- Recent findings suggest that the arylhydrocarbon receptor (AhR) plays a vital role inthe development of colon cancer. While there is evidence that AhR ligands modulatethe intestinal epithelium, the extent to which gut microbiota shape the tumor suppressiveeffects associated with exposure to AhR ligands remains an important unresolvedquestion. We provide novel preliminary data demonstrating that microbiota-derived AhRligand levels are decreased under high fat diet (obesogenic) conditions. This isnoteworthy, because a growing body of preclinical and epidemiological data indicate thatthe risk of colon cancer is strongly associated with obesity. Since transformation of adultstem cells is an extremely important route towards initiating intestinal cancer, wepropose to interrogate the effect of microbiota-derived AhR ligands on intestinal stemcell homeostasis and colon tumorigenesis using tissue-specific AhR knock out andcontrol compound mice fed high fat versus low fat diets. This objective is supported byour novel preliminary data indicating that microbial-derived AhR ligands have a directeffect on the intestinal epithelium (without the contribution of the mesenchymal niche)and modulate stemness. Based on these findings, we hypothesize that microbial-derived AhR ligands are important determinants of colonic malignant transformation. Tounravel the intricacies of AhR effects on intestinal biology, the following specific aims willbe addressed: (1) Identify microbiota-derived AhR ligands that are modulated by high-fatfeeding; (2) Determine the effect of microbiota-derived AhR ligands on intestinal stemcell responses in vivo and ex vivo; and (3) Determine whether microbe-derived AhRligands modulate colon cancer initiation and progression. At the completion of thisproject, we anticipate that our novel approaches will provide us with a unique snap shotof host-microbe metabolite interactions during tumorigenesis.