Recent findings suggest that the arylhydrocarbon receptor (AhR) plays a vital role in the development of colon cancer. While there is evidence that AhR ligands modulate the intestinal epithelium, the extent to which gut microbiota shape the tumor suppressive effects associated with exposure to AhR ligands remains an important unresolved question. We provide novel preliminary data demonstrating that microbiota-derived AhR ligand levels are decreased under high fat diet (obesogenic) conditions. This is noteworthy, because a growing body of preclinical and epidemiological data indicate that the risk of colon cancer is strongly associated with obesity. Since transformation of adult stem cells is an extremely important route towards initiating intestinal cancer, we propose to interrogate the effect of microbiota-derived AhR ligands on intestinal stem cell homeostasis and colon tumorigenesis using tissue-specific AhR knock out and control compound mice fed high fat versus low fat diets. This objective is supported by our novel preliminary data indicating that microbial-derived AhR ligands have a direct effect 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. To unravel the intricacies of AhR effects on intestinal biology, the following specific aims will be addressed: (1) Identify microbiota-derived AhR ligands that are modulated by high-fat feeding; (2) Determine the effect of microbiota-derived AhR ligands on intestinal stem cell responses in vivo and ex vivo; and (3) Determine whether microbe-derived AhR ligands modulate colon cancer initiation and progression. At the completion of this project, we anticipate that our novel approaches will provide us with a unique snap shot of host-microbe metabolite interactions during tumorigenesis.
The proposed studies will promote our understanding of how an obesogenic-cancer promoting diet modulates microbiota-derived AhR ligands. We will test the hypothesis that select microbiota generated AhR ligands suppress stem cell homeostasis and the initiation / progression of malignant transformation in the colon.
