title: Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis.
abstract: Vitamin D insufficiency is a global health issue. Although classically associated with rickets, low vitamin D levels have also been linked to aberrant immune function and associated health problems such as inflammatory bowel disease (IBD). To test the hypothesis that impaired vitamin D status predisposes to IBD, 8-wk-old C57BL/6 mice were raised from weaning on vitamin D-deficient or vitamin D-sufficient diets and then treated with dextran sodium sulphate (DSS) to induce colitis. Vitamin D-deficient mice showed decreased serum levels of precursor 25-hydroxyvitamin D(3) (2.5 +/- 0.1 vs. 24.4 +/- 1.8 ng/ml) and active 1,25-dihydroxyvitamin D(3) (28.8 +/- 3.1 vs. 45.6 +/- 4.2 pg/ml), greater DSS-induced weight loss (9 vs. 5%), increased colitis (4.71 +/- 0.85 vs. 1.57 +/- 0.18), and splenomegaly relative to mice on vitamin D-sufficient chow. DNA array analysis of colon tissue (n = 4 mice) identified 27 genes consistently (P < 0.05) up-regulated or down-regulated more than 2-fold in vitamin D-deficient vs. vitamin D-sufficient mice, in the absence of DSS-induced colitis. This included angiogenin-4, an antimicrobial protein involved in host containment of enteric bacteria. Immunohistochemistry confirmed that colonic angiogenin-4 protein was significantly decreased in vitamin D-deficient mice even in the absence of colitis. Moreover, the same animals showed elevated levels (50-fold) of bacteria in colonic tissue. These data show for the first time that simple vitamin D deficiency predisposes mice to colitis via dysregulated colonic antimicrobial activity and impaired homeostasis of enteric bacteria. This may be a pivotal mechanism linking vitamin D status with IBD in humans.
authors.affiliation: Room 410D, Orthopaedic Hospital Research Center, University of California Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Venu
authors.initials: V
authors.lastname: Lagishetty
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Misharin
authors.forename: Nancy Q
authors.initials: NQ
authors.lastname: Liu
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lisse
authors.forename: Rene F
authors.initials: RF
authors.lastname: Chun
authors.forename: Yi
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Sandra M
authors.initials: SM
authors.lastname: McLachlan
authors.forename: John S
authors.initials: JS
authors.lastname: Adams
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
mesh_terms: D000818:Animals; D003092:Colitis / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000382:microbiology; D003106:Colon / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004269:DNA, Bacterial / Q000235:genetics; D016264:Dextran Sulfate / Q000009:adverse effects; D005434:Flow Cytometry; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D013163:Splenomegaly / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D014808:Vitamin D Deficiency / Q000503:physiopathology*; D015431:Weight Loss
chemical_list: D004269:DNA, Bacterial; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D016264:Dextran Sulfate; C519253:Ang4 protein, mouse; D012259:Ribonuclease, Pancreatic
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