INVESTIGATION OF THE ROLE OF DIETARY AND MICROBIAL LIGANDS AS MODIFIERS OF INFLAMMATION AND COLON CANCER DEVELOPMENT. Projects in this research area are designed to assess how microbiota-derived tryptophan metabolites mediate AhR-dependent intestinal function. Since transformation of adult stem cells is an extremely important route towards initiating intestinal cancer, we have interrogated the effect of diet and microbiota-derived AhR ligands on intestinal stem cell homeostasis and colon tumorigenesis using tissue and stem cell-specific AhR knock out and control compound mice. 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. In addition, we have demonstrated 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. Collectively, our results provide a critical new paradigm in understanding the molecular mechanisms through which microbes modulate colon cancer risk.
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