Characterization of immune response and effects of energy balance on severity of colitis after infection with Helicobacter hepaticus in the SMAD3-/- mouse model.

The SMAD3-/- mouse model is used study the pathogenesis of ulcerative colitis and colon cancer development in humans. The absence of SMAD3 causes dysregulation in TGF-beta signaling and impairment of T regulatory cell development; however, current information regarding alterations in immune cell populations in this model is lacking. Therefore, we designed a study to identify and characterize SMAD3-dependent changes in immune cell populations in response to infection with the pathogenic bacteria H. hepaticus. We found significant alterations in NK cells, T cells and T cell subsets in SMAD3-/- mice, indicating that these mice have an inherently increased susceptibility to colitis due to a decreased ability to respond infection with Helicobacter hepaticus. These novel data provide potential immunological changes by which genetic alterations can affect the severity of colitis and subsequent tumorigenesis.

We then used the SMAD3-/- model to examine potential effects of energy balance on the severity of colitis and dysplasia following infection. We found that calorie-restricted mice died shortly after infection, and that there was no difference in severity of colitis between high-fat and control mice. These results are likely due to the fact that we were unable to achieve significantly increased body weight or fat percentages in the high-fat mice compared to control, especially after 18 weeks of age. Future studies will be designed to account for age-related changes in body composition prior to infection.