Colonic vitamin D metabolism: Implications for the pathogenesis of inflammatory bowel disease and colorectal cancer

In epidemiological studies serum levels below 30 nM of 25-OHD3, the precursor of the active vitamin D metabolite 1,25-(OH)2D3, were consistently associated with incidence of colorectal cancer. The active vitamin D metabolite possesses antimitotic, prodifferentiating and proapoptotic capacity in vivo and in vitro.The intestinal autocrine/paracrine vitamin D system, which is the main source of local 1,25-(OH)2D3 plays a critical role in maintaining both mucosal immunity and normal growth of epithelial cells. It has been hypothesized that the VDR-mediated signaling antagonizing TNF-α and IL-6 receptor-activated pro-inflammatory and proliferative intracellular pathways, may prevent development of IBD and colitis-associated colorectal cancer. Conversely, any situation that impairs the efficiency of the 1,25-(OH)2D3/VDR signaling system at the level of the gut mucosa, e.g. vitamin D insufficiency, may increase risk for the development of IBD and colorectal cancer. Therefore, not only adequate serum levels of the precursor 25-OHD3 are essential, but also optimal expression of the 1α-hydroxylating enzyme CYP27B1. The 1,25-(OH)2D3 catabolizing hydroxylase CYP24A1 is increasingly expressed during colon cancer progression, indicating that colonocytes are released from normal growth control by the steroid hormone. Securing adequate levels of calcitriol by inhibition of catabolism and support of 1α-hydroxylation by calcium, phytoestrogens and folate could be a valid approach to control, at least in part, IBD and CRC pathogenesis.

► Calcitriol maintains mucosal integrity and normal growth of colonic epithelial cells.
► Calcitriol enhances innate immunity and represses the adaptive immune response.
► Vitamin D insufficiency increases the risk for colonic inflammation and malignancy.
► Calcitriol is synthesized and degraded by epithelial and immune cells of the colon.
► Calcitriol accumulation in colonic mucosa may be enhanced by nutrition.