PROJECT SUMMARYThe prevalence of type 2 diabetes (T2D) is steadily increasing highlighting a critical need to understand theetiology of this condition. In line with the dramatic rise in T2D chronic insecticide and herbicide use has alsoincreased with RoundUp being the most applied herbicide in the US. As glyphosate the active ingredient inRoundUp targets the shikimate pathway in found in plants but not mammals glyphosate is proposed to be safefor human use. However our preliminary data show that even at a dose equivalent to the US Acceptable DailyIntake chronic glyphosate exposure impairs oral glucose tolerance in mice. Unlike mammalian cells severalspecies of gut bacteria utilize the shikimate pathway and data from our lab and others indicates that chronicglyphosate exposure alters the gut microbiome. It is now well-known that the gut microbiome impacts host healthmediated at least in part by bacterial modification of host endogenous compounds including bile acids. Primarybile acids produced in the liver are biotransformed into secondary bile acid species by gut bacteria and act assignaling molecules involved in glucose homeostasis. My preliminary data shows that chronic glyphosateexposure in mice is associated with a decrease in secondary bile acids likely occurring due to gut microbiomeshifts. As secondary bile acids primarily agonize the G-protein coupled bile acid receptor 1 (Gpbar1 also knownas TGR5) and TGR5 activation is beneficial for glucose tolerance it is plausible that glyphosate-mediated shiftsin the gut microbiome impact glucose homeostasis via modification of bile acids and TGR5 signaling. Thishypothesis will be tested in the following Aims: 1) Determine the impact of glyphosate exposure on glucosetolerance and the gut microbiome and determine if the gut microbiome is necessary for the effects; 2) Determinehow glyphosate alters enterohepatic bile acid homeostasis and if TGR5 mediates the effects of glyphosate onglucose tolerance. This fellowship will provide training in transgenic mouse colony maintenance shotgunmetagenomic sequencing and analyses and bile acid quantification as well as opportunities for collaborationwith experienced scientists in the field and professional development through conference attendance andpresentations. The lab of Dr. Frank Duca and the University of Arizona provide an excellent environment for thisresearch with access to the Microbiome Core at the Steele Childrens Research Center the University of ArizonaGnotobiotic Facility as well as knowledge from researchers in the fields of pharmacology and toxicology andmetabolism.