Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract (GIT), including Crohn's disease (CD) and ulcerative colitis (UC), which differ in the location and lesion extensions. Both diseases are associated with microbiota dysbiosis, with a reduced population of butyrate-producing species, abnormal inflammatory response, and micronutrient deficiency (e.g., vitamin D hypovitaminosis). Vitamin D (VitD) is involved in immune cell differentiation, gut microbiota modulation, gene transcription, and barrier integrity. Vitamin D receptor (VDR) regulates the biological actions of the active VitD (1α,25-dihydroxyvitamin D3), and is involved in the genetic, environmental, immune, and microbial aspects of IBD. VitD deficiency is correlated with disease activity and its administration targeting a concentration of 30 ng/mL may have the potential to reduce disease activity. Moreover, VDR regulates functions of T cells and Paneth cells and modulates release of antimicrobial peptides in gut microbiota-host interactions. Meanwhile, beneficial microbial metabolites, e.g., butyrate, upregulate the VDR signaling. In this review, we summarize the clinical progress and mechanism studies on VitD/VDR related to gut microbiota modulation in IBD. We also discuss epigenetics in IBD and the probiotic regulation of VDR. Furthermore, we discuss the existing challenges and future directions. There is a lack of well-designed clinical trials exploring the appropriate dose and the influence of gender, age, ethnicity, genetics, microbiome, and metabolic disorders in IBD subtypes. To move forward, we need well-designed therapeutic studies to examine whether enhanced vitamin D will restore functions of VDR and microbiome in inhibiting chronic inflammation.

Keywords: Crohn’s disease; VDR; antimicrobial peptides (AMP); dysbiosis; epigenetics; inflammation; metabolites; microbiome; micronutrient; nuclear receptor; probiotics; tight junctions; ulcerative colitis; vitamin D.

Figure 1

Consequences of the main genetic variants present in the IBD. Bacterial MDP is transported by hPepT1 into the epithelial cell and is recognized by the NOD-2 receptor variant. This interaction activates the kinase TAK1 and its downstream effectors NF-kB and MAPK, leading to the production of pro-inflammatory cytokines. NOD-2 receptor also interacts with genes related to autophagy ATG16L1 and IRGM, reducing the production of AMPs and bacterial killing. In IBD, these mechanisms are impaired due to genetic variants and contribute to the pathogenesis of the disease. (AMP: antimicrobial peptides; ATG16L1: autophagy related 16 like 1; hPepT1: human peptide transporter 1; IRGM: immunity related GTPase M; MAPK: mitogen-activated protein kinase; MDP: muramyl dipeptide; NF-κB: nuclear factor kappa B; NOD2: nucleotide-binding oligomerization domain containing 2; TAK1: transforming growth factor beta activated kinase 1; TNF-α: tumor necrosis factor alpha).

Figure 2

Chemical structure and activation of vitamin D. The vitamin D obtained by the exposure of skin to sunlight or consumed in food or supplements is transported to the liver and converted to 25(OH)D (25-hydroxyvitamin D) by the enzyme 25-hydroxylase (CYP2R1). Thereafter, a second hydroxylation occurs in the kidneys by the enzyme 1-α-hydroxylase (CYP27B1) generating the active vitamin D (1,25-(OH)₂D or 1,25-dihydroxyvitamin D), which biological functions are mediated by the VDR (vitamin D receptor). The VDR bounded to 1,25-(OH)₂D forms a heterodimer with the retinoic acid receptor (RXR), which in turn attaches to the vitamin D-response element (VDRE) acting as a nuclear transcription regulator.

Figure 3

Vitamin D/VDR is involved in the genetic, environmental, immune, and microbial aspects of inflammatory bowel disease (IBD). Thus, the vitamin D supplement and activation of VDR could be considered as a multifunctional factor in IBD treatment.