Inflammation Modulation by Vitamin D and Calcium in the Morphologically Normal Colorectal Mucosa of Colorectal Adenoma Patients in a Clinical Trial.

Gibbs, David Corley; Fedirko, Veronika; Baron, John A; Barry, Elizabeth L; Flanders, W Dana; McCullough, Marjorie L; Yacoub, Rami; Raavi, Tapasya; Rutherford, Robin E; Seabrook, March E; Bostick, Roberd M

Increased cyclooxygenase-2 (COX-2) and decreased 15-hydroxyprostaglandin dehydrogenase (15-HPGD) expression promote prostaglandin-mediated inflammation and colorectal carcinogenesis. Experimental studies suggest that vitamin D and calcium may inhibit these pathways, but their effects on colorectal tissue COX-2 and 15-HPGD expression in humans are unknown. We tested the effects of supplemental vitamin D (1,000 I.U./day) and/or calcium (1,200 mg/day) on COX-2 and 15-HPGD expression in the morphologically-normal rectal mucosa from 62 colorectal adenoma patients in a placebo-controlled chemoprevention trial. We measured biomarker expression using automated immunohistochemistry and quantitative image analysis at baseline and 1-year follow-up, and assessed treatment effects using mixed linear models. The primary outcome was the COX-2/15-HPGD expression ratio, since these enzymes function as physiologic antagonists. After 1 year of treatment, the mean COX-2/15-HPGD expression ratio in full-length crypts proportionately decreased 47% in the vitamin D group (P = 0.001), 46% in the calcium group (P = 0.002), and 34% in the calcium + vitamin D group (P = 0.03), relative to the placebo group. Among individuals with the functional vitamin D-binding protein isoform DBP2 (GC rs4588*A), the COX-2/15-HPDG ratio decreased 70% (P = 0.0006), 75% (P = 0.0002), and 60% (P = 0.006) in the vitamin D, calcium, and combined supplementation groups, respectively, relative to placebo. These results show that vitamin D and calcium favorably modulate the balance of expression of COX-2 and 15-HPGD-biomarkers of inflammation that are strongly linked to colorectal carcinogenesis-in the normal-appearing colorectal mucosa of colorectal adenoma patients (perhaps especially those with the DBP2 isoform).