Effects of Dietary Vitamin D in Mediating Protection Against Colitis and Colitis-Associated Colon Cancer in Smad3-/- Mice

Thesis (Ph.D.)--University of Washington, 2015Epidemiologic studies suggest that low serum vitamin D levels are associated with an increased risk of colon cancer and inflammatory diseases such as inflammatory bowel disease (IBD). We have utilized 129-Smad3tm1Par/J (Smad3-/-) mice, which have dysregulated transforming growth factor β signaling and are a model of colitis and inflammation-associated colon cancer to evaluate the effects of modulated dietary vitamin D on colitis and colon cancer. Through these studies, we have determined that increased dietary vitamin D reduces typhlocolitis and colon cancer using both bacterially-induced colitis through infection with Helicobacter bilis and chemically-induced colitis using dextran sodium sulfate. Our data suggest that increased dietary vitamin D is beneficial in preventing inflammation-associated colon cancer at least in part through suppression of inflammatory responses during tumor initiation or early stage carcinogenesis. Importantly, the protective effects afforded by dietary vitamin D are dependent in part upon the presence of CD4+ cells. In addition to evaluating the effects of increased dietary vitamin D, we have utilized a model of chronic vitamin D deficiency to evaluate the effects of vitamin D deficiency on colitis and colitis associated colon cancer. Interestingly, while vitamin D deficiency did not affect the disease severity or progression in H. bilis-infected Smad3-/- mice, vitamin D-deficient Smad3-/- mice were protected against DSS-induced colon cancer due to increased cellular proliferation during the healing phase following DSS-treatment. Finally, we have utilized our model to demonstrate that the alteration of vitamin D concentrations in the diet is sufficient to significantly alter the gut microbiome. Together, these studies provide important insights into the mechanisms through which dietary vitamin D modulates inflammation and tumor development in a genetically susceptible host