title: 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-Smad3(tm1Par)/J (Smad3(-/-)) mice are a model of bacteria-driven colitis and colon cancer when infected with Helicobacter bilis (H. 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 postinoculation to assess inflammation, dysplasia, and neoplasia incidence. At 16 weeks postinfection, 11% of mice fed high vitamin D diet had cancer compared with 41% of mice fed maintenance diet (P = 0.0121). Evaluation at an early time point (1 week postinfection) 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.
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington.
authors.forename: Stacey
authors.initials: S
authors.lastname: Meeker
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington.
authors.forename: Audrey
authors.initials: A
authors.lastname: Seamons
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington.
authors.forename: Jisun
authors.initials: J
authors.lastname: Paik
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington.
authors.forename: Piper M
authors.initials: PM
authors.lastname: Treuting
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington.
authors.forename: Thea
authors.initials: T
authors.lastname: Brabb
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Gastroenterology, University of Washington Medical School, Seattle, Washington.
authors.forename: William M
authors.initials: WM
authors.lastname: Grady
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington. lmprice@uw.edu.
authors.forename: Lillian
authors.initials: L
authors.lastname: Maggio-Price
mesh_terms: D000818:Animals; D003092:Colitis / Q000201:enzymology / Q000517:prevention & control*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000517:prevention & control*; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D051900:Smad3 Protein / Q000378:metabolism; D014807:Vitamin D / Q000008:administration & dosage*
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D014807:Vitamin D