Vitamin D and gastrointestinal diseases: inflammatory bowel disease and colorectal cancer

Abstract

Over the past 5 years, there has been a rapid resurgence of interest in vitamin D outside of its traditional role in metabolic bone disease. Some nontraditional roles ascribed to vitamin D include anti-inflammatory and immune-modulating effects. These effects have led to possible implications in the pathophysiology of immune-mediated diseases including multiple sclerosis and inflammatory bowel disease (IBD). In addition, vitamin D insufficiency has been linked to higher rates of cancers including colon, prostate and breast cancers. Given these diverse associations of vitamin D and disease states, this review describes recent advances with regard to vitamin D and gastrointestinal diseases, in particular IBD and colorectal cancer.

Keywords: colorectal cancer; immunology; inflammatory bowel disease; vitamin D.

Figure 1.

Classical calcium and vitamin D homeostasis pathways. Vitamin D metabolism and functions. Under ultraviolet B light exposure, 7-dehydroxycholesterol is converted to vitamin D₃ in the shin. Vitamin D₃ is transported to the liver where it is converted to 25-hydroxyvitamin D₃ (25-OHD) by 25-hydroxylase (25-OHase). 25-hydroxyvitamin D₃ (25-OHD) is further converted to 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃), the hormonal metabolite, by renal 1α-hydroxylase (1-OHase). 1α-hydroxylase. the rate-limiting enzyme, is stimulated by parathyroid hormone and feedback inhibited by 1,25(OH)₂D₃. 25-OHD and 1,25(OH)₂D₃ are further metabolized by 24-hydroxylase (24-OHase) to initiate their catabolism, which is stimulated by 1,25(OH)₂D_3. 1,25(OH)₂D₃ feedback inhibits parathyroid homione production. 1,25(OH)₂D₃ targets the intestine, kidney and bone to regulate calcium and phosphate homeostasis. The hormone also has other noncalcemic physiologic functions. 1,25(OH)₂D₃, 1α,25-dihydroxyvitamin D₃; 25-OHD, 25-hydroxyvitamin D₃; 1-OHase, 1α-hydroxylase; 24-OHase, 24-hydroxylase; 25-OHase, 25-hydroxylase; PTH, parathyroid hormone; UVB, ultraviolet B light. [Holick, M.F. (2007) Vitamin D deficiency. N Engl J Med 357: 266-281] Copyright^© [2007] Massachusetts Medical Society. All rights reserved.

Figure 2.

Ligand-dependent gene transcription by 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃). Lipid soluble 1,25(OH)₂D₃ from serum, autocrine or paracrine sources enters the target cell and binds to the nuclear vitamin D receptor (VDR). This induces a conformational change and promotes heterodimerization with the retinoid X receptor (RXR). The VDR/RXR has an increased affinity for the vitamin D responsive element (VDRE). VRDE is a specific sequence of nucleotides in the promoter region of the vitamin D responsive gene. Binding of the VDR/RXR complex to the VDRE attracts a complex of co-activator proteins connecting VDRE with RNA polymerase II. Gene transcription then occurs, producing mRNA transcripts, which leave the nucleus for translation into the coded protein in the cytoplasm.