Diet and its modulatory effects on inflammatory bowel disease : a focus on vitamin D and infectious colitis

Vitamin D deficiency increases the risk of developing inflammatory bowel disease (IBD), a disease characterized by exaggerated immune responses to luminal bacteria. While it is unclear how vitamin D impacts IBD development, it is recognized that vitamin D plays an important role in host defense against pathogenic microbes. However, the mechanisms underlying vitamin D’s ability to affect a host’s susceptibility to infection is poorly understood. Escherichia coli is a pathobiont associated with IBD. Intestinal mucosa associated E. coli have been observed in greater numbers in patients with IBD compared to healthy controls, and these bacteria have been shown to play a role in driving intestinal inflammation. Since clinically important strains of E. coli generally do not colonize mice, researchers often rely on the related but mouse-specific attaching and effacing bacterial pathogen Citrobacter rodentium. This thesis explores the impact of vitamin D in modulating host defenses and intestinal homeostasis during infection with C. rodentium. In chapter 2, I describe how treatment with active vitamin D, calcitriol worsens colitis during C. rodentium infection. Surprisingly, calcitriol treatment of infected mice led to increased pathogen burdens, exaggerated tissue pathology and mucosal erosions. In association with their increased susceptibility, calcitriol-treated mice had substantially reduced numbers of Th17 T-cells within their infected colons and defects in their production of the antimicrobial peptide RegIIIγ. In chapter 3, I describe how dietary induced vitamin D3 deficiency also increases susceptibility to C. rodentium infection. Vitamin D3 deficient mice carried higher C. rodentium burdens, developed worsened histological damage and had higher inflammatory tone. Notably, these exaggerated inflammatory responses accelerated the loss of commensal microbes and were associated with an impaired ability to detoxify bacterial lipopolysaccharide. Together, these studies show that vitamin D plays an important role in regulating host response during enteric infection. Vitamin D deficiency impairs host defense, yet treatment with the active vitamin D also suppresses Th17 T-cell responses in vivo, and may impair mucosal host defense against bacteria. These findings have important implications for patients with IBD who suffer from overactive immune responses, yet are also have a high risk of enteric infection.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat