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This Article Full Text Full Text (PDF) All Versions of this Article: 294/1/G208    most recent 00398.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kong, J. Articles by Li, Y. C. PubMed PubMed Citation Articles by Kong, J. Articles by Li, Y. C.

MUCOSAL BIOLOGY

Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier

Departments of ¹Medicine and ⁴Pathology, The University of Chicago, Chicago, Illinois; ²The Huck Institutes for Life Sciences, The Pennsylvania State University, University Park, Pennsylvania; and ³Gastroenterology and Hepatology Division, Department of Medicine, University of Rochester Medical Center, Rochester, New York

Submitted 31 August 2007 ; accepted in final form 23 October 2007

Emerging evidence supports a pathological link between vitamin D deficiency and the risk of inflammatory bowel disease (IBD). To explore the mechanism we used the dextran sulfate sodium (DSS)-induced colitis model to investigate the role of the vitamin D receptor (VDR) in mucosal barrier homeostasis. While VDR^+/+ mice were mostly resistant to 2.5% DSS, VDR^–/– mice developed severe diarrhea, rectal bleeding, and marked body weight loss, leading to death in 2 wk. Histological examination revealed extensive ulceration and impaired wound healing in the colonic epithelium of DSS-treated VDR^–/– mice. Severe ulceration in VDR^–/– mice was preceded by a greater loss of intestinal transepithelial electric resistance (TER) compared with VDR^+/+ mice. Confocal and electron microscopy (EM) revealed severe disruption in epithelial junctions in VDR^–/– mice after 3-day DSS treatment. Therefore, VDR^–/– mice were much more susceptible to DSS-induced mucosal injury than VDR^+/+ mice. In cell cultures, 1,25-dihydroxy-vitamin D₃ [1,25(OH)₂D₃] markedly enhanced tight junctions formed by Caco-2 monolayers by increasing junction protein expression and TER and preserved the structural integrity of tight junctions in the presence of DSS. VDR knockdown with small interfering (si)RNA reduced the junction proteins and TER in Caco-2 monolayers. 1,25(OH)₂D₃ can also stimulate epithelial cell migration in vitro. These observations suggest that VDR plays a critical role in mucosal barrier homeostasis by preserving the integrity of junction complexes and the healing capacity of the colonic epithelium. Therefore, vitamin D deficiency may compromise the mucosal barrier, leading to increased susceptibility to mucosal damage and increased risk of IBD.

tight junction; inflammatory bowel disease; dextran sulfate sodium