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

Abstract

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.

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

“…As recently demonstrated, active vitamin D can reduce matrix metalloproteinase 9 expression in brain endothelial cells and prevent the hypoxia‐mediated loss of cell‐cell contact 36. Our observations are in line with previous studies where active vitamin D preserved the integrity of intestinal mucosal barrier and stimulated epithelial cell migration 38. Together, our findings suggest that paricalcitol limits uremia‐induced endothelial damage by enhancing endothelial barrier integrity and recovery capacity following a disruptive hit.…”

Vitamin D and immune function: an overview

“…In a similar fashion to type 1 diabetes and multiple sclerosis, epidemiology suggests that patients with Crohn's disease, a form of IBD have decreased serum levels of 25OHD (144)(145)(146) . Likewise, studies using various experimentally induced forms of IBD in mice indicate that 1,25(OH) 2 D plays a crucial role in the pathophysiology of this disease (111,(147)(148)(149) . Crohn's disease is considered to be an autoimmune disease, with the disease aetiology appearing to be due to aberrant colonic immune responses to enteric bacteria.…”

Optimal vitamin D levels in Crohn's disease: a review

“…Compromised barrier function in Crohn's disease has been associated with inflammation, dysbiosis (74) , disease pathogenesis and as a predictor of clinical relapse (75,76) . Evidence suggests that vitamin D increases tight junction proteins and enhances gut mucosal healing post-injury (77) . For example, following exposure to dextran sulphate sodium, a chemical which induces colitis, the VDR knock out mice were unable to maintain the integrity of the epithelial barrier (69,78) and had lower expression of tight junction proteins than in wild-type mice (77)(78)(79) .…”

“…Evidence suggests that vitamin D increases tight junction proteins and enhances gut mucosal healing post-injury (77) . For example, following exposure to dextran sulphate sodium, a chemical which induces colitis, the VDR knock out mice were unable to maintain the integrity of the epithelial barrier (69,78) and had lower expression of tight junction proteins than in wild-type mice (77)(78)(79) . As a result of reduced tight junction proteins, vitamin D-deficient and VDR knock out mice had increased gut permeability compared with vitamin D-sufficient wild-type mice (78) .…”