Does Vitamin D Protect the Gut Mucosal Barrier? Mechanistic Insights from Experimental Colitis.

Abstract

There is growing interest in how vitamin D and the vitamin D receptor (VDR) regulate immune responses in inflammatory bowel disease (IBD), a topic addressed by Golan et al. [1] in this issue of Digestive Diseases and Sciences. Vitamin D deficiency, measured by low circulating serum 25-hydroxyvitamin D concentration, is common in IBD and may correlate with higher disease risk, severity, and relapse rates, suggesting that targeting vitamin D pathways may provide the basis for novel therapeutic strategies [2, 3]. This hypothesis is supported by data obtained from animal models, in which vitamin D deficiency accelerates the development of experimental colitis, whereas vitamin D treatment protects against colitis and attenuates inflammation [4, 5]. The VDR is expressed in multiple cell types including T cells, macrophages, and intestinal epithelial cells. There is a considerable body of evidence from murine models of colitis indicating that the immune modulatory effects of vitamin D on T cells are mediated through the VDR [6]. Vitamin D may also regulate intestinal barrier function [7–9], although the mechanism by which vitamin D alters the intestinal barrier in IBD is unclear. In line with this, Golan et al. [1] report their data on vitamin D/VDR-mediated mechanisms in maintaining gut barrier function in experimental colitis. Increased intestinal permeability and impaired barrier function, well-documented features of human and murine IBD, have been implicated in disease pathogenesis and clinical relapse [10]. Building on past work [7, 8], Golan et al. [1] report that intestinal inflammation was attenuated through upregulation of epithelial VDR signaling. In the study, the authors introduced the human (h) VDR protein into intestinal epithelial cells obtained from the interleukin10 knockout (IL-10 KO) mouse model of colitis which expressed the hVDR transgene specifically in intestinal epithelial cells (IL-10 KO/Tg) and thus overexpressed VDR relative to IL-10 KOs. Of note, significantly reduced intestinal inflammation and reduced intestinal epithelial apoptosis were present in the IL-10 KO/Tg mice, supporting the hypothesis that increasing hVDR expression in intestinal epithelial cells attenuated colitis via epithelial VDR signaling. The findings broadly support recent work by the author group reporting that gut epithelial VDR signaling inhibited experimental colitis [8]. In interpreting the findings, the authors also propose that the overexpression of the hVDR strengthened the integrity of the epithelial barrier. Indeed, this study has nicely demonstrated that targeting epithelial VDR signaling mechanisms appears to reduce intestinal inflammation. Based on the present study alone [1], however, the assertion that this reduction in intestinal inflammation is a direct result of a VDR-mediated permeability reduction in the intestinal barrier is not supported based on the data presented. In this respect, direct evidence to support changes in barrier integrity such as changes in transepithelial electrical resistance (TER), measurement of permeability to small molecules, or expression of epithelial junctional proteins would be required. For example, determining expression and/or localization of members of the zonula occludens (ZO), claudin, or junctional adhesion molecule families would help corroborate the hypothesis that the VDR-mediated inhibition of colitis was achieved through strengthening the gut mucosal barrier. Although not investigated in the present study [1], similar work from the & Maria O’Sullivan maria.osullivan@tcd.ie