于TGR5)，和TGR5的激活有利于糖耐量，这是可信的，草甘膦介导的转变 在肠道中，微生物通过修饰胆汁酸和TGR5信号来影响葡萄糖的动态平衡。这 假设将在以下目的进行检验：1)确定草甘膦暴露对血糖的影响 耐受性和肠道微生物群，并确定肠道微生物群是否对效果是必要的；2)确定 草甘膦如何改变肠-肝胆汁酸稳态以及TGR5是否介导了草甘膦对胆汁酸代谢的影响 葡萄糖耐量。该奖学金将提供转基因小鼠群体维持方面的培训。 元基因组测序和分析、胆汁酸量化以及合作机会 与该领域经验丰富的科学家一起参加会议和进行专业发展 演示文稿。弗兰克·杜卡博士的实验室和亚利桑那大学为此提供了一个极好的环境 研究，访问亚利桑那大学斯蒂尔儿童研究中心的微生物组核心 灵生生物设施，以及药理学和毒理学领域研究人员的知识 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.