The role of environmental factors in gut homeostasis and experimental inflammatory bowel disease

Open Access
- Author:
- Ooi, Jot Hui
- Graduate Program:
- Pathobiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- October 01, 2012
- Committee Members:
- Margherita Teresa Anna Cantorna, Dissertation Advisor/Co-Advisor
Margherita Teresa Anna Cantorna, Committee Chair/Co-Chair
Na Xiong, Committee Member
Eric Thomas Harvill, Committee Member
Bhushan M Jayarao, Committee Member
Edward G Dudley, Committee Member - Keywords:
- Vitamin D
Diet
Inflammatory bowel disease
Gut microbiota
Immunity - Abstract:
- The etiology of inflammatory bowel disease (IBD) is complex. In addition to genetic factors, IBD onset is proposed to be triggered by environmental exposures. Studies have shown that environmental factors influence the bacterial composition in the gut. Intestinal bacterial flora have also been linked to IBD susceptibility. Using mouse models of colitis, I explored the role of two environmental factors in IBD pathogenesis: diet and vitamin D. The first objective was to evaluate the effect of different dietary intake on intestinal bacterial flora and IBD susceptibility. My study shows that variation in diet resulted in differential susceptibility to dextran-sodium sulfate (DSS)-induced colitis and Citrobacter rodentium infection in mice that were not genetically susceptible. In addition, 20% of lactose intake exacerbated the symptoms of DSS-induced colitis. Dramatic changes in gut bacterial composition were induced by dietary feeding in a short period of time. Furthermore, the depletion of bacteria using antibiotics protected mice from colitis regardless of diet. These findings suggest that diet-induced changes in susceptibility to colitis were associated with different varieties and amounts of bacteria present in the gut and that high lactose intake may contribute to the increased susceptibility to colitis. The second objective was to determine whether vitamin D regulates experimental IBD by modulating intestinal bacterial flora. My data show that the increased susceptibility of vitamin D-deficient mice to DSS-induced colitis was mediated by the alterations in gut bacterial flora. Vitamin D deficiency resulted in increased potentially pathogenic bacteria and decreased beneficial bacteria in the gut before colitis induction. In addition to bacterial flora, impaired epithelial barrier and decreased frequency of tolerogenic dendritic cells in vitamin D-deficient mice also predisposed them to DSS-induced colitis. These results suggest that vitamin D plays a role in regulating gut bacterial flora, intestinal epithelial integrity, and IBD pathogenesis. Lastly, I examined the source and role of extrarenal Cyp27B1 in the immune system. Cyp27B1 is an enzyme critical for vitamin D synthesis. My study shows that CD8+ T cells but not CD4+ T cells produced Cyp27B1 activity. T cells from Cyp27B1 knockout mice showed elevated IFN-gamma production post activation compared to wild-type T cells. Cyp27B1 knockout mice were protected from DSS-induced colitis by reconstitution with wild-type bone marrow cells, suggesting an anti-inflammatory role of immune-derived Cyp27B1. This study provides direct evidence of extrarenal Cyp27B1 and vitamin D production in regulating IFN-gamma-induced pro-inflammation and experimental IBD. Together, the work presented in this thesis advocates the critical role of environmental factors in gut homeostasis and IBD susceptibility through the regulation of intestinal bacterial flora and host immunity.