Increased Dietary Vitamin D Suppresses MAPK Signaling, Colitis, and Colon Cancer

Abstract

Epidemiologic studies associate low serum vitamin D levels with an increased risk of colon cancer and inflammatory diseases such as inflammatory bowel disease (IBD). 129-Smad3tm1Par/J (Smad3−/−) mice are a model of bacterial-driven colitis and colon cancer when infected with Helicobacter bilis. Thus, we used this mouse model to determine whether increased dietary vitamin D would reduce inflammation and colon cancer. Smad3−/− mice were fed purified diet with either maintenance (1 IU vitamin D/g diet; maintenance) or increased concentrations of vitamin D (5 IU vitamin D/g diet; high vitamin D). One week after diet initiation, mice were inoculated with broth or H. bilis and were necropsied at several time points post-inoculation to assess inflammation, dysplasia, and neoplasia incidence. At 16 weeks post infection, 11% of mice fed high vitamin D diet had cancer compared to 41% of mice fed maintenance diet (p=0.0121). Evaluation at an early time point (1 week post-infection) showed that animals fed high vitamin D had decreased MAPK (p-p38 and p-JNK) activation in lamina propria leukocytes as well as decreased NFκB activation in colonic epithelial cells. Reduction in MAPK and NFκB activation correlated with decreased IBD scores (2.7 vs 15.5, p<0.0001) as well as decreased inflammatory cell infiltrates and reduced expression of proinflammatory cytokines in cecal tissue. These findings suggest that increased dietary vitamin D is beneficial in preventing inflammation-associated colon cancer through suppression of inflammatory responses during initiation of neoplasia or early stage carcinogenesis.

Vitamin D, Inflammation, and Colorectal Cancer Progression: A Review of Mechanistic Studies and Future Directions for Epidemiological Studies

“…The decrease was accompanied with decreased inflammatory cell infiltrates and a reduced expression of proinflammatory cytokines. However, no change in p38 MAPK in colonic epithelial cells was observed in these mice (36).…”

“…Calcitriol also increases the expression of the inhibitor of NF-kB, IkB (32,33,35). These effects of calcitriol on NF-kB have also been shown in a mouse model of colon cancer where an increase in dietary vitamin D resulted in a 4.5-fold decrease in NFkB activation in colonic epithelial cells (36). Furthermore, colon cancer cells treated with a vitamin D-receptor antagonist showed increased NF-kB activity and reduced IkB expression (37).…”

Isolation and characterization of a novel Helicobacter species, Helicobacter jaachi sp. nov., from common marmosets (Callithrix jaachus)

“…Further, numerous experimental Helicobacter sp. infections in mice have reproduced salient features of IBD and hepatobiliary disease observed in marmosets (Erdman et al, 2009;Fox, 2002;Fox et al, 1996Fox et al, , 2011Hailey et al, 1998;Knutson et al, 2013;Maggio-Price et al, 2005;Mangerich et al, 2012;Meeker et al, 2014).…”

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

“…A suppressed production of inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, IL-17, and TNF-␣ is consistently demonstrated in in vitro and in vivo cancer models (5,162,240,330) (FIGURE 7). In a preclinical SMAD3 knockout model of colitis and colon cancer, Meeker et al (304) showed that a high vitamin D diet decreases NF-B activation in colonic epithelial cells, which is reflected by decreased inflammatory cell infiltrates and reduced expression of proinflammatory cytokines during initiation of carcinogenesis (304). In line with this, a strong inverse association is found between 25(OH)D status and the risk of colorectal cancer with high-level lymphocytic reactions which suggests a role for vitamin D in cancer immunoprevention through modulation of the host-tumor interaction (419).…”