Vitamin D, vitamin D receptor gene polymorphisms, and inflammatory bowel disease outcomes: From molecular mechanisms to clinical application

Abstract

Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, arise from intricate interactions among genetic, environmental, microbial, and immune factors. Beyond its classical role in calcium and bone metabolism, vitamin D has emerged as a key regulator of the intestinal barrier integrity and immune homeostasis. Vitamin D deficiency is highly prevalent in these disorders, mainly because of malabsorption, dietary restrictions, chronic inflammation, and impaired metabolic activation. Genetic variants of the vitamin D receptor, such as ApaI, TaqI, BsmI, and FokI polymorphisms, may alter receptor function and downstream signaling, influencing disease susceptibility and progression. These polymorphisms have been linked to impaired epithelial barrier function, dysregulated nucleotide-binding oligomerization domain-containing protein 2 signaling, and exaggerated immune activation, central to IBD pathogenesis. Despite growing evidence, clinical assessment and correction of vitamin D deficiency in IBD remain inconsistent, and the influence of vitamin D receptor polymorphisms on therapeutic responses has not been sufficiently characterized. Understanding the interplay between vitamin D status and genetic background could support individualized management strategies. This review underscores the potential of vitamin D supplementation as an adjunctive approach, particularly in patients receiving immunosuppressive or biologic therapies, and emphasizes the need for personalized monitoring to optimize outcomes in IBD.

Key Words: Vitamin D; Vitamin D receptor; Genetic polymorphisms; Crohn’s disease; Ulcerative colitis; Inflammatory bowel disease

Core Tip: Vitamin D is essential in the pathogenesis and managing inflammatory bowel diseases. In addition to its classical bone metabolism function, vitamin D modulates intestinal epithelial integrity and immune responses. Genetic polymorphisms in the vitamin D receptor may influence disease activity and treatment outcomes. This minireview emphasizes the need for routine assessment of vitamin D status and consideration of vitamin D receptor genetic variants in personalized therapeutic strategies for inflammatory bowel diseases, especially in patients receiving immunosuppressive or biologic therapies.

INTRODUCTION

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by a spectrum of intestinal inflammation marked by alternating periods of remission and active phase[1]. Initially discovered in highly industrialized regions, such as Oceania, Europe, and North America, the incidence of IBD has progressively increased after World War II, stabilizing in early industrialized countries and, more recently, rising sharply in emerging regions, such as Asia, Africa, and Latin America[2]. This epidemiological expansion has been linked to globalization and the westernization of lifestyle habits, including smoking, physical inactivity, and the adoption of Western diets, all of which directly affect the composition of the gut microbiota[2,3]. Although the pathophysiology of IBD has not been fully elucidated, it is considered a result of a complex interplay between genetic predisposition, environmental factors, intestinal barrier dysfunction, dysbiosis, and innate and adaptive immune responses, culminating in a self-perpetuating cycle of chronic inflammation[4].

In addition to environmental influences, more than 200 genetic loci have been associated with IBD pathophysiology, many of which are related to intestinal barrier integrity and innate immunity. In this context, barrier dysfunction is central to disease onset[4]. In 2025, Dell'Anna et al[5] discussed the role of vitamin D in the pathophysiology of IBD and highlighted that this fat-soluble vitamin is involved in innate immune modulation, thereby linking it to inflammatory mechanisms. This modulation occurs through the binding of 1,25-dihydroxyvitamin D [1,25(OH)₂D] to the vitamin D receptor (VDR), a nuclear receptor for which more than 900 single-nucleotide polymorphisms (SNPs) have been identified. Among these, four variants, ApaI (rs7975232), FokI (rs10735810), BsmI (rs1544410), and TaqI (rs731236), are associated with chronic diseases related to inflammation and the gut microbiota[5,6].

Although theoretical reasoning supports the relevance of vitamin D and VDR polymorphisms in the pathophysiology of IBD, current evidence remains inconclusive. It does not allow for a definitive understanding of how these factors influence the clinical course, disease phenotype, and therapeutic response. Accordingly, this review aimed to discuss the importance of vitamin D status and VDR genetic variants in IBD, including its pathophysiology and disease course, and to explore the potential role of vitamin D supplementation as an adjuvant strategy, particularly in patients receiving biologic or targeted therapies. Furthermore, it proposes a personalized approach for monitoring and correcting vitamin D levels, which may contribute to optimizing therapeutic outcomes and deserve greater attention in clinical research and future treatment guidelines. For the preparation of this review a comprehensive literature search was conducted in PubMed, Scopus, Web of Science and the Cochrane Library databases, using the following descriptors: “Inflammatory bowel disease”; “Crohn’s disease”; “Ulcerative colitis”; “Vitamin D”; “Polymorphism, Genetic”; “Vitamin D receptor”; “Gut microbiota”; “Vitamin D metabolism”; “Intestinal Mucosa”.

VITAMIN D METABOLISM AND FUNCTION

The metabolite, 25-hydroxyvitamin D [25(OH)D] is essential for calcium and phosphorus homeostasis. Primarily, 25(OH)D is produced via cutaneous synthesis, in which 7-dehydrocholesterol is converted into previtamin D₃ under ultraviolet B radiation. Another source is dietary intake, which contributes to a lesser extent, mainly through fatty fish, dairy products, eggs, and sun-exposed mushrooms[7,8]. After absorption, cholecalciferol undergoes hepatic hydroxylation to produce 25(OH)D, which is subsequently converted in the kidneys into 1,25(OH)₂D or calcitriol, its biologically active form[5,7]. Calcitriol exerts its effects by binding to VDR, which heterodimerizes with the retinoid X receptor and regulates the expression of multiple genes involved in bone metabolism and immune modulation[9,10]. The metabolic pathways are summarized in Figure 1.

Figure 1 Vitamin D metabolism. Endogenous vitamin D synthesis occurs in cutaneous keratinocytes under ultraviolet B rays exposure, which converts 7-dehydrocholesterol into previtamin D₃. Dietary contribution is relatively limited, derived mainly from fatty fish, dairy products, eggs, and sun-exposed mushrooms, with the absorption of vitamin D₂/D₃ occurring in the jejunum and ileum. Following synthesis or ingestion, cholecalciferol undergoes hepatic hydroxylation, generating 25-hydroxyvitamin D, and subsequently in the kidneys, producing 1,25-dihydroxyvitamin D (or calcitriol), its biologically active form. Calcitriol binds to the vitamin D receptor, which heterodimerizes with the retinoid X receptor. This complex associates with the vitamin D response element and translocates into the cell nucleus, where it regulates the expression of multiple genes involved in calcium and phosphorus metabolism, as well as in the modulation of innate and adaptive immunity. This figure was created by the authors using BioRender (Supplementary material). UVB: Ultraviolet B rays; 25(OH)D: 25-hydroxyvitamin D; 1,25(OH)₂D: 1,25-dihydroxyvitamin D; VDRE: Vitamin D response element.

Several factors can modulate vitamin D metabolism and its biological functions. Parathyroid hormones play a key role in regulating calcium homeostasis via their interaction with vitamin D[11,12]. In addition, genetic variants or reduced activity of CYP2R1 and CYP27B1 enzymes, responsible for hepatic 25-hydroxylation and renal 1α-hydroxylation, respectively, may impair vitamin D conversion and activation[7]. VDR expression and its SNPs influence vitamin D homeostasis[10,13]. The interaction between these factors is essential for adequate vitamin D function, and disruptions in this process may compromise its biological action even in the presence of apparently normal serum vitamin D.

VITAMIN D, INTESTINAL PERMEABILITY, AND GUT MICROBIOTA

The intestinal barrier is a critical defense system that separates luminal and internal environments. It comprises multiple layers, including commensal microbiota and its metabolites, such as short-chain fatty acids[14], a mucus layer, and the intestinal epithelium. Epithelial integrity is maintained by intercellular junctions, including tight junction proteins, such as claudins, occludin, and zonula occludens-1. Zonula occludens-1 is a key modulator that promotes redistribution of its components and transiently increases intestinal permeability[14-17].

Experimental evidence in mice indicates that vitamin D plays both direct and indirect roles in preserving intestinal barrier integrity[16,17]. In these models, vitamin D-VDR complex-mediated signaling modulates the expression of the claudin-2 gene, which encodes claudin-2, and overexpression of claudin-2 tends to increase intestinal permeability[16]. Furthermore, vitamin D contributes to mucus production by goblet cells and is essential for the first line of defense produced by the intestinal barrier[16]. The VDR signaling pathway also influences gut microbiota composition[16-18]. The modulation of proteins such as myosin light chain kinase and nuclear factor kappa B, which are essential for immune responses, affects the environment in which different microbial strains proliferate[18]. Therefore, alterations in vitamin D signaling may influence microbiota profiles, suggesting a complex bidirectional relationship between vitamin D, the intestine, and gut bacteria. SNPs, such as those identified in the ApaI, TaqI, BsmI, and FokI variants, may compromise these pathways, leading to increased intestinal permeability, mucosal inflammation, and greater susceptibility to IBD[16,18]. The schematic representation in Figure 2 illustrates the complex interplay among vitamin D metabolism, immune regulation, and intestinal homeostasis.

Figure 2 Schematic representation of the interplay between vitamin D metabolism, immune regulation, and intestinal homeostasis. Vitamin D modulates T cell differentiation (regulatory T cell, T helper 1, and T helper 17), regulates calcium metabolism, and influences gut microbiota composition. Vitamin D receptor (VDR)-mediated signaling controls the expression of tight junction proteins, such as claudin-2, and stimulates mucus production by goblet cells, thereby promoting intestinal barrier integrity. Genetic polymorphisms in the VDR (SNPs) may disrupt these pathways, increasing intestinal permeability and favoring inflammatory responses. This figure was created by the authors using BioRender (Supplementary material). Tregs: Regulatory T cells; Th1: T helper 1; Th17: T helper 17; CLDN2: Claudin-2; VDR: Vitamin D receptor; SNPs: Single-nucleotide polymorphisms; NF-кB: Nuclear factor kappa B.

Although most studies have been conducted using animal models, observational studies in humans have supported this association[19,20]. For instance, a pilot study in India reported that healthy individuals with serum vitamin D levels above 30 ng/mL exhibited a higher abundance of bacterial genera, such as Bacteroides and Subdoligranulum, which are associated with fiber fermentation and short-chain fatty acid production, in contrast to the predominance of Pseudobutyrivibrio and Odoribacter observed in individuals with vitamin D deficiency[19,20]. Similarly, an analysis of Spanish Caucasian adults found that the VDR TaqI SNP is associated with gut microbiota dysbiosis. Individuals with the CC genotype, which is associated with lower vitamin D levels, showed reductions in the genera Parabacteroides and Butyricimonas, and an increase in members of the phylum Firmicutes[19].

In summary, evidence suggests an essential role for vitamin D, mediated through the VDR, in maintaining intestinal barrier integrity and modulating the gut microbiota. However, the predominance of experimental animal studies and human observational analyses limits the extrapolation of these findings to clinical practice. Well-designed clinical trials are essential to elucidate the causal mechanisms and explore the potential therapeutic implications for managing IBD.

Vitamin D deficiency in patients with IBD

Vitamin D deficiency is common in patients with IBD, and its prevalence varies across population[21,22]. It is associated with disease activity, mucosal inflammation, dietary restrictions, malabsorption, and drug interactions[23,24]. Patients with vitamin D deficiency frequently exhibit a more severe disease course and a greater need for medical interventions[25,26]. Seasonal factors influence vitamin D levels, with a greater deficiency observed during winter and spring[27].

Ingested or supplemented vitamin D may not be adequately absorbed by patients with IBD, particularly CD. Determinant factors include disease extent and activity and bile acid malabsorption, which are common in cases with ileal resections or involvement of the distal ileum since fat-soluble vitamins rely on micellar transport[5-8]. Furthermore, genetic factors such as SNPs in CYP2R1 and CYP27B1 can impair endogenous vitamin D activation, which is responsible for hepatic and renal hydroxylation, respectively[7]. Elevated parathyroid hormone levels are associated with vitamin D deficiency in IBD[28].

A meta-analysis by Sadeghian et al[29], which included 63 observational studies, reported a prevalence of 57.7% among patients with CD. The analysis also found that patients with CD had lower 25(OH)D levels compared with healthy controls [-3.99 ng/mL; 95% confidence interval (CI): -5.91 to -2.08]. Individuals with IBD have an approximately 64% higher likelihood of presenting with vitamin D deficiency [odds ratio (OR) = 1.64; 95%CI: 1.30-2.08; P < 0.0001][5].

Another important aspect is the relationship between vitamin D deficiency and IBD risk. However, Mendelian randomization studies and analyses of large cohorts have suggested that vitamin D deficiency may be a consequence, rather than a causal factor, of IBD[23,30,31]. A prospective study of United States military personnel demonstrated that serum vitamin D levels were not low before CD diagnosis but decreased after disease onset, highlighting that chronic inflammation affects vitamin D absorption, metabolism, and activity[32]. A European cohort study with more than 350000 participants supported this observation, showing no significant association between vitamin D levels and the risk of developing CD or UC[33].

Vitamin D levels and clinical outcomes in patients with IBD

Retrospective clinical trials have suggested that normal vitamin D levels are associated with improved clinical outcome. A systematic review and meta-analysis of 8316 patients with IBD revealed that low vitamin D levels were associated with increased disease activity (OR = 1.53; 95%CI: 1.32-1.77; I² = 0%), poorer quality of life (OR = 1.30; 95%CI: 1.06-1.60; I² = 0%), higher risk of clinical relapse (OR = 1.23; 95%CI: 1.03-1.47; I² = 0%), and mucosal inflammation (OR = 1.25; 95%CI: 1.06-1.47; I² = 0%)[34].

Clinical trials and observational studies have investigated the effects of vitamin D supplementation in patients with IBD, evaluating both the increase in serum vitamin D levels and their impact on clinical outcomes. Narula et al[35] in 2017 demonstrated that, in the intention-to-treat analysis, clinical relapse rates did not differ significantly between high- and low-dose vitamin D₃ groups (68.8% vs 33.3%; P = 0.0844). However, in the per-protocol analysis, clinical relapse in CD was significantly lower in patients who received a high dose (0%) than in those who received a low dose (37.5%; P = 0.049). Similarly, a double-blind randomized placebo-controlled study evaluated 60 patients with UC and vitamin D deficiency (< 40 ng/mL). The patients were divided into two groups: 30 received 60000 IU/day of oral nano-vitamin D and 30 received placebo for 8 days, with reassessment after 4 weeks[36]. Supplementation increased mean vitamin D levels from 15.4 ng/mL to 40.83 ng/mL (P ≤ 0.001) and resulted in a more pronounced reduction in the UC disease activity index (53% vs 13%; P = 0.001), which correlated with the increase in vitamin D levels (P ≤ 0.001). Patients who achieved levels > 40 ng/mL experienced greater clinical improvement (80% vs 20%; P < 0.001) as well as reduced levels of inflammatory markers, including C-reactive protein (CRP) (P = 0.041), fecal calprotectin (P = 0.023), histological score (P = 0.011), and erythrocyte sedimentation rate (P = 0.049). Vitamin D supplementation was an independent predictor of clinical response (OR = 9.17; P = 0.004) and baseline histological activity (OR = 1.92; P = 0.007)[36].

A retrospective outpatient study conducted between 2017 and 2018 evaluated 470 patients with CD (57.9%) or UC (42.1%); 60.2% presented with vitamin D deficiency (< 30 ng/mL), and 53.6% were receiving vitamin D supplementation[37]. Patients with active CD exhibited lower vitamin D levels (P = 0.049 and P = 0.04, respectively), whereas supplementation had a protective effect, although 45.7% of those who received vitamin D supplementation remained deficient (P < 0.0001). Multivariate analysis confirmed the inverse association between disease remission and vitamin D deficiency (OR = 2.01; P = 0.02) and highlighted, in CD, the effect of biologic therapy (OR = 0.35; P = 0.01), and in UC, the associations with male sex (OR = 2.70; P = 0.003) and age (OR = 1.02; P = 0.04). A 27.5 ng/mL cutoff distinguished remission from active disease, and higher levels were observed in the summer (P = 0.002)[37].

Vitamin D deficiency is also associated with a higher risk of hospitalization (incidence rate ratio = 1.44; 95%CI: 1.11-1.87)[38] and greater clinical disease severity, including increased inflammatory activity, greater disease extent, presence of complications, higher risk of intestinal surgery [hazard ratio (HR) of 1.93 for CD; HR of 2.77 for UC], and risk of cytomegalovirus colitis in patients with UC[39]. Low vitamin D levels (< 20 ng/mL) are associated with an increased risk of surgery and hospitalization, particularly in CD, whereas normalization of vitamin D levels significantly reduces these outcomes[40]. Clinical trials have confirmed increases in serum vitamin D levels with supplementation and have indicated a trend toward lower relapse rates, although without definitive statistical significance. These findings underscore the importance of maintaining adequate vitamin D levels as a potential strategy for improving prognosis, especially in CD[40,41]. Consistent with previous findings, patients with CD undergoing intestinal resection with serum vitamin D levels > 30 ng/mL exhibited higher rates of postoperative endoscopic remission and a lower risk of recurrence, an effect similar to that observed with anti-tissue necrosis factor (TNF)-α therapy. However, the causality has not been established[42].

Overall, studies suggest that vitamin D levels of > 30 ng/mL are associated with improved clinical outcomes, including reduced inflammatory activity, lower risk of hospitalization, and potential benefits in therapeutic response. However, results from clinical trials remain heterogeneous, particularly regarding high-dose supplementation and prevention of postoperative relapse, indicating that deficiency management, although important, does not guarantee complete protection. Thus, vitamin D has emerged as a promising prognostic biomarker of IBD. However, its use as a standalone therapeutic strategy lacks robust evidence, underscoring the need for multicenter, controlled, and long-term studies to establish precise clinical recommendations.

Vitamin D and VDR polymorphisms in the pathophysiology and pathogenesis of IBD

Vitamin D is widely expressed in enterocytes, where it plays a critical role in regulating the intestinal epithelium, gut microbiota composition, and inflammatory responses, primarily through the induction of defensins and other antimicrobial peptides[7,43]. At the molecular level, its interaction with VDR directly modulates the proliferation and differentiation of immune cells, particularly T lymphocytes[7]. A pilot study in Chinese participants suggested that VDR gene polymorphisms may influence vitamin D metabolism by modulating VDR-dependent enzymes such as 1α-hydroxylase. Mutations in FokI, ApaI, and TaqI can indirectly affect serum 25(OH)D levels[44].

In experimental models of induced colitis, vitamin D supplementation reduces the expression of pro-inflammatory cytokines, reinforcing its potential anti-inflammatory effect, which[45] also extends to antigen-presenting cells such as macrophages and dendritic cells[9,46]. In T lymphocytes, the vitamin D-VDR complex regulates interleukin-2 (IL-2) expression, promotes the differentiation of regulatory T cells (Tregs) facilitates the balance between T helper 1 (Th1)/Th2 profiles, and shifts the response from pro-inflammatory to anti-inflammatory[7]. Additionally, 1,25-(OH)₂D inhibits dendritic cell differentiation and IL-12 production, while stimulating IL-10 synthesis[12]. Conversely, vitamin D deficiency impairs regulatory T cells function and contributes to loss of immune regulation[7,46].

VDR gene SNPs have been associated with the clinical course of IBD and alterations in the gut microbiota and immune responses through interactions with target genes, DNA-binding sites, and heterodimer formation[47,48]. VDR genetic SNPs can modify the response to vitamin D by interfering with various stages of the regulatory process, including transcription factor activity, VDR expression, initiation of protein translation, and mRNA stability, ultimately affecting disease activity[13,17,49].

The current hypothesis is that BsmI, ApaI, and TaqI SNPs located within the VDR gene may create strong linkage disequilibrium among themselves and with other functional loci of the same gene, such as Tru9I and poly(A) microsatellites. Although these polymorphisms do not alter the amino acid sequence of the VDR protein, they appear to influence the regulatory mechanisms, particularly mRNA stability and degradation. In vitro functional evidence indicated that the BsmI variant is associated with increased VDR mRNA expression. Moreover, the AAC haplotype formed by these SNPs exhibited higher receptor transcriptional activity than the guanine-cytosine-thymine haplotype, which correlated with elevated mRNA levels[16,18,50,51]. In addition, in vitro studies have suggested that the FokI polymorphism generates a shorter VDR with an increased capacity to transactivate vitamin D target genes. At the same time, alterations in the 5’ region may modulate mRNA expression[44,52,53]. Observations in patients with CD and UC indicate that these mutations, in combination with vitamin D deficiency, may impact disease risk and modulate enzymes involved in vitamin D metabolism[44]. Despite these associations, the mechanisms linking specific SNPs to clinical manifestations remain poorly understood, highlighting the need for functional studies integrating molecular, cellular, and clinical data to elucidate how VDR structure, DNA-binding affinity, and co-regulator interactions contribute to disease phenotypes.

In support of these findings, a prospective study conducted at the Beth Israel Deaconess Medical Center included 37 patients with CD, of whom 20 had active disease and 17 were in remission. Clinical, laboratory, and immunological variables were related to vitamin D. Patients with active CD exhibited significantly lower serum vitamin D levels than those in remission (27 ng/mL vs 38 ng/mL; P = 0.02), with an inverse correlation between serum vitamin D levels and the Harvey-Bradshaw Index (HBI) (r = -0.5; P = 0.005), although no association was observed with CRP. Following infliximab treatment, eight patients showed a mean increase in vitamin D levels from 23 ng/mL to 40 ng/mL (P < 0.005) regardless of the initial clinical response. Increased CYP27B1 gene expression was observed in active CD (P < 0.001), whereas VDR expression did not differ significantly between the groups (P = 0.057) and did not correlate with serum vitamin D levels[39].

In vitro experiments, vitamin D supplementation tripled the proportion of CD25+ CD4+ cells and increased CD4+ T cell proliferation, although without statistical significance, whereas the frequency of CD39+ cells remained unchanged. These results suggest that reduced vitamin D levels are associated with CD inflammatory activity, and anti-TNF therapy can rapidly restore these levels in parallel with immunoregulatory changes[54].

In CD, the ApaI polymorphism was associated with a higher rate of penetrating disease (36.7% vs 8.7%; P = 0.012), whereas the AA genotype of this SNP appeared to be an independent predictor of hospitalization. Conversely, the TT genotype of the TaqI variant has been linked to reduced VDR expression in peripheral blood mononuclear cells, resulting in the upregulation of pro-inflammatory IL-1β mRNA and increased activation of lymphocyte adhesion molecules. Moreover, this variant has been associated with a higher risk of developing a penetrating B3 phenotype[18]. In contrast, Gisbert-Ferrándiz et al[49] in 2024 reported an association between the ApaI SNP and a lower risk of developing perianal fistulas as well as reduced levels of inflammatory markers in patients with CD with penetrating behavior.

In UC, a case-control study conducted in a Han Chinese population, including 404 patients with UC and 612 healthy controls, associated the FokI SNP (mutant allele C and TC + CC genotype) with milder forms of the disease than in severe cases (P < 0.001), suggesting that this genetic variation may be related to less severe clinical manifestations. The same study also identified a direct correlation between the mutant allele (TC + CC) and reduced serum 25(OH)D levels (OR = 2.01; P = 0.004)[50].

The literature also includes studies investigating the presence of VDR polymorphisms and risk of IBD. Śledzińska et al[13] in 2024 analyzed VDR gene polymorphisms, including rs11568820 (Cdx2), rs10735810 (FokI), rs1544410 (BsmI), rs7975232 (ApaI), and rs731236 (TaqI), in children with IBD compared to the control group. The authors did not observe any significant differences in the incidence of individual genotypes between groups. However, the likelihood of developing IBD was 2.3 times higher in individuals with the GA genotype of the rs11568820 (Cdx2) polymorphism and two times higher in those with the GA genotype of the rs1544410 (BsmI) polymorphism. Furthermore, individuals carrying the CC genotype of the rs731236 (TaqI) polymorphism exhibit reduced serum 25(OH)D levels.

A meta-analysis demonstrated an association between the CC genotype of the rs731236 (TaqI) polymorphism and the prevalence of CD in European populations. However, the frequency of this genotype was similar between patients with IBD and healthy controls[55]. In a Caucasian population, a case-control study including 660 patients with IBD and 699 healthy individuals analyzed four VDR variants (rs7975232, rs731236, rs1544410, and rs10735810) using logistic regression, and found no significant association between this set of polymorphisms and increased IBD risk[56].

The study suggested further investigation of the rs731236 (TaqI) SNP and the risk of developing IBD, as this polymorphism involves a thymine-to-cytosine substitution in exon 9, located at the 3’ end of the VDR gene; however, this change does not result in an amino acid substitution, since both codons encode isoleucine. Nevertheless, the region near this polymorphic site regulates gene expression and affects mRNA stability. Additionally, the CC genotype may be in linkage disequilibrium with other functional factors, potentially contributing to an increased risk of developing CD[53].

In summary, the available data suggest that VDR SNPs may modulate vitamin D bioavailability and the immune response in IBD, thereby influencing the clinical phenotype and inflammatory activity. However, the results remain heterogeneous across different populations and study designs, reflecting the complexity of interactions among genetic, environmental, and immunological factors. A deeper understanding of these mechanisms may clarify IBD pathophysiology and pave the way for personalized therapeutic strategies in which the assessment of vitamin D status and VDR genetic profile plays a relevant role in clinical practice. A summary of the main findings of clinical studies investigating the relationship between SNPs, VDR, and vitamin D levels in IBD is presented in Table 1.

Table 1 Clinical studies investigating the relationship between single-nucleotide polymorphisms, vitamin D receptor, and vitamin D in inflammatory bowel diseases.

Ref.	Aims	Study type	Main findings
Hughes et al[56], 2011	To determine if common VDR polymorphisms affected IBD risk in an Irish population	Cohort - observational, n = 1359 (413 CD, 247 UC, and 699 healthy controls)	No significant correlation was observed between VDR polymorphisms (FokI, BsmI, ApaI, and TaqI) and the risk of IBD
Xia et al[44], 2016	To investigate the association of VDR polymorphisms and 25(OH)D levels in Chinese patients with CD	Case-control - observational, n = 297 patients with CD and 446 controls	The BsmI and TaqI SNPs were less prevalent in CD patients than in controls
			The AAC haplotype, formed by BsmI, ApaI, and TaqI, was less prevalent in patients with CD
			Vitamin D deficiency in patients with CD interacted with the mutant genotypes of FokI (TC + CC), ApaI (CA + AA), and TaqI (TC + CC)
Szymczak-Tomczak et al[50], 2019	To investigate the association of the TaqI polymorphism (rs731236, c.1056T>C) in the VDR gene with serum vitamin D concentration and BMD in patients with IBD	Observational, n = 172 patients with IBD (85 with CD and 87 with UC) and 39 healthy controls	Serum vitamin D levels in patients with IBD were not reduced compared with healthy controls
			Patients with UC carrying the tt TaqI SNP of the VDR gene exhibited higher femoral neck BMD than those with the TT and Tt genotypes (P = 0.02)
			The tt genotype was more frequent in patients with UC than in controls and patients with CD (23% vs 7.7% and 16.5%, respectively)
Gisbert-Ferrándiz et al[49], 2024	To analyze the association of BsmI, ApaI, TaqI, and FokI SNPs in the VDR gene with the clinical characteristics of CD	Observational, n = 115 patients with CD and 20 healthy individuals	The aa genotype of the ApaI SNP in the VDR gene is associated with a lower risk of perianal fistulas in CD
			No significant association was detected between the FokI, BsmI, ApaI, and TaqI VDR gene polymorphisms and the risk of developing CD compared with healthy controls
			Patients with the aa genotype of ApaI had a lower risk of perianal fistulas than the other genotypes (Aa/AA) (P = 0.0360)
			The AA genotype of ApaI was associated with an increased risk of penetrating behavior compared with the combination of the other two genotypes (P = 0.0347)
			The BB genotype of BsmI was significantly associated with an increased risk of penetrating behavior compared with the combination of the other two genotypes (P = 0.0235)
Śledzińska et al[13], 2024	To investigate the correlation between the incidence of VDR gene polymorphisms (rs11568820, rs10735810, rs1544410, rs7975232, and rs731236, commonly described as Cdx2, FokI, Bsm, ApaI, and TaqI, respectively) and vitamin D concentration with the clinical course of IBD (disease activity, extent of the intestinal lesions)	Observational, n = 109 children (34 with CD and 28 with UC) and 47 healthy controls	Increased likelihood of developing IBD in heterozygotes for the Cdx2 polymorphism (rs11568820) (OR = 2.3, 95%CI: 0.88-6.18, P = 0.04)
			Heterozygotes for the BsmI polymorphism (rs1544410) hada 207-fold higher likelihood of developing IBD (OR = 2.07, 95%CI: 0.89-4.82, P = 0.048)
			GG homozygotes for the ApaI polymorphism (rs7975232) (OR = 0.47, 95%CI: 0.21-1.04, P = 0.05) and TT homozygotes for the TaqI polymorphism (rs731236) (OR = 0.47, 95%CI: 0.21-1.03, P = 0.04) were associated with a reduced likelihood of developing IBD
			Correlation between vitamin D levels and the BsmI polymorphism (rs1544410) was observed in patients with IBD (P = 0.04) and in patients with CD (P = 0.04)
Kafentzi et al[18], 2025	To investigate how ApaI, BsmI, TaqI, and FokI SNPs affect IBD phenotype and progression	Observational, n = 144 patients (76 with CD and 68 with UC)	The aa genotype of ApaI was independently associated with a reduced risk of IBD-related hospitalization (OR = 0.17; P = 0.013) and a decreased risk of IBD-related surgery (OR = 0.055; P = 0.014)
			The AA genotype of ApaI was associated with higher rates of penetrating CD (B3) (36.7% vs 8.7%; P = 0.012)
			The ff genotype of FokI was associated with disease location, predisposing to upper gastrointestinal tract involvement (36.4% vs 7.7%; P = 0.044) or colonic participation (90.9% vs 50.8%; P = 0.038)
			All patients carrying the aa genotype were less likely to experience steroid-refractory or steroid-dependent disease (11.1% vs 37.6%; P = 0.022)
			The TT genotype of TaqI was independently associated with increased risk of hospitalization (OR = 4.79; P = 0.044)

VDR: Vitamin D receptor; IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; BMD: Bone mineral density; SNP: Single-nucleotide polymorphism; OR: Odds ratio; CI: Confidence interval.

CLINICAL IMPLICATIONS: TOWARD A MORE PERSONALIZED APPROACH

The presence of VDR in the intestine and the biological role of its interaction with vitamin D have been described as beneficial for maintaining epithelial integrity, supporting healthy gut microbiota composition, and regulating both innate and adaptive immune responses[7]. In this context, vitamin D deficiency has been associated with increased inflammatory activity and poorer clinical outcomes in patients with IBD, suggesting that normal levels may exert a protective effect potentially related to immunomodulatory actions that influence both innate and adaptive immune responses and contribute to intestinal barrier integrity[23,47,51]. Additionally, evidence indicates that correcting this deficiency may be associated with reduced clinical relapse in patients with CD, highlighting its potential as an adjunctive therapeutic strategy[7].

Some risk factors for vitamin D deficiency in patients with IBD have been postulated and must be screened: High body mass index (> 30 kg/m²), non-Caucasian ethnicity, longer disease duration, increased disease activity, smoking, small bowel involvement (CD), dietary restrictions, reduced sun exposure, high-latitude countries, concomitant medications such as cholestyramine, and IBD-related surgery (such as ileum resection and ileal pouch anal anastomosis)[5]. However, this must be cautiously interpreted because chronic inflammation may lead to reduced vitamin D levels[57].

A meta-analysis published in 2020 focused on vitamin D supplementation in patients with IBD and vitamin D deficiency, confirming that this practice is effective at correcting vitamin D levels and is associated with improved clinical and biochemical disease activity scores, by enhancing the HBI by -1.47 points (95%CI: -2.47 to -0.47, P = 0.004, I² = 0%) and decreasing the high sensitivity CRP by -1.58 mg/L (95%CI: -2.95 to -0.21, P = 0.02, I² = 0%). However, this study has significant limitations. The included studies showed substantial heterogeneity due to variations in the vitamin D dosage regimens and treatment durations. Other notable limitations include the small number of studies available for analysis and the limited data on objective changes in disease activity[58].

Similarly, another systematic review and meta-analysis performed 1 year later investigated the effect and safety of oral vitamin D supplementation in patients with IBD. It included 17 trials with 1127 patients and revealed that oral vitamin D supplementation effectively increased the concentration of serum 25(OH)D (weighted mean difference: 12.15 ng/mL; 95%CI: 9.26-15.03; I² = 90%) and decreased serum CRP levels [standard mean difference (SMD): -0.33; 95%CI: -0.61 to -0.05;I² = 55]; however, it did not decrease erythrocyte sedimentation rate (SMD: 0.35; 95%CI: -4.33 to 5.03; I² = 57%), disease activity index (SMD: -0.13; 95%CI: -0.66 to 0.39; I² = 84%), or relapse rate (relapse rate: 0.59; 95%CI: 0.19-1.86; I² = 79%)[59].

A 2023 Cochrane systematic review assessed the benefits and disadvantages of vitamin D supplementation for treating IBD. The review’s findings were limited by the very low certainty of the evidence analyzed. A small benefit of fewer clinical relapses was noted in patients receiving vitamin D than in those receiving a placebo; however, this conclusion was based on low-certainty evidence, and no other definitive conclusions could be drawn regarding the clinical response or patient quality of life. Furthermore, the review found no significant differences in clinical relapse rates between high and low doses of vitamin D in CD, and no conclusions could be drawn regarding other outcomes. When comparing all doses of vitamin D to supplemental-dose vitamin D, a lack of available data for clinical relapses and responses limited reaching any conclusions, and other outcomes were also limited by a very low certainty of evidence or missing data[45].

Despite this evidence, supplementation trials with high-dose vitamin D3 (25000 IU/week for 26 weeks) have demonstrated increased serum vitamin D levels; however, they yielded inconsistent results regarding the prevention of postoperative recurrence following ileocolic resection in patients with CD. Supplementation significantly increased serum 25(OH)D concentrations but did not reduce clinical or endoscopic recurrence compared with placebo or improve quality-of-life outcomes. The intervention was safe, with no cases of hypercalcemia; however, no postoperative anti-inflammatory benefits were observed, indicating that correcting vitamin D deficiency does not necessarily prevent disease relapse after surgery[60].

Studies have explored the immunomodulatory role of vitamin D as an adjuvant in treating IBD. Winter et al[61] investigated the relationship between vitamin D levels and remission in patients undergoing anti-TNF-α therapy. They found that patients with normal vitamin D levels at the initiation of treatment had 2.64 times higher odds of achieving remission at 3 months than those with low vitamin D levels. Similarly, a study by Zator et al[62] showed that patients with insufficient vitamin D levels experienced earlier cessation of anti-TNF-α therapy (HR = 2.13; 95%CI: 1.03-4.39; P = 0.04). This was particularly true for patients who discontinued treatment due to loss of response (HR = 3.49; 95%CI: 1.34-9.09), suggesting that vitamin D levels may influence the long-term effectiveness of anti-TNF-α therapy.

A Chinese retrospective cohort study of 73 patients with CD also demonstrated favorable outcomes for vitamin D in anti-TNF-α treatment. Of the enrolled patients, 37 received regular vitamin D3 supplements. The clinical remission rate in this group was significantly higher than that in the patients who did not receive supplementation (83.8% vs 61.6%, P = 0.030). Additionally, the decrease in the HBI from baseline to 54 weeks was more pronounced in the group that received supplementation (7.41 ± 3.0 vs 6.28 ± 2.75, P = 0.023). The study also found that vitamin D3 supplementation was an independent predictor of an increased remission rate at 54 weeks. Notably, the beneficial effects of supplementation were only significant in patients with baseline vitamin D3 deficiency but not in those with non-deficient levels[63].

In contrast to these findings, data from a large prospective observational cohort, the personalized anti-TNF therapy in CD study, did not support the predictive role of vitamin D. This study evaluated the pre-treatment vitamin D concentrations in 659 patients and 448 patients treated with infliximab and adalimumab, respectively. The prevalence of vitamin D deficiency (< 25 nmol/L) and insufficiency (25-50 nmol/L) was 17.1% and 47.7%, respectively. Of the 1107 patients, 246 (22.2%) received vitamin D supplementation. However, vitamin D supplementation failed to predict a positive response or remission to anti-TNF therapy at either week 14 or 54, with all findings being statistically insignificant (P > 0.05)[64].

One prospective study evaluated the effects of vitamin D on infliximab-induced remission in adult patients with moderate to severe CD. Among the 28 participants, those with baseline vitamin D levels < 75 nmol/L exhibited a higher rate of clinical remission at week 14 (80% vs 23%; P = 0.007) and maintained this response through week 22 (79% vs 17%; P = 0.005), even after supplementation. Furthermore, the low-vitamin D group demonstrated greater reductions in inflammatory cytokines and a significant improvement in quality of life (P = 0.03), suggesting that vitamin D status may be a relevant predictor of the response to infliximab[65].

The relationship between the vitamin D levels and vedolizumab treatment outcomes was also investigated. Abraham et al[66] investigated the factors before the initiation of vedolizumab in 88 patients that best predicted treatment response, emphasizing vitamin D levels. Among patients with UC, the UC Endoscopic Index of Severity scores after 6 months of therapy were significantly lower in patients with vitamin D ≥ 30 ng/mL at the initiation of vedolizumab therapy than in those with low pre-treatment vitamin D levels (1.5 vs 3.87, P = 0.037). However, in patients with CD, inflammatory markers, including HBI, CRP, erythrocyte sedimentation rate, and Simple Endoscopic Score for Crohn’s Disease, were not significantly different between the two groups (P > 0.05). In a study of vedolizumab-naïve patients with IBD, Gubatan et al[34] used mass cytometry and gene expression to investigate the relationship between vitamin D levels and immune cell profiles. They found that low serum vitamin D levels were associated with an α4β7+ immunophenotype and predicted future vedolizumab treatment failure.

The role of vitamin D supplementation as an adjuvant therapy for IBD remains unclear based on the current literature. Furthermore, optimal supplementation strategies for patients with IBD are not well defined and require additional research to maximize the clinical benefits while minimizing the risks of vitamin D hypervitaminosis, including hypercalcemia, hypercalciuria, renal impairment, and soft tissue or vascular calcification. Therefore, dosage regimens must be individualized, considering factors such as baseline vitamin D status, the extent and location of the disease (especially ileal involvement in CD), body mass index, smoking status, and individual absorption capacity[5].

Considering these data, the therapeutic potential of vitamin D in IBD has recently been a topic of interest, and its clinical recommendations have been debated in recent consensus guidelines. The most recent recommendation from the 2025 European Crohn’s and Colitis Organization Consensus on Dietary Management of Inflammatory Bowel Disease states that there is insufficient evidence to recommend vitamin D supplementation for induction therapy or remission of IBD[67]. Conversely, other guidelines have recommended monitoring and supplementation. The ECCO-ESGAR-ESP-IBUS Guidelines on Diagnostics and Monitoring of Patients with IBD (2025) suggest serum 25-(OH)D levels greater than 20 ng/mL (50 nmol/L)[68]. Similarly, the British Society of Gastroenterology consensus guidelines (2019) suggest that vitamin D levels should be measured and corrected in patients with IBD[69]. The Second Brazilian Consensus on the Management of Crohn’s Disease in Adults (2023) recommends screening for vitamin D deficiency in patients who are malnourished or at risk for vitamin D deficiency[70].

Additionally, the European Society for Clinical Nutrition and Metabolism guideline, Clinical Nutrition in Inflammatory Bowel Disease (2017), recommends monitoring and supplementation of 25-(OH)D levels in patients with active disease and in those receiving steroid therapy to help prevent low bone mineral density[71]. Specific guidelines for supplementation remain limited due to study heterogeneity, dosage, variation in therapeutic objectives, and low methodological robustness[45]. However, the optimal serum vitamin D level for IBD treatment remains undefined and requires further investigation. Although a consensus has not been reached, evidence suggests that serum levels above 50 ng/mL[72] or 75 nmol/L[73] are associated with improved clinical outcomes in patients with IBD. The safe levels and corrective dosages of vitamin D according to the major guidelines are presented in Table 2. Based on bone health, recommended serum concentrations vary among guidelines, generally between 20 ng/mL and 30 ng/mL (50-75 nmol/L)[6-10,28]. Commonly prescribed doses range from 1800 IU to 10000 IU daily or 50000 IU weekly or biweekly[5].

Table 2 Thresholds for classifying vitamin D insufficiency and deficiency according to major guidelines and vitamin D supplementation protocols.

Organization	Reference range (ng/mL)	Toxicity (ng/mL)	Supplementation
World Health Organization[74]	< 10 - deficiency. < 20 - insufficiency	-	-
Endocrine Society[75]	> 20 - sufficient	> 60	-
Institute of Medicine[76]	< 12 - deficiency. < 20 - insufficiency	> 50
European Society for Clinical Nutrition and Metabolism[71]	No defined cutoff	-	-
Brazilian Society of Endocrinology and Metabolism[77]	30-60 ng/mL - sufficient	> 100	-
Position Statement of the Brazilian Association of Nutrology (Abran)[78]	> 40 - sufficient	> 100	6000 IU/day or 50000 IU/week in case of deficiency
British Society of Gastroenterology[69]	< 20 - deficiency	-	800-1000 mg/day of calcium and 800 IU/day of vitamin D for patients with active disease and receiving corticosteroids
Central and Eastern European Expert Consensus[79]	< 20 - deficiency. < 30 - insufficiency	> 100	6000-10000 IU/day in case of deficiency
Second Brazilian Consensus on Managing Crohn's Disease in Adults[70]	No defined cutoff	-	800-1000 mg/day of calcium and 800 IU/day of vitamin D in case of deficiency
Endocrine Society - Update[80]	No defined cutoff	-	-
European Crohn’s and Colitis Organization[67]	< 30 - deficiency	-	-
European Crohn’s and Colitis Organization in collaboration with: European Society of Gastrointestinal and Abdominal Radiology; European Society of Pathology and International Bowel Ultrasonography Group[68]	< 20 - insufficiency	-	-

Based on the current review, it is suggested that patients with IBD should have their 25(OH)D levels measured annually and during disease flare-ups. If a vitamin D deficiency is confirmed, follow-up measurements should be performed every 3-4 months. Treatment can be administered using various doses and routes, and should be individualized with a duration tailored to the patient’s response[5]. Despite evidence suggesting a significant role of vitamin D in maintaining epithelial integrity, supporting healthy gut microbiota, and modulating the immune response, its ability to achieve clinically meaningful outcomes in IBD remains uncertain. The optimal serum levels of vitamin D have not been clearly defined and whether its supplementation is essential, either as a standalone intervention or as an adjuvant to advanced therapies, has not been established. The current recommendations for vitamin D supplementation are limited to patients with confirmed deficiencies or insufficiencies.

A comparison between the Cochrane systematic review (2023)[45] and the European Crohn’s and Colitis Organization consensus (2025)[67] highlights that the translation of strong biological plausibility into clinical recommendations for vitamin D use in IBD remains constrained by low-quality evidence. Although the immunomodulatory role of vitamin D and its association with increased disease activity in deficient states are well recognized, supported by animal models in which VDR knockout leads to severe intestinal inflammation and studies linking serum normalization to reduced surgical risk in CD, clinical data remain insufficient. The Cochrane review (2023) identified a possible reduction in clinical relapses compared with placebo but emphasized the very low certainty of evidence regarding clinical response, quality of life, and adverse events. Similarly, the European Crohn’s and Colitis Organization consensus (2025) acknowledges the importance of vitamin D for bone health and its potential benefits in inflammatory markers, hospitalizations, and relapse rates. However, this underscores the lack of robust randomized controlled trials supporting its use as an active therapy for the induction or maintenance of remission. Consequently, methodological heterogeneity and low-quality evidence hinder the translation of biological plausibility into consistent clinical recommendations for IBD treatment. Therefore, prospective interventional studies are warranted to determine the benefits of vitamin D supplementation, identify the optimal dosage and route of administration, and establish the ideal serum concentration thresholds[45,67].

Future clinical studies should simultaneously evaluate serum 25(OH)D levels and VDR SNPs, considering their individual and combined effects. Genotype-stratified trial designs, including dominant, recessive, and base-pair substitution combinations, are recommended to clarify how these genetic differences may modulate serum vitamin D levels, supplementation response, and intestinal homeostasis. Integrating these genetic and clinical data into predictive models could reduce the heterogeneity observed in previous studies and help identify patient subgroups with higher responsiveness. We also suggest incorporating CD phenotypic characteristics into these analyses to better understand their relationship with VDR SNPs. Finally, supplementation should be considered when serum levels are < 30 ng/mL, respecting the safety limits described in Table 2.

LIMITATIONS

Despite the comprehensive scope of the reviewed evidence, it is essential to acknowledge the critical methodological limitations that permeate the current research on vitamin D and IBD. Most available data are derived from observational studies, in which active inflammatory status may be a confounding factor by reducing the hepatic synthesis of 25(OH)D, thereby obscuring the causal relationship between vitamin D deficiency and disease activity. Furthermore, substantial heterogeneity exists among supplementation trials, with marked variations in dosing regimens, formulations, treatment duration, and outcome measures, limiting the comparability and reliability of the pooled analyses. Another critical issue is the lack of standardized protocols for VDR SNP genotyping and interpretation, which compromise reproducibility and hinder the consolidation of robust genetic evidence. These methodological constraints must be carefully considered when interpreting current findings and underscore the need for genotype-stratified, well-controlled clinical trials with standardized protocols and rigorous adjustment for confounding variables to advance the understanding of the role of vitamin D in IBD.

CONCLUSION

Current evidence indicates that serum vitamin D concentration is more closely related to clinical course and severity of IBD than to its underlying pathophysiology. The role of VDR gene variants and their interactions with intestinal microbiota remain insufficiently understood, highlighting the need for larger, methodologically rigorous studies in human populations. Maintaining adequate vitamin D levels may enhance responses to biological and emerging targeted therapies. In contrast, excessive supplementation, which leads to serum concentrations above 30 ng/mL, appears to provide no additional clinical benefit. These findings underscore the importance of individualized monitoring and adjustment of vitamin D levels as a potential strategy for optimizing clinical outcomes and guiding clinical practice and future research.

ACKNOWLEDGEMENTS

The authors express their sincere gratitude to the Department of Internal Medicine, Medical School, São Paulo State University (UNESP), Botucatu, Brazil; the School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil; and the Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University (AAU), Copenhagen, Denmark for their institutional support and collaboration. The authors also thank all the colleagues and staff who contributed to the development of this study. Costa BG and Spiller AL have received Master scholarship grant from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Programa de Excelência Acadêmica (PROEX) - Finance Code 88887.807663/2023-00. De Freitas MB was supported by the grant DNRF148 from the Danish National Research Foundation Center of Excellence.