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

点击翻译按钮获取中文摘要

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.