Review
Critical roles of intestinal epithelial vitamin D receptor signaling in controlling gut mucosal inflammation

https://doi.org/10.1016/j.jsbmb.2015.01.011Get rights and content

Highlights

  • ā€¢

    Intestinal epithelial VDR inhibits colitis by protecting the mucosal barrier.

  • ā€¢

    Intestinal epithelial VDR levels are reduced in patients with IBD.

  • ā€¢

    Intestinal epithelial VDR is down-regulated by a microRNA-mediated mechanism.

  • ā€¢

    VDR is a key molecule in a regulatory circuit controlling mucosal inflammation.

  • ā€¢

    Increasing gut epithelial VDR levels are a valuable strategy for IBD treatment.

Abstract

Although vitamin D receptor (VDR) is highly expressed in the intestine, the role of VDR signaling in the gut is not fully understood. Our recent studies unveil a regulatory circuit that centers gut epithelial VDR as a key molecule in the control of mucosal inflammation and colitis development. On the one hand, intestinal epithelial VDR signaling protects the integrity of the mucosal barrier by inhibiting inflammation-induced epithelial cell apoptosis. This barrier-protecting, anti-colitic activity is independent of the non-epithelial immune VDR actions. A healthy and intact mucosal barrier prevents bacterial invasion and thus reduces mucosal inflammation. On the other hand, inflammation in turn down-regulates epithelial VDR expression by inducing VDR-targeting microRNA-346, thus compromising mucosal barrier functions. Consistently, colonic epithelial VDR levels are markedly reduced in patients with inflammatory bowel diseases or in experimental colitis models, whereas vitamin D analog therapy that ameliorates colitis up-regulates epithelial VDR. Thus, gut epithelial VDR signaling appears to play an essential role in controlling mucosal inflammation and thus could be a useful therapeutic target in the management of inflammatory bowel diseases.

This article is part of a special issue entitled ā€˜17th Vitamin D Workshopā€™ .

Introduction

The gut, particularly the large intestine, contains an enormous amount of commensal bacteria and other immuno-activating substances in the lumen that can cause mucosal inflammation once invading the lamina propria, where the immuno-activating components of the bacteria activate the immune cells. The gut mucosal epithelial barrier separates the body from the luminal microorganisms and inflammatory and toxic substances. This mucosal barrier consists of a monolayer of epithelial cells with intercellular junctions formed between adjacent cells that seal the paracellular space and regulate permeability of the barrier [1]. Dysfunction of the barrier leads to increased translocation of luminal substances to the lamina propria, triggering inflammatory response [2], [3]. In fact, impaired gut mucosal barrier is a significant pathogenic factor for inflammatory bowel diseases (IBD) [4], the major inflammatory disorders in the gastrointestinal tract in humans that include ulcerative colitis (UC) and Crohnā€™s disease (CD). Mucosal inflammation results in excess production of pro-inflammatory cytokines that can in turn increase mucosal permeability by altering intercellular tight junction structure and induce apoptosis of intestinal epithelial cells (IEC) [4], [5]. Excess IEC apoptosis causes focal disruption of the mucosal barrier independent of the tight junction. Indeed, increased IEC apoptosis has been reported in patients with UC and CD [6], [7], [8] as well as in murine models of colitis [9], [10]. This vicious cycle of mucosal events drives chronic mucosal inflammation and promotes the development of colitis.

Vitamin D hormone is a pleiotropic hormone that has a broad range of biological activities [11]. Vitamin D is converted to the active metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D3) via two steps of hydroxylation in the liver and kidney, and the latter is catalyzed by Cyp27B1, a rate-limiting hydroxylase. Cyp27B1 is also expressed in extra-renal tissues, including the intestine, to drive local production of 1,25(OH)2D3. Interestingly, colonic Cyp27B1 expression is influenced by toll-like receptor activation and colonic inflammation [12], [13], but the significance is unclear.

A growing body of epidemiological data has documented an association between vitamin D-deficiency and increased risk of IBD [14], [15], [16], including both CD and UC [17], [18], [19], [20], [21], [22], [23], [24]. A high prevalence of vitamin D deficiency was reported in patients with established as well as newly diagnosed IBD [25], [26], [27]. Vitamin D-deficiency is independently associated with lower quality of life and greater disease activity in IBD [28]. Higher vitamin D status is associated with lowered risk of CD [29]. These observations suggest that vitamin D status might be an environmental determinant for IBD.

The biological activity of 1,25(OH)2D3 is mediated by the vitamin D receptor (VDR), a member of the nuclear hormone receptor superfamily [30]. VDR is abundantly expressed in the intestine. The classic action of the VDR in the small intestine is to regulate transcellular calcium transport, but its role in the large intestine is less clear. Our recent studies reveal a regulatory circuit that centers gut epithelial VDR as a key molecule in the control of mucosal inflammation and colitis development, suggesting that VDR status might be a key genetic factor influencing IBD development. In this article we summarize these studies.

Section snippets

Potent anti-colitic activity of intestinal epithelial VDR signaling

We and other groups have reported that global VDR deletion increases mucosal injury that lead to high mortality in dextran sulfate sodium (DSS)-induced experimental colitis model [31], [32], [33]. In this model VDRāˆ’/āˆ’ mice showed markedly reduced colonic transepithelial electrical resistance (TER), an indicator of epithelial barrier integrity, before colonic histological abnormalities were seen, suggesting an important role of VDR signaling in maintaining the integrity of the mucosal barrier.

Rescue of severe colitis phenotype of VDR-null mice with the hVDR transgene

We previously showed that VDRāˆ’/āˆ’ mice developed severe colitis and high mortality in the DSS model [32], but because of the global deletion of the VDR gene, the role that the epithelial and non-epithelial VDR plays in colitis development is unknown. We reasoned that, if the anti-colitic activity of the epithelial VDR is a primary and essential protective mechanism, then reconstitution of the gut epithelial cells in VDRāˆ’/āˆ’ mice with the hVDR transgene should be able to prevent or attenuate the

Mucosal barrier-protecting mechanism of intestinal epithelial VDR signaling

In IBD colonic mucosal permeability is usually increased before clinical symptoms or histological damage are developed. We observed that, in contrast to WT controls, the colonic mucosal transepithelial electrical resistance (TER), an indicator of mucosal permeability, was well preserved in the villin-hVDR Tg mice in the early stage of colitis [35], indicating that epithelial hVDR signaling protects the integrity of the mucosal epithelial barrier. Increased apoptosis in gut epithelial cells is a

Reduced colonic epithelial VDR in IBD patients

Given the mucosal barrier-protecting role for VDR, it is conceivable that epithelial VDR reduction increases the risk of mucosal barrier dysfunction and promotes mucosal inflammation. Indeed, we found that epithelial VDR levels are substantially reduced in patients with IBD [35], [49]. We examined the VDR status in colonic biopsies from both CD and UC patients in comparison with normal colon samples in two cohorts, one from Chicago, USA and the other from Shenyang, China. In the Chinese cohorts

MicroRNA-mediated mechanism for inflammation-induced VDR down-regulation

Based on the animal and human data we reasoned that epithelial VDR reduction likely compromises the gut mucosal barrier and contributes to the development of IBD. Therefore, it is important to understand the molecular mechanism underlying the down-regulation of epithelial VDR in colitis. To test the hypothesis that inflammation down-regulates VDR expression, we examined the effect of several pro-inflammatory cytokines (TNF-Ī±, IL-1Ī² and IL-6) on VDR expression in colon cancer cells, and found

Discussion and conclusion

Taken together, our recent studies unveil a critical role of intestinal epithelial VDR in the regulation of mucosal inflammation. Whereas the VDR signaling maintains the integrity of the mucosal barrier by inhibiting inflammation-induced apoptosis of intestinal epithelial cells, VDR abundance is influenced by mucosal inflammation in turn, as its expression is down-regulated by mucosal pro-inflammatory cytokines. Thus, epithelial VDR appears to be a central molecule in a regulatory circuit

Conflict of interest

No authors declare a conflict of interest.

Acknowledgements

This work was supported by grants from National Institutes of Health, R01CA180087 and Foundation for Clinical Research in Inflammatory Bowel Disease (FCRIBD).

References (63)

  • I. Okayasu et al.

    A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice

    Gastroenterology

    (1990)
  • F. Powrie

    T cells in inflammatory bowel disease: protective and pathogenic roles

    Immunity

    (1995)
  • R. Kuhn et al.

    Interleukin-10-deficient mice develop chronic enterocolitis

    Cell

    (1993)
  • Y. Chen et al.

    1,25-Dihydroxyvitamin D(3) suppresses inflammation-induced expression of plasminogen activator inhibitor-1 by blocking nuclear factor-kappaB activation

    Arch. Biochem. Biophys.

    (2011)
  • J.F. Colombel et al.

    Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial

    Gastroenterology

    (2007)
  • D.P. Bartel

    MicroRNAs: genomics, biogenesis, mechanism, and function

    Cell

    (2004)
  • T.T. Wang et al.

    Direct and indirect induction by 1,25-dihydroxyvitamin D3 of the NOD2/CARD15-defensin beta2 innate immune pathway defective in Crohn disease

    J. Biol. Chem.

    (2010)
  • J.M. Yuk et al.

    Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin

    Cell Host Microbe

    (2009)
  • M.G. Laukoetter et al.

    Regulation of the intestinal epithelial barrier by the apical junctional complex

    Curr. Opin. Gastroenterol.

    (2006)
  • A. Fasano et al.

    Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases

    Nat. Clin. Pract. Gastroenterol. Hepatol.

    (2005)
  • P.R. Gibson

    Increased gut permeability in Crohn's disease: is TNF the link?

    Gut

    (2004)
  • K.L. Edelblum et al.

    Regulation of apoptosis during homeostasis and disease in the intestinal epithelium

    Inflamm. Bowel Dis.

    (2006)
  • M. Iwamoto et al.

    Apoptosis of crypt epithelial cells in ulcerative colitis

    J. Pathol.

    (1996)
  • C. Hagiwara et al.

    Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery

    J. Gastroenterol. Hepatol.

    (2002)
  • A. Di Sabatino et al.

    Increased enterocyte apoptosis in inflamed areas of Crohn's disease

    Dis. Colon Rectum

    (2003)
  • A. Nenci et al.

    Epithelial NEMO links innate immunity to chronic intestinal inflammation

    Nature

    (2007)
  • R. Bouillon et al.

    Vitamin D and human health: lessons from vitamin D receptor null mice

    Endocr. Rev.

    (2008)
  • N. Liu et al.

    Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation

    Endocrinology

    (2008)
  • W.C. Lim et al.

    Mechanisms of disease: vitamin D and inflammatory bowel disease

    Nat. Clin. Pract. Gastroenterol. Hepatol.

    (2005)
  • S.H. Scharla et al.

    Bone mineral density and calcium regulating hormones in patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis)

    Exp. Clin. Endocrinol.

    (1994)
  • S.C. Bischoff et al.

    Altered bone metabolism in inflammatory bowel disease

    Am. J. Gastroenterol.

    (1997)
  • Cited by (105)

    • Vitamin D, inflammation, and cancer

      2023, Feldman and Pike's Vitamin D: Volume Two: Disease and Therapeutics
    • Role of probiotics in the management of respiratory infections

      2022, Probiotics in the Prevention and Management of Human Diseases: A Scientific Perspective
    View all citing articles on Scopus
    View full text