Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

Abstract

The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4 + CD45RB hi T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.

Serum 25-hydroxyvitamin D concentration is inversely associated with mucosal inflammation in patients with ulcerative colitis,

“…Taken together with our results demonstrating the association between serum 25(OH)D concentrations and disease activity, these conclusions support data from in vitro cell culture studies and in vivo animal models that the vitamin D-VDR axis exerts dual roles in protecting against colitis by maintaining epithelial barrier function and decreasing mucosal inflammation (22,23 gene transcription and stabilizing the VDR protein (45)(46)(47). Previous work has demonstrated that the VDR-retinoid X receptor heterodimer binds at the VDR gene itself, and VDR transcripts have been reported to increase with vitamin D 3 treatment in lymphoblastoid cells (48).…”

“…Specifically, our group has demonstrated that, as a protective mechanism against mucosal inflammation, vitamin D signaling inhibits gut epithelial cell apoptosis by downregulating nuclear transcription factor kB (NF-kB), which in turn downregulates the p53 modulator of apoptosis, a key positive regulator of gut epithelial cell apoptosis (23). As such, we hypothesize that this inhibition of apoptosis contributes to preserving epithelial tight junction proteins.…”

“…In addition to its anti-inflammatory effects, our group has reported that vitamin D-VDR signaling protects against colitis by maintaining intestinal epithelial barrier integrity by suppressing epithelial apoptosis and abrogating myosin light-chain kinasedependent tight junction dysfunction (22)(23)(24). Although there are 2 studies that have demonstrated an inverse correlation between serum 25(OH)D and fecal calprotectin in patients with IBD, there are no data to our knowledge comparing serum 25(OH)D concentrations with endoscopic mucosal disease activity or epithelial barrier function in patients with IBD (25,26).…”

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

“…Having identified the essential role of EZH2 in DSS-induced colitis, we used another disease model to substantiate this idea. The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model acts via acute destruction of the intestinal barrier and involves Th1-mediated mucosal inflammation, thereby mimicking CD in humans (27,28). We challenged wild-type and EZH2 IEC−/− mice with TNBS to assess the role of epithelial EZH2 in this model.…”

Coeliac disease and asthma association in children: the role of antibiotic consumption

“…For instance, vitamin D deficiency, which is common among coeliac [17,18] and asthmatic patients [19,20], seems to have unfavourable effects on immune regulation [21], gut microbial balance and the intestinal mucosal barrier [22][23][24]. Therefore, vitamin D deficiency may be a common factor capable of increasing the risk of developing both coeliac disease and asthma.…”