Vitamin D deficiency in mice impairs colonic antibacterial activity and predisposes to colitis.
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.
Lagishetty
Venu
V
Room 410D, Orthopaedic Hospital Research Center, University of California Los Angeles, Los Angeles, California 90095, USA.
Misharin
Alexander V
AV
Liu
Nancy Q
NQ
Lisse
Thomas S
TS
Chun
Rene F
RF
Ouyang
Yi
Y
McLachlan
Sandra M
SM
Adams
John S
JS
Hewison
Martin
M
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
D004269:DNA, Bacterial; D014807:Vitamin D; C097949:1,25-dihydroxyvitamin D; D016264:Dextran Sulfate; C519253:Ang4 protein, mouse; D012259:Ribonuclease, Pancreatic
Curr Opin Immunol. 2008 Aug;20(4):371-6
18602003
J Immunol. 2003 Aug 1;171(3):1556-63
12874249
N Engl J Med. 2009 Apr 23;360(17):1785-6
19369659
Ann N Y Acad Sci. 2007 Nov;1117:94-105
17656563
Inflamm Bowel Dis. 2006 Dec;12(12):1162-74
17119391
J Clin Endocrinol Metab. 2001 Feb;86(2):888-94
11158062
Scand J Gastroenterol. 2002 Feb;37(2):192-9
11843057
BMC Immunol. 2007 Mar 30;8:5
17397543
Biol Reprod. 2009 Mar;80(3):398-406
19005165
Nutr Rev. 2008 Oct;66(10 Suppl 2):S135-8
18844840
Gut. 2004 Aug;53(8):1129-36
15247180
Mol Endocrinol. 2003 Dec;17(12):2386-92
14500760
Gut. 1985 Nov;26(11):1197-203
3877663
Nat Clin Pract Endocrinol Metab. 2008 Feb;4(2):80-90
18212810
J Exp Med. 2007 Jun 11;204(6):1257-65
17502665
J Biol Chem. 2010 Jan 22;285(4):2227-31
19948723
Curr Opin Gastroenterol. 2007 Jul;23(4):370-8
17545771
Gastroenterology. 2002 Jun;122(7):2011-25
12055606
Pediatrics. 2006 Nov;118(5):1950-61
17079566
Nature. 2001 May 31;411(6837):603-6
11385577
Gut. 2006 Jun;55(6):824-32
16401687
Endocrinology. 2008 Oct;149(10):4799-808
18535110
Immunology. 2006 Mar;117(3):310-8
16476050
JPEN J Parenter Enteral Nutr. 2007 Jul-Aug;31(4):311-9
17595441
Am J Clin Nutr. 1985 Oct;42(4):644-9
4050723
Curr Opin Investig Drugs. 2008 May;9(5):485-90
18465658
Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G208-16
17962355
Nature. 2001 May 31;411(6837):599-603
11385576
Ann Epidemiol. 2009 Feb;19(2):73-8
18329892
J Immunol. 2009 Apr 1;182(7):4289-95
19299728
Biol Reprod. 2006 Dec;75(6):816-22
16957024
Cell Tissue Res. 2004 Nov;318(2):313-23
15338270
Gut. 1980 Apr;21(4):287-92
6253363
N Engl J Med. 2007 Jul 19;357(3):266-81
17634462
Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20834-9
19095793
J Clin Invest. 2007 Mar;117(3):803-11
17290304
Am J Clin Nutr. 1991 Sep;54(3):548-52
1652198
Diabetologia. 2005 Jul;48(7):1247-57
15971062
World J Gastroenterol. 2008 Sep 28;14(36):5499-503
18810765
J Immunol. 2006 Nov 15;177(10):6780-6
17082591
Semin Immunol. 2007 Apr;19(2):70-83
17485224
Curr Opin Infect Dis. 2009 Jun;22(3):292-301
19352175
Science. 2006 Mar 24;311(5768):1770-3
16497887
Gastroenterology. 2002 Apr;122(4):867-74
11910337
J Immunol. 2007 Apr 15;178(8):4737-48
17404253
Life Sci. 2007 Jun 20;81(2):115-20
17574630
Adv Drug Deliv Rev. 2007 Sep 30;59(11):1073-83
17825455
J Immunol. 2003 Jun 1;170(11):5382-90
12759412
Am J Gastroenterol. 2008 Jun;103(6):1451-9
18422819
Eur J Clin Nutr. 2006 Jul;60(7):889-96
16493452
Nat Immunol. 2003 Mar;4(3):269-73
12548285