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Address correspondence to Ioanna Aggeletopoulou, Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece.
Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, GreeceDivision of Hematology, Department of Internal Medicine, Laboratory of Immunohematology, Medical School, University Hospital of Patras, Patras, Greece
Studies of systemic autoimmune diseases point to characteristic microbial patterns in various diseases, including inflammatory bowel disease (IBD). Autoimmune diseases, and IBD in particular, show a predisposition to vitamin D deficiency, leading to alterations in the microbiome and disruption of intestinal epithelial barrier integrity. In this review, we examine the role of the gut microbiome in IBD and discuss how vitamin D–vitamin D receptor (VDR)–associated molecular signaling pathways contribute to the development and progression of IBD through their effects on gut barrier function, the microbial community, and immune system function. The present data demonstrate that vitamin D promotes the proper function of the innate immune system by acting as an immunomodulator, exerting anti-inflammatory effects, and critically contributing to the maintenance of gut barrier integrity and modulation of the gut microbiota, mechanisms that may influence the IBD development and progression. VDR regulates the biological effects of vitamin D and is related to environmental, genetic, immunologic, and microbial aspects of IBD. Vitamin D influences the distribution of the fecal microbiota, with high vitamin D levels associated with increased levels of beneficial bacterial species and lower levels of pathogenic bacteria. Understanding the cellular functions of vitamin D–VDR signaling in intestinal epithelial cells may pave the way for the development of new treatment strategies for the therapeutic armamentarium of IBD in the near future.
Crohn disease (CD) and ulcerative colitis (UC) are two chronic diseases characterized by chronic inflammation in the gastrointestinal tract and are referred to as inflammatory bowel disease (IBD). Although the exact cause of IBD remains unclear, significant progress has been made in recent years in deciphering the pathophysiology of these diseases. Over the past decade, IBD has become a global public health challenge,
The pathogenesis and development of IBD include impaired regulation of immune responses, environmental changes, and disease-related genetic alterations.
In the pathology of IBD, alterations in the gut microbiota are a common feature; however, it is not clear whether these alterations are the cause or consequence of gut inflammation and how these bacterial communities contribute to the pathogenesis of IBD.
Vitamin D malabsorption has been associated with inadequate sunlight exposure, deficient enzymatic activation, decreased bioavailability, increased catabolism or excretion, inadequate exercise, and smoking.
Vitamin D exerts a variety of effects on the immune system, including regulation of immune modulation, cell proliferation and differentiation, and maintenance of intestinal homeostasis.
In parallel, vitamin D–associated vitamin D receptor (VDR) signaling has been shown to regulate immunity to gut pathogens and maintain gut barrier integrity, demonstrating a potential role in IBD pathogenesis.
The human microbiome in the gastrointestinal tract consists of a community of commensal, symbiotic, and pathogenic microorganisms that live in the human body.
This population directly or indirectly influences human physiology by contributing to metabolic functions, protecting against pathogens, and modulating the immune system.
The microbiome is of great importance in autoimmune responses under the concept of molecular mimicry, in which microbial peptides have a similar structure and sequence to self-antigens, resulting in immune cell autoreactivity.
Impaired VDR signaling has been associated with the mucosal inflammation and damage observed in patients with IBD; however, the question of whether impaired VDR signaling causes IBD or whether IBD is the consequence of this impairment has not yet been answered.
This review presents advances in the molecular mechanisms linking the gut microbiome and IBD, as well as recent findings on the interaction between vitamin D and the gut microbiome and how this relationship influences IBD pathogenesis and progression. Emphasis will be placed on preclinical experimental IBD models and translational data on clinical IBD.
Biosynthesis, Physiology, and Metabolism of Vitamin D
Vitamin D was first referred to as a vitamin, but it is actually a fat-soluble steroid hormone that occurs in two different isoforms, vitamin D2 (ergocalciferol, mainly derived from plants) and vitamin D3 (cholecalciferol, mainly derived from animals) (Figure 1A). Both are synthesized endogenously in the skin by exposure to UVB and by conversion of 7-dehydrocholesterol to previtamin D3 and subsequent isomerization, or they are absorbed in the small intestine.
Vitamin D binds to vitamin D–binding protein; this complex is transferred to the liver and converted to the circulating form 25-hydroxyvitamin D by the 25-hydroxylase cytochrome P450, family 2, subfamily R, polypeptide 1.
25-Hydroxyvitamin D is the most abundant circulating vitamin D metabolite. It is then converted to the biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], by sequential hydroxylation by the mitochondrial cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1) in the kidney
Renal CYP27B1 activity is essential for the production and maintenance of normal concentrations of circulating 1,25(OH)2D3. CYP27B1 production and activity are tightly regulated by endocrine factors induced in response to changes in plasma calcium and/or phosphorus; the major factors associated with CYP27B1 activity are parathyroid hormone and fibroblast growth factor 23 (FGF23).
The vitamin D endocrine circuit may be involved in a feedback mechanism by which 1,25(OH)2D3 inhibits the expression of CYP27B1 in the kidney, down-regulates the production of parathyroid hormone by the parathyroid gland, and up-regulates FGF23 via the skeletal system.
Similarly, FGF23 acts via a negative feedback mechanism in the kidney to down-regulate CYP27B1 and in the parathyroid gland to inhibit parathyroid hormone.
In parallel, the role of vitamin D in modulating the immune system and maintaining the homeostasis of the intestinal barrier and the composition of the gut microbiota has received increasing attention.
In particular, vitamin D contributes directly to the modulation of the innate immune response by exerting its effect on the proper function of monocytes, macrophages, and dendritic cells and the resulting secretion of cytokines. In addition, vitamin D influences the adaptive immune response, including the development and progression of various autoimmune diseases, by regulating the activation, proliferation, and differentiation of T and B cells.
One of the most important actions of vitamin D is the regulation of gene expression in certain tissues; this action is mediated by VDR, a ligand-activated transcription factor that belongs to the nuclear receptor superfamily
VDR interacts directly with regulatory sequences near target genes and recruits chromatin-active complexes that contribute to genetic and epigenetic modifications of transcriptional output.
Therefore, the biological functions of vitamin D are directly associated with 1,25(OH)2D3-dependent changes in the transcriptome in VDR-expressing cells.
On activation by vitamin D, a conformational rearrangement of VDR occurs, allowing heterodimerization of VDR with the retinoid X receptor. The VDR–retinoid X receptor complex is translocated to the nucleus, binds to specific genomic sequences (vitamin D response elements) in the promoter of various genes, and modulates their transcription.
There is growing evidence that vitamin D is an important modulator of the immune system that can directly influence both innate and adaptive immune responses. Considering that VDR is expressed in almost all immune cells,
it is hardly surprising that vitamin D is closely associated with immune modulation and the development of autoimmune diseases, including IBD.
Physiological Functions of the Gut Microbiome
The epithelium of the gut is in close contact with the gut microbial community, revealing a commensal and/or mutualistic dynamic interaction. The gut microbiome has important metabolic, immunologic, and protective functions. Regarding its role in metabolism, the microbiome can break down otherwise indigestible food components, degrade potentially toxic food components, and synthesize certain metabolites, including vitamins, amino acids, and short-chain fatty acids, such as butyrate, acetate, and propionate, which provide energy to the intestinal epithelium.
In parallel, the gut microbiome produces vitamins K and B, niacin, biotin, and folic acid, and it contributes to the enterohepatic cycling of bile acids.
It also regulates gut immunity by interacting with adaptive and innate immune responses through the production of microbial-associated molecular patterns.
Finally, the gut microbiome inhibits the development of potentially pathogenic bacteria by preventing their access to nutrients and receptors, synthesizing antimicrobial factors, and resisting colonization.
The development of an inflammatory response in the gut is hindered by the mucosal layer and gut epithelium, which prevent the invasion of bacteria or their products into the interstitial space.
The development of dysbiosis of the gut microbiota and the entry of immunogenic products into the interstitial space activate the immune system, potentially leading to the development and progression of IBD.
The lumen of the human gut, particularly the colon, contains a complex ecosystem of microorganisms, including bacteria, fungi, parasites, viruses, and archaea that live in symbiosis and are referred to as the gut microbiota.
The gastrointestinal microbiota is predominantly composed of bacteria from four different bacterial phyla (namely, Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria).
The gut microbiome encodes approximately 3 million genes and is estimated to harbor 100 times more genes than the host. The presence of a dysbiotic microbiota can lead to a loss of immunoregulatory action on the intestinal mucosa, resulting in a range of inflammatory and immune-mediated diseases.
Over the past decade, a decline in the diversity of species composing the microbiome has been demonstrated in stool samples, associated with changes in inflamed mucosal tissues.
In addition, adherent-invasive bacteria, such as Escherichia coli (phylum: Proteobacteria) and Fusobacterium (phylum: Fusobacteria), appear to be more prevalent in North American, Italian, and Japanese patients with IBD.
Molecular diversity of Escherichia coli in the human gut: new ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohn's disease.
Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis.
Vitamin D influences the distribution of the fecal microbiota, with increased vitamin D levels associated with higher levels of beneficial bacterial species and lower levels of pathogenic bacteria.
The effect of various doses of oral vitamin D(3) supplementation on gut microbiota in healthy adults: a randomized, double-blinded, dose-response study.
The VDR gene is not expressed in the bacterial microbiome, so the effect of vitamin D in IBD is likely mediated through VDR signaling in immune cells and IECs.
Studies in experimental animal models of IBD have shown how vitamin D affects IBD through its effects on the gut microbiota. Vitamin D–deficient mice exhibited dysbiosis and deficient antimicrobial activity and were susceptible to dextran sulfate sodium (DSS)–induced colitis.
In addition, vitamin D may influence the susceptibility of mice to DSS-induced colitis by modulating the gut microbiota and the number of RORγt/FoxP3+ regulatory T cells in the colon.
These data highlight the potential role of vitamin D in alleviating intestinal inflammation and reducing disease activity in IBD by altering the gut microbiota, resulting in higher numbers of beneficial bacteria and lower numbers of pathogenic bacteria.
Human Studies
Studies have shown that oral vitamin D supplementation was associated, at least in part, with a change in gut microbial composition in patients with IBD
(Table 1). Vitamin D supplementation resulted in a positive outcome, with an increase in Enterobacteriaceae and a decrease in overall gut inflammation in both CD and UC.
Administration of vitamin D (40,000 IU, once weekly) for a period of 8 weeks did not alter α diversity, except for a small decrease in Ruminococcus gnavus in patients with UC.
Despite a significant increase in the abundance of Enterobacteriaceae in patients with UC, no changes in total fecal bacterial diversity were observed.
Vitamin D supplementation (300,000 IU in 4 weeks) caused a change in the composition of the gut microbiota in patients with CD in remission, with an increase in favorable bacteria, such as Roseburia, Alistipes, Parabacteroides, and Faecalibacterium.
The effect of vitamin D supplementation was transient, as the microbial profile recovered within 4 weeks, although vitamin D levels continued to increase.
In addition, vitamin D has a positive effect on the treatment of IBD by modulating the gut microbiome. When vitamin D was administered, an increase in beneficial bacteria and a decrease in pathogenic bacteria were observed in stool samples from healthy individuals.
The effect of various doses of oral vitamin D(3) supplementation on gut microbiota in healthy adults: a randomized, double-blinded, dose-response study.
In addition, vitamin D supplementation resulted in a dose-dependent increase in bacteria (Bacteroides and Parabacteroides) associated with decreased IBD activity,
The effect of various doses of oral vitamin D(3) supplementation on gut microbiota in healthy adults: a randomized, double-blinded, dose-response study.
Recently, vitamin D was shown to have a specific effect on bacterial communities in CD. In patients with CD, vitamin D intake modulated gut bacterial composition by increasing the abundance of potentially beneficial bacterial species.
Pediococcus, Clostridium, and Escherichia/Shigella species were enriched in summer/fall, whereas Eggerthella lenta, Helicobacter species, Fusobacterium species, and Faecalibacterium prausnitzii were relatively rare.
Probiotics, which produce vitamins, have attracted increasing interest because of their effectiveness in reducing the adverse effects of medications. Lactic acid bacteria are most commonly used because they block the inflammatory process through multiple mechanisms, including protecting the intestinal barrier and mucosal function, regulating immune response, and modulating gut flora in patients with IBD.
Probiotics, including Lactobacillus rhamnosus GG and Lactobacillus plantarum, have beneficial effects on vitamin D and VDR activity. In parallel, the role of probiotics in modulating VDR signaling in vivo was investigated using a Salmonella colitis model in VDR knockout (KO). The results showed that probiotics provided physiological and histologic protection in VDR-positive mice, whereas they had no effect in VDR KO mice.
In addition, it was shown that bile salt hydrolase–active Lactobacillus reuteri NCIMB 30,242 can regulate plasma vitamin D concentrations. The combination of L. reuteri, vitamin D, and krill oil significantly decreased the pathologic score and secretion of inflammatory markers and induced mucosal healing.
Treatment of HCT116 cells or intestinal organoids with probiotic lactic acid bacteria resulted in the release of P40 and P75 proteins, which contribute to the anti-inflammatory function by increasing VDR and promoting autophagy.
Cosupplementation of Vitamin D and Probiotics in IBD
There is increasing evidence of the synergistic effect of combined supplementation with vitamin D and probiotic bacteria in regulating the gut microbiota and metabolome.
At the same time, VDR plays an important role in modulating the mechanisms underlying the action of probiotics and regulating their immunomodulatory and anti-inflammatory effects.
In a recent systematic review, combined supplementation with vitamin D and probiotics was recommended to be superior to vitamin D or probiotics alone or placebo.
In this model, specific probiotic bacteria can increase circulating vitamin D levels and induce VDR expression and activity in the mucosa, resulting in modulation of mucosal immunity, enhancement of innate immunity and antibacterial defenses, reduction of type 1 helper T-cell (Th1) cytokine expression, and increase of anti-inflammatory effects in the mucosa.
This process leads to transient colonization with supplemental probiotics and proliferation of butyrate-producing bacteria that activate vitamin D–VDR pathway in a loop-like manner.
Paracellular permeability occurs via intercellular junctional complexes, such as adherens junctions, tight junctions (TJs), and desmosomes. Vitamin D contributes significantly to maintaining the integrity of the intestinal epithelium and modulates intestinal epithelial cell function by maintaining the expression of TJs in epithelial cells and preventing cytokine-triggered epithelial cell apoptosis.
Recent evidence has shown that vitamin D deficiency can attenuate the defective function of the intestinal epithelial barrier and increase susceptibility to DSS-induced colitis in experimental models.
Mechanisms involved in the development of dysbiosis in VDR KO and CYP27B1 KO mice include lower E-cadherin expression on the gut epithelium and immune cells, and lower numbers of tolerogenic dendritic cells, resulting in higher intestinal inflammation.
Clinical studies have shown that vitamin D deficiency resulted in decreased expression of VDR, occludin, E-cadherin, and zonula occluden-1 in patients with UC
Clinical evaluation of vitamin D status and its relationship with disease activity and changes of intestinal immune function in patients with Crohn's disease in the Chinese population.
Figure 2Schematic representation of the effect of vitamin D and the microbiota on the intestinal epithelial barrier. Vitamin D–vitamin D receptor (VDR) signaling is essential for maintaining intestinal barrier integrity by modulating apical junctional complexes through up-regulation of tight junctional proteins, zonula occluden-1 (ZO-1) and occludin, and adherent junctional proteins, such as E-cadherin, and down-regulation of myeloid differentiation primary response (MyD88) expression. Gut barrier permeability is also maintained by vitamin D–VDR signaling through the control of claudins. Vitamin D–VDR signaling protects against tumor necrosis factor (TNF)-α–induced intestinal barrier injury by contraction of the actin cytoskeleton via blockade of NF-κB–mediated activation of long myosin light chain kinase (L-MLCK). The vitamin D–VDR pathway is intimately involved in the autophagy process through its action on autophagy-related 16-like 1 (ATG16L1), nucleotide-binding oligomerization domain protein 2 (NOD2), and Beclin-1 and protects against apoptosis of intestinal epithelial cells (IECs) via down-regulation of the PUMA (P53 up-regulated modulator of apoptosis) gene, which occurs through suppression of NF-κB stimulation. The microbiome induces VDR expression in IECs, whereas it is regulated by vitamin D supplementation and by secretion of antimicrobial peptides (α-defensins from Paneth cells and β-defensin 2 and cathelicidin by IECs). Vitamin D deficiency induces secretion of IL-1α, IL-1β, IL-21, IL-10, TNF-α, and interferon (IFN)-γ. TNF-α promotes disruption of gastrointestinal barrier integrity and colon inflammation. Vitamin D increases the expression of alkaline phosphatase and maltase, which, in turn, promotes microvilli formation. AJ, adherent junction; ALP, alkaline phosphatase; AMP, antimicrobial peptide; CAMP, cathelicidin antimicrobial peptide; DEFB2/HBD2, antimicrobial peptide defensin β2; FGF-23, fibroblast growth factor 23; hPepT1, human PEPT1; IRGM, immunity-related GTPase M; MDP, muramyl dipeptide; MMP-7, matrix metalloproteinase 7; RXR, retinoid X receptor; TJ, tight junction; VDRE, vitamin D response element.
Mucosal barrier homeostasis is protected by vitamin D by maintaining the integrity of TJs by inducing the expression of TJ-related mRNA and proteins in mice.
These findings were confirmed by in vitro studies showing that vitamin D rescued epithelial barrier function in rat IECs by improving permeability and restoring TJs (zonula occluden-1 and claudin-2), resulting in a reduction in inflammation.
In an in vitro model of the intestinal epithelial barrier, 1,25(OH)2D3 increased the expression of E-cadherin and TJ components, such as occludin and claudins (Figure 2).
Overexpression of VDR protected mice from bacterial- and chemical-induced colitis by promoting claudin-15 expression, whereas claudin-15 expression was suppressed in VDR KO mice.
VDR deletion resulted in decreased claudin-2 expression by abolishing VDR/promoter binding, whereas VDR deletion in IECs resulted in significantly lower claudin-2 levels in VDR KO and VDR-conditional KO mice in vivo.
In parallel, the vitamin D–VDR pathway may be involved in the control of gut barrier integrity through modulation of myosin light chain kinase (Figure 2).
Myosin light chain kinase promotes actomyosin ring contraction through phosphorylation of related proteins and has been proposed as a regulator of TJ permeability.
Long myosin light chain kinase isoform expression is up-regulated in the intestine during inflammation, and vitamin D/VDR signaling controls epithelial permeability in cultured intestinal cells and in experimental models by regulating the myosin light chain kinase pathway.
These data highlight that vitamin D/VDR signaling maintains the integrity of the intestinal mucosal barrier by regulating IECs that have a major impact on Paneth cells, autophagy, and the gut microbiome.
Paneth Cell Dysfunction
Mice with intestinal epithelium VDR KO showed impaired Paneth cell function, impaired autophagy, and dysbiosis accompanied by decreased expression of autophagy-related 16-like 1, a protein closely associated with IBD risk and an important regulator of autophagy (Figure 2).
VDR-deficient mice showed impaired ileal Paneth cell secretion of α-defensins and the matrix metalloprotease 7 in the ileum, which may lead to dysbiosis (Figure 2).
Vitamin D signaling through induction of Paneth cell defensins maintains gut microbiota and improves metabolic disorders and hepatic steatosis in animal models.
A recent study showed that Paneth cells derived from VDR KO mice exhibited decreased inhibition of pathogenic bacterial growth and autophagic responses (Figure 2).
These mice had significantly higher rates of inflammation and were highly susceptible to small intestinal injury after Salmonella infection, suggesting that loss of VDR in Paneth cells leads to deficient antibacterial activity and increased rates of inflammation.
VDR deficiency in the intestinal epithelium caused increased apoptosis of epithelial cells and abnormal autophagy due to decreased autophagy-related 16-like 1 and Beclin-1 expression (Figure 2).
One possible mechanism linking vitamin D deficiency to IBD pathogenesis is the dysregulation of autophagy by miR-142-3p (Figure 2); increased ileal expression of the autophagy-suppressing miR-142-3p was detected in vitamin D–deficient mice and in colon biopsies from vitamin D–deficient pediatric patients with IBD.
In parallel, Paneth cells from vitamin D–deficient mice exhibited impaired morphology and increased levels of the autophagy adaptor protein p62, a protein that was absent throughout the crypt epithelium,
Although the effect of vitamin D level on mucus production has not been demonstrated, studies in experimental models suggest the absence of VDR on goblet cells.
Effects of supplemental calcium and vitamin D on tight-junction proteins and mucin-12 expression in the normal rectal mucosa of colorectal adenoma patients.
Vitamin D/VDR Effects on the Intestinal Microbiome and Their Role on the Immunologic Barrier in IBD
Intestinal homeostasis is maintained by the interaction between the gut microbiome, IECs, and immune cells. A defect in any component of this complex interaction can lead to the development of an inflammatory response, as seen in IBD.
Vitamin D contributes significantly to the regulation of immune responses through its binding to VDR, which is expressed in most immune cells, including activated or naive CD4+ and CD8+ T cells, B cells, neutrophils, APCs, monocytes, macrophages, and dendritic cells (Figure 1C).
The various T-cell subpopulations and the cytokines they secrete are critical to the physiological function of the intestinal mucosa and continuously modulate intestinal homeostasis and inflammation.
A growing body of evidence points to the role of T cells, particularly Th1/type 17 helper T cells, in experimental and human IBD; some of it is conflicting.
A useful tool to study the immunologic background of IBD is the experimental IBD model, which involves adoptive transfer of T cells to immunocompromised mice.
In this model, adoptive transfer of naive CD4+ T cells to syngeneic severe combined immunodeficiency or RAG KO mice leads to the development of chronic progressive colitis that simulates IBD.
The vitamin D–VDR–retinoid X receptor complex induces chemotactic and phagocytic capabilities and concurrently stimulates the transcription of AMPs in various cells, including colon cells (Figure 2).
In human macrophages, stimulation of the toll-like receptor promotes expression of the cathelicidin antimicrobial peptide via a vitamin D–dependent pathway.
Vitamin D–mediated up-regulation of cathelicidin antimicrobial peptide enhances antimicrobial activity against pathogens by down-regulating cathelicidin leucine–leucine-37 and up-regulating phagosome formation.
DEFB4/HBD2 and cathelicidin antimicrobial peptide were found to be induced both directly and indirectly by 1,25(OH)2D3 stimulation in human monocytic and intestinal cell lines through activation of the intracellular pattern recognition receptor nucleotide-binding oligomerization domain protein 2.
These results suggest that the action of AMPs has a major impact on the composition of the gut microbiota. AMPs and IgAs synergistically protect the mucus layer outside epithelial cells.
In addition, data have shown that activation of 1,25(OH)2D3 in the intestinal epithelial cell line DLD1 promotes cathelicidin expression, inhibits E. coli growth in vitro, and protects against experimental colitis in vivo.
In IECs, the expression of AMP is also regulated by the bioproducts of gut metabolism, which form a mucosal barrier and prevent the interaction of microbes and pathogens with the gut epithelium.
The vitamin D–VDR pathway is involved in this activation, as the regulation of cathelicidin expression in the colon by secondary bile acids is VDR regulated.
In addition, VDR signaling in mice is also controlled by bacterially produced metabolites, similar to butyrate, which are associated with higher epithelial VDR levels.
Deletion of VDR in the epithelium of a chemically induced colitis mouse model resulted in excessive apoptosis in colon epithelia due to overactivation of the gene PUMA (p53 up-regulated modulator of apoptosis), leading to epithelial barrier dysfunction (Figure 2). The disruption of the mucosal barrier led to increased invasion of antigens and luminal bacteria and triggered mucosal inflammatory responses.
Vitamin D has been associated with the expression of intestinal alkaline phosphatase; alkaline phosphatase is a protein responsible for the hydrolysis of monophosphate esters and is a critical feature of the gut defense system, preventing the uptake of bacteria across the intestinal mucosal barrier and thereby maintaining gut homeostasis (Figure 2).
1-alpha,25-Dihydroxyvitamin D(3) up-regulates the expression of 2 types of human intestinal alkaline phosphatase alternative splicing variants in Caco-2 cells and may be an important regulator of their expression in gut homeostasis.
Bacteria can affect vitamin D metabolism and function, as germ-free mice had low vitamin D levels and hypocalcemia, a situation that was reversed when these mice were colonized with other commensal bacterial species.
In parallel, bacteria secrete substances that induce VDR signaling, such as butyrate, which increases VDR expression in the intestinal epithelium in mice,
and lithocholic acid (produced by Clostridium species in the gut), which suppresses Th1 immune responses and IL-2 production by stimulating VDR signaling in T cells.
Another study showed that commensal and pathogenic bacteria directly modulated VDR expression and localization in colonic epithelium, whereas VDR negatively regulated activation of bacterially induced intestinal NF-κB and attenuated the response to infection in the IECs of Salmonella-infected mice compared with VDR KO mice.
Mouse models fed a vitamin D–deficient diet and models lacking expression of VDR in the intestinal epithelium exhibited higher susceptibility to experimental colitis, which may be due to different mechanisms of vitamin D action.
Microbiota-dependent induction of colonic Cyp27b1 is associated with colonic inflammation: implications of locally produced 1,25-dihydroxyvitamin D3 in inflammatory regulation in the colon.
Vitamin D–deficient mice developed more severe DSS-induced colitis, had more bacteria in the colonic lumen (>50-fold), and had reduced antimicrobial protein angiogenin-4.
However, the above data are at odds with studies showing that VDR-deficient mice had normal gut permeability with normal mucosal morphology in both the large
This evidence for experimental colitis in animal models supports the critical role of vitamin D/VDR signaling in maintaining the integrity of the mucosal barrier. In contrast, data from human studies are unclear. VDR expression was found to be reduced in UC and CD colon biopsies and in UC activated inflamed colon, compared with high VDR expression in normal colon epithelial cells.
The intestinal vitamin D receptor in inflammatory bowel disease: inverse correlation with inflammation but no relationship with circulating vitamin D status.
showed no significant differences, although VDR expression was negatively associated with inflammatory activity. It was also shown that in patients with IBD, mucosal inflammation was related to tumor necrosis factor-α–mediated VDR down-regulation and induction of CYP27B1.
Microbiota-dependent induction of colonic Cyp27b1 is associated with colonic inflammation: implications of locally produced 1,25-dihydroxyvitamin D3 in inflammatory regulation in the colon.
The immunomodulatory and anti-inflammatory effects of vitamin D provide plausible mechanisms for how vitamin D may influence the development, progression, and severity of IBD. Vitamin D contributes to the proper function of the innate and adaptive immune response, intestinal barrier integrity, and gut homeostasis. Specifically, the vitamin D/VDR pathway stimulates specialized epithelial cells (eg, Paneth cells) and lamina propria cells (eg, B cells/plasma cells) to limit the uptake of microbiota and their products into the interstitium. In the event of bacterial invasion of the lamina propria, immune cells, such as macrophages, dendritic cells, and Th1 and type 17 helper T cells, clear the affected tissue by direct or indirect action. After clearance, vitamin D exerts its immunoregulatory properties (ie, inhibits Th1 and type 17 helper T cells, activates T regulatory cells, and restores intestinal homeostasis). At the cellular level, vitamin D modifies the expression of TJ proteins, autophagy, and apoptosis, ensures proper epithelial barrier function, and induces the expression of AMPs. Many of these functions result from the complex ligand-receptor interaction between vitamin D and VDR, which has a major impact on the human microbiome.
Recently, the gut microbiome has attracted much interest because of rapid advances in sequence-based screening and the humanized gnotobiotic model to study the dynamic functions of the commensal microbiota. Vitamin D modulates the gut microbiota as vitamin D deficiency causes microbial imbalance in the gastrointestinal tract. The antibacterial role of vitamin D is closely linked to the expression of AMPs. The gut microbiota responds to vitamin D supplementation, and various fermentation products of the microbiota appear to promote VDR expression. More robust data on the immunologic, biochemical, functional, and genetic interplay between vitamin D and the human gut microbiota will pave the way to explore the complex function of the gut.
Although current understanding of the functional properties of the complex gut microbiome remains elusive, the results of recent studies promise to elucidate the etiology of IBD, which could lead to the development of new treatment strategies. However, the use of experimental models to study the mechanisms underlying IBD in humans appears to have limitations. Research on experimental animal models is usually conducted under specific conditions (eg, special diet and pathogen-free conditions). In contrast, patients with IBD often have severe comorbidities, including neuropsychological disorders, cardiovascular disease, and metabolic syndrome.
In particular, most gene expression motifs (estimated at 80%) are identical in mice and humans, which may be related to the presence of transcriptional regulators that control some of the similarities. On the other hand, the differences limit the translation of results from animal studies to humans, underlining the importance of interspecies inference. In parallel, the favorable results of vitamin D/VDR signaling in both experimental IBD models and human IBD have been associated with changes in the resident microbiota. However, most studies have been of insufficient duration to investigate the potential impact of microbiota resilience.
For example, after a disruption (harmful or therapeutic) of microbial composition, the altered state may persist or return to the pretreatment state. Exploring the resilience mechanisms that determine long-term community stability and understanding the perturbations are critical elements for a better understanding of the gut and important prerequisites for exploring microbiome-based precision medicine. Thus, the development of novel systems, such as culturing human primary epithelial cells or intestinal organoids derived from patients with IBD, may provide useful tools for the development of alternative therapies for this disease.
It is clear that the immune system and the microbiome are interconnected, and vitamin D is an essential mediator in this dynamic relationship. Therefore, a comprehensive understanding of the effects of vitamin D deficiency and supplementation on the gut microbiome in health and autoimmunity is needed.
Author Contributions
I.A. designed the article, collected the data, wrote the article, and approved the article to be published; M.M., S.F.A., Α.Μ., and K.T. revised the article critically for important intellectual content and approved the article to be published; and C.T. designed the article, revised the article critically for important intellectual content, and approved the article to be published. I.A. is the guarantor of this work and, as such, had full access to all of the data in the study.
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Cook M.C.
Updated assessment of the prevalence, spectrum and case definition of autoimmune disease.
Molecular diversity of Escherichia coli in the human gut: new ecological evidence supporting the role of adherent-invasive E. coli (AIEC) in Crohn's disease.
Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis.
The effect of various doses of oral vitamin D(3) supplementation on gut microbiota in healthy adults: a randomized, double-blinded, dose-response study.
Clinical evaluation of vitamin D status and its relationship with disease activity and changes of intestinal immune function in patients with Crohn's disease in the Chinese population.
Vitamin D signaling through induction of Paneth cell defensins maintains gut microbiota and improves metabolic disorders and hepatic steatosis in animal models.
Effects of supplemental calcium and vitamin D on tight-junction proteins and mucin-12 expression in the normal rectal mucosa of colorectal adenoma patients.
1-alpha,25-Dihydroxyvitamin D(3) up-regulates the expression of 2 types of human intestinal alkaline phosphatase alternative splicing variants in Caco-2 cells and may be an important regulator of their expression in gut homeostasis.
Microbiota-dependent induction of colonic Cyp27b1 is associated with colonic inflammation: implications of locally produced 1,25-dihydroxyvitamin D3 in inflammatory regulation in the colon.
The intestinal vitamin D receptor in inflammatory bowel disease: inverse correlation with inflammation but no relationship with circulating vitamin D status.
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