The mechanism of vitamin D mediated protection from experimental colitis

Fa Wang, Purdue University


Inflammatory bowel disease (IBD) describes chronic and relapsing digestive system inflammation and affects over 1.5 million people in the US. Current treatment strategies for IBD are expensive and often lead to unsatisfactory outcomes. Therefore it is essential to understand the mechanism of IBD progression and develop prevention strategies. Epidemiological evidence showed that IBD risk is negatively associated with vitamin D status. This is consistent with the clinical observation that people with vitamin D deficiency have increased IBD severity. To establish the causal link between vitamin D status and IBD development, our lab used dextran sulfate sodium (DSS) to induce experimental colitis in mice which were fed either a high or low vitamin D diet. We found that low vitamin D intake caused more severe body weight loss and spleen enlargement in mice. Since colitis development is regulated by both colon epithelial cells and infiltrating immune cells, our next research goal was to separate the vitamin D effect on the two cell compartments and investigate their independent roles in the development of experimental colitis. To test the role of vitamin D signaling in colon epithelial cells, we developed a DSS inducible, large intestine specific transgenic mouse model, which enabled the examination of vitamin D receptor (VDR) function in colon epithelial cells during DSS-colitis. We found that deleting VDR in colon epithelial cells (CAC; VDR KO) caused more severe colon damage but did not affect colon mucosa healing, immune cell activation or systemic colitis response (i.e., body weight loss, disease activity and spleen enlargement). To test the role of VDR in non-epithelial cells (primarily immune cells) during DSS-colitis, we used HV2; VDR KO mouse model non-epithelial cell VDR deletion. We demonstrated that deleting VDR from non-epithelial cells caused more robust colitis in both local and systemic levels, indicating that VDR in non-epithelial cells plays a more important role in colitis prevention than VDR in colon epithelial cells. We further tested the colonic cytokine profile in both CAC; VDR KO and HV2; VDR KO mice and found delayed healing corresponding to elevated M1 macrophage (M&phis;) activity. Therefore, we hypothesized that vitamin D can directly regulate M&phis; phenotype during colitis. This hypothesis was supported by a series of in vitro experiments using murine peritoneal M&phis;s, which showed that 1,25(OH)2D treatment inhibited M1 while facilitating M2 M&phis; polarization and phenotype switching. The major finding of my thesis work is that vitamin D signaling protects against experimental colitis in mice through the primary effect of regulating M&phis; phenotype and the secondary effect of colon epithelial cell VDR response. Further experiments are needed to investigate the upstream regulation of vitamin D on monocyte- M&phis; lineage response during colitis.




Fleet, Purdue University.

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