Vitamin D in mucosal healing: therapeutic potential and current evidence in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic and progressive disorder of the digestive tract, including Crohn’s disease and ulcerative colitis. Over the last decade, IBD has been extensively studied due to its association with dysregulated intestinal microbiota, increased mucosal permeability, and immune imbalance. Despite available pharmacological treatments, there is no definitive cure. Mucosal healing (MH) has emerged as a crucial therapeutic target, as it aims to restore the integrity of inflamed mucosae and is associated with improved clinical outcomes. However, most clinical studies rely primarily on clinical indices rather than direct endoscopic or histologic assessment of MH, and the optimal vitamin D (VD) dosing required to achieve true MH remains unclear. This review aims to examine the diverse functions of VD in modulating pathways relevant to MH within the context of IBD, highlighting its role in immune modulation, intestinal barrier integrity, and gut microbiota composition, and to discuss its potential therapeutic value in IBD management. Relevant experimental, translational, and human clinical studies focusing on VD status, supplementation, and mechanisms related to MH, immune regulation, and intestinal barrier function in IBD were considered. MH involves epithelial restitution, cell proliferation, and differentiation, and its achievement has been associated with reduced symptoms, lower relapse rates, and decreased need for surgical interventions. Beyond its traditional role in bone health, VD plays a critical role in preserving intestinal barrier integrity and regulating immune homeostasis. While biological evidence indicates that VD modulates immune responses, enhances tight junction integrity, and influences gut microbiota composition, clinical data primarily support its role in improving clinical and biochemical disease activity rather than definitively inducing mucosal repair. This review highlights VD as a relevant immunomodulatory and barrier-protective factor with potential complementary value in the clinical management of patients with IBD.

Plain language summary

Vitamin D and intestinal healing in inflammatory bowel disease

Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a chronic condition that causes inflammation in the digestive tract. People living with IBD often experience abdominal pain, diarrhea, fatigue, and reduced quality of life. Although several treatments exist, there is currently no cure. One important treatment goal is “mucosal healing,” which means repairing the lining of the intestine and reducing inflammation to prevent relapses and complications. Vitamin D is best known for its role in bone health, but growing evidence shows that it also plays an important role in immune function and gut health. Many patients with IBD have low vitamin D levels, and this deficiency has been linked to more severe disease, increased hospitalizations, and higher relapse rates. This review summarizes current research on how vitamin D may help promote mucosal healing in IBD. Studies suggest that vitamin D helps strengthen the intestinal barrier, reduce harmful inflammation, and support a balanced gut microbiota. It also regulates immune responses and promotes the production of protective molecules that help repair intestinal tissue. Clinical studies indicate that vitamin D supplementation may reduce disease activity and improve quality of life in patients with IBD. However, optimal dosing remains unclear, as vitamin D levels can vary depending on factors such as diet, sun exposure, disease severity, and individual metabolism. Overall, maintaining adequate vitamin D levels appears to be a safe and promising complementary strategy for improving outcomes in patients with IBD. Future research is needed to determine the best supplementation strategies and to better understand how vitamin D contributes to long-term intestinal healing.

Introduction

Inflammatory Bowel Diseases (IBD) are chronic, progressive disorders of the digestive system, primarily including Crohn’s disease (CD) and ulcerative colitis (UC). ¹ The prevalence of IBD continues to rise, affecting an estimated 20.2–24.3 per 100,000 individuals globally each year, which has made it a significant focus of research due to its strong association with dysregulated intestinal microbiota. ² While CD can compromise any part of the digestive tract, UC is confined to the colon. The pathogenesis of IBD involves a complex interplay of genetic predisposition, environmental factors, and immune dysregulation.^3,4 Contributing factors include lifestyle aspects such as diet, smoking, stress, certain medications, and notably, low vitamin D (VD) levels. ⁵ Recent Mendelian randomization studies have reinforced this link, demonstrating that genetically determined higher VD levels are associated with a lower risk of developing CD. ⁶ Furthermore, other environmental factors such as long-term exposure to air pollution have also been identified as significant risk factors for immune-mediated diseases, including IBD. ⁷ A defining feature of IBD is the disruption of the epithelial barrier, resulting from increased apoptosis of intestinal epithelial cells (IEC), which leads to elevated mucosal permeability and inflammation. This disruption triggers an immune imbalance, which further exacerbates intestinal damage. Despite the availability of pharmacological treatments, there remains no definitive cure for IBD, highlighting the urgent need for novel therapeutic strategies aimed at preserving gut barrier integrity. ⁸

Mucosal healing (MH) has emerged as a key therapeutic target in IBD and represents a cornerstone of the “treat-to-target” strategy aimed at restoring both structural and functional integrity of the intestinal mucosa. Although initially loosely defined, MH is now primarily characterized by the resolution of visible inflammation on endoscopic assessment, complemented by histological improvement and reduced clinical disease activity. ⁹ The STRIDE-II (Selecting Therapeutic Targets in Inflammatory Bowel Disease) consensus recommends that MH be defined using objective outcomes encompassing endoscopic, histological, and—particularly in CD—transmural dimensions. ¹⁰ In clinical practice, endoscopic evaluation relies on validated indices such as the Mayo Endoscopic Score (MES ⩽1) or UCEIS in UC, and the SES-CD or CDEIS in CD. ¹¹ However, clinical indices such as disease activity index (DAI), Bradshaw Index (HBI), or Crohn’s Disease Activity Index (CDAI; remission <150) do not necessarily reflect mucosal or biological healing. ¹² MH involves epithelial restitution, cell proliferation, and differentiation, and its achievement is associated with improved clinical outcomes, including reduced relapse rates and decreased need for surgical interventions. ¹³ Importantly, MH should be distinguished from deeper levels of remission, such as histological and transmural healing, whose integration defines the concept of “deep remission” and is associated with improved long-term outcomes. ¹⁴

Subsequent research has revealed that VD, beyond its traditional role in bone health, is also crucial for maintaining intestinal barrier integrity and regulating immune homeostasis. ¹⁵ Recent evidence links VD levels with several inflammatory and autoimmune diseases, exhibiting immunomodulatory properties. ¹⁶ Consequently, VD’s impact on IBD progression has garnered considerable attention over the past decade. Epidemiological studies consistently report low circulating levels of cholecalciferol (or 25(OH)D) in patients with UC and CD. ¹⁷ While the precise mechanism through which low VD levels contribute to IBD onset remains uncertain, reduced VD concentrations have been associated with a higher risk of disease exacerbation, hospitalization, surgeries, poor response to TNF-α inhibitors, and a lower quality of life of CD and UC patients.^18,19 Prospective studies in patients with inactive UC have shown that higher 25(OH)D serum levels are associated with a greater ratio of anti-inflammatory to pro-inflammatory cytokines. This anti-inflammatory profile was also correlated with improved MH and a lower risk of clinical relapses. ¹⁹ Thus, VD supplementation may emerge as a promising therapeutic strategy for promoting MH in IBD patients. ¹⁵

This review seeks to explore the role of VD in the context of MH in IBD, focusing on the underlying mechanisms of VD-mediated immune modulation, its effects on intestinal barrier integrity, and its influence on the gut microbiota, highlighting the potential therapeutic value of VD in IBD management. This narrative review is based on a targeted, non-systematic search of the literature. Literature was identified through targeted searches in PubMed, Scopus, and Web of Science for articles published between 2001 and 2025, using combinations of the terms: VD, IBD, MH, intestinal barrier, immune modulation, and gut microbiota. Relevant experimental, translational, and human clinical studies published in peer-reviewed scientific journals and written strictly in English were included. Priority was given to randomized controlled trials (RCTs) and large meta-analyses, whereas non-peer-reviewed articles, conference abstracts, case reports, and studies involving overlapping patient cohorts without novel data extraction were excluded. When conflicting data emerged, both perspectives were objectively presented and weighed against the methodological limitations of the respective studies. While mechanistic insights are frequently derived from experimental models, this review strictly distinguishes them from human translational data, emphasizing human clinical evidence and its relevance to therapeutic decision-making in IBD. In contrast to previous literature, this work specifically emphasizes MH as a central therapeutic target and integrates current clinical frameworks, including STRIDE-II, to provide a more clinically oriented perspective.

Pathophysiology of IBD

IBD arises from a complex interplay of multiple factors, leading to disruption of the intestinal barrier and an exacerbated immune response. A hallmark of the disease is the loss of barrier integrity, which in healthy individuals protects against luminal antigens while allowing for nutrient absorption. ²⁰ In IBD, this dysfunction alters immune homeostasis and perpetuates chronic inflammation, underscoring the importance of MH in reducing relapse risk and improving clinical outcomes. ²¹

The intestinal epithelium is protected by a mucus layer secreted by goblet cells. This layer not only provides a physical shield but also supports commensal colonization and regulates microbial composition. ²² In IBD, goblet cell dysfunction and reduced mucin secretion lead to mucus depletion and instability, exposing epithelial cells to direct contact with the microbiota. ²³ Proteomic analyses of patient biopsies confirm a disrupted mucus profile, with alterations in Mucin-2 expression and glycosylation that impair host-microbiota interactions. ²² These changes compromise barrier integrity, increase permeability, and sustain chronic inflammation during active IBD. ²⁴

Tight junction (TJ) proteins, such as claudins, zonula occludens (ZO), occludins, among others, regulate paracellular permeability. TJs are multiprotein complexes composed of transmembrane and cytoplasmic proteins, along with cytosolic adaptor proteins that coordinate junction assembly and stability.^25,26 Among these, the ZO protein family plays a pivotal role by forming a plaque beneath the membrane that acts as a scaffold linking the junction to the actin cytoskeleton. ²⁷ Integral membrane proteins, such as occludins, interact with ZO proteins to seal the space between adjacent cells, ensuring intercellular cohesion. ²⁸

In IBD, claudins 4, 5, and 8 are reduced, while occludin—essential for barrier homeostasis—is downregulated, both contributing to enhanced intestinal permeability and inflammation.^29,30 Additionally, depletion or downregulation of ZO proteins has been associated with impaired TJ assembly and increased intestinal permeability.^27,31 This disruption alters immune homeostasis and perpetuates chronic inflammation, driven by the nuclear factor kappa B (NF-κB) pathway, which triggers the overproduction of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-17 by Th1 and Th17 subsets, while regulatory T cells and anti-inflammatory mediators like IL-10 are significantly impaired.

Innate immune components exacerbate inflammation in IBD and tend to be upregulated. For example, Triggering Receptors Expressed on Myeloid cells (TREM) proteins modulate the threshold of LPS-TLR4 signaling. TREM-1 amplifies innate responses to microbial products.^32,33 NOD-like receptors (NLRs) and inflammasomes also contribute to innate immune activation in IBD, specifically the NLRP3 inflammasome, as its activation promotes the secretion of IL-1β and IL-18, both of which are upregulated in active IBD patients. ³⁴ Additionally, chemokines such as CXCL8 (IL-8) drive neutrophil recruitment, further damaging the mucosa. ³⁵ Adaptive immunity is also imbalanced in IBD patients, as the Th1 and Th17 subsets overproduce IFN-γ, IL-17, and TNF-α, while regulatory T cells are impaired. B cells contribute through antigen presentation and increased immunoglobulin (Ig) G responses against gut microbiota, correlating with disease severity. This imbalance between effectors and regulatory pathways sustains chronic inflammation.^35,36

In synthesis, IBD pathogenesis is characterized by mucus depletion, TJ disruption, and imbalanced immune activation. These events compromise barrier integrity, amplify inflammation, and perpetuate mucosal damage. Understanding these mechanisms highlights why therapeutic strategies aimed at restoring barrier function and immune homeostasis, such as MH, are central to improving clinical outcomes.

VD: Biological functions and immune modulation

VD is a fat-soluble secosteroid essential for multiple physiological processes, extending beyond its traditional role in calcium absorption and bone health. VD exists in two primary forms: vitamin D2 (ergocalciferol), obtained from mushrooms, and vitamin D3 (cholecalciferol), primarily synthesized in the skin through exposure to ultraviolet B light (UVB). VD3 can also be acquired through diet, found in higher amounts in cod liver oil, salmon, tuna, egg yolks, and fortified foods such as milk. After ingestion or synthesis, VD is transported in the circulation mainly bound to VD-binding protein (~85%–90%) and albumin (~10%–15%). ³⁷

Oral VD is absorbed in the intestine via micelle formation, similar to lipids incorporated into chylomicrons. ³⁸ VD undergoes two hydroxylation steps to become biologically active: the first in the liver, forming 25(OH)D, the primary circulating marker of VD status, and the second occurs in the proximal renal tubules, producing 1,25-dihydroxyvitamin D (calcitriol), the active form of VD. ³⁹ Active VD enters target cells either by simple diffusion or through membrane carriers, depending on serum concentrations and the binding to transport proteins, which determines whether its action occurs via genomic or non-genomic pathways. ⁴⁰ Genomic pathways are mediated through the vitamin D receptor (VDR), a nuclear receptor expressed in immune cells (T and B lymphocytes, macrophages, dendritic cells (DCs)), IECs, and connective tissue such as fibroblasts, regulating genes involved in immune response, inflammation, and gut barrier integrity. ²⁷ Non-genomic pathways are mediated by several protein families. ⁴⁰

Upon activation, 1,25-dihydroxyvitamin D3 binds to the VDR, forming a complex with the retinoid X receptor, which then translocate to the nucleus and activates VD response elements (VDRE) in DNA. ⁴¹ This complex functions as a transcription factor that modulates genes related to calcium homeostasis, immune regulation, cellular differentiation, apoptosis, and proliferation. ⁴² Figure 1 summarizes VD sources, metabolism, and its genomic and non-genomic pathways.

Figure 1.

VD sources, metabolism, genomic and non-genomic effects. VD is obtained from sunlight, diet, and supplements. UVB radiation induces vitamin D3 synthesis in the skin, while diet provides vitamin D2 or D3. VD is hydroxylated in the liver to 25-hydroxyvitamin D and then in the kidneys to the active form, 1,25-dihydroxyvitamin D. The active form binds to the VDR, regulating gene expression through VDRE with the RXR, and mediates rapid non-genomic signaling pathways. These mechanisms contribute to immune modulation and epithelial barrier integrity.

Source: Created with BioRender.

RXR, retinoid X receptor; UVB, ultraviolet B; VD, Vitamin D; VDR, vitamin D receptor; VDRE, vitamin D response element.

VDRE regulates genes that encode antimicrobial peptides such as cathelicidin (LL-37) and defensins in epithelial and immune cells. ⁴³ These peptides help control the intestinal microbiota by limiting the proliferation of pathogenic bacteria, although their excess can be detrimental. In fact, increased LL-37 expression has been reported in the mucosa of patients with UC, suggesting a dysregulation of VD metabolism in IBD. ⁴⁴ This observation highlights the complexity of VD biology, indicating that increased VD activity is not necessarily linearly beneficial at the level of individual mediators, even though systemic VD deficiency is clearly associated with adverse outcomes. Beyond these direct effects, VD also exhibits interactions with the intestinal microbiota, which are associated with the production of short-chain fatty acids (SCFAs), particularly butyrate, a metabolite that reinforces TJs, improves barrier function, and facilitates epithelial repair. ⁴⁵ This is supported by clinical observations where VD administration in CD patients coincided with significant shifts in intestinal bacterial composition, including an increase in SCFA-producing taxa such as Faecalibacterium and Roseburia. ⁴⁶ These genera are well-recognized butyrate producers, and butyrate, in turn, supports epithelial repair by serving as the primary energy source for colonocytes and promoting epithelial differentiation and mucosal integrity.

VD deficiency could exacerbate the pathogenesis and clinical course of inflammatory diseases due to the expression of VDR. In vivo models with suppressed VDR in the intestinal epithelium are prone to manifest colitis, typically resembling a colonic, colitis-like phenotype rather than a CD-like transmural inflammation, which may be relevant when considering translational implications, while dietary VD depletion increases intestinal permeability.^6,47 Reducing excessive intestinal inflammation enhances the epithelial barrier function, creating a more favorable environment for the resident gut bacteria. This promotes an anti-inflammatory state, as these beneficial microorganisms can produce metabolites that suppress inflammatory signals mediated by NF-kB. This process establishes a positive feedback loop between VD and microbiota, reinforcing anti-inflammatory effects. ⁴⁸

VD acts as a key modulator of intestinal health by regulating the gut microbiota, reducing inflammation, and reinforcing the epithelial barrier. Through VDR activation, inhibition of pro-inflammatory pathways, and the promotion of a beneficial bacterial environment, VD emerges as a promising therapeutic agent for managing IBD.

Potential role of VD in MH

Various protein families regulate intestinal permeability through distinct structural functions, which are crucial for assembling and maintaining functional barriers. These protein families include intercellular junction complexes known as TJs or ZO at epithelial and endothelial levels, mediating internal cell connections, as previously described. Among these, the ZO protein family and integral membrane proteins such as occludin play essential roles in TJ assembly and maintenance. Their depletion or downregulation has been associated with delayed TJ assembly and increased intestinal permeability, particularly in the context of IBD.^27,31

The disruption of the intestinal mucosal barrier is a key feature of IBD, leading to increased permeability and exacerbated immune responses. ⁴⁹ This dysregulated immune response also drives dysbiosis within the gut microbiome, further compromising the mucosal barrier. ⁵⁰ VD plays a multifaceted role in this context by interacting with the gut microbiome and modulating its composition under healthy and diseased conditions. For instance, Singh et al. ⁵¹ demonstrated in a non-randomized trial that supplementing VD-deficient women significantly increased microbiota richness and diversity. This capacity to enhance microbial diversity supports barrier integrity, immune homeostasis, and MH.^49–51

While the molecular mechanisms of VDR-mediated TJ synthesis and cytokine suppression are well characterized, translating these structural pathways into human therapeutic applications requires a clear distinction between experimental models and clinical reality. To facilitate the interpretation of current evidence and remaining uncertainties, a comprehensive breakdown of these translational limits is presented in Table 2. As synthesized there, preclinical data provide robust biological plausibility for TJ regulation; however, human clinical data predominantly validate the role of VD in systemic immune modulation and clinical disease management, rather than demonstrating standalone structural tissue healing or independent induction of objective MH. Therefore, VDR activation highlights a key pathway for barrier support, but its clinical integration must be interpreted through a strict hierarchy of evidence (Figure 2).

Table 2.

Summary of VD thresholds, dosing considerations and current uncertainties in IBD.

Aspect	Evidence from current studies	Key findings	Limitations
Deficiency threshold	General consensus 86	<20 ng/mL defined as deficiency	May not reflect optimal levels in IBD
Target serum levels	Observational studies in IBD 90	Lowest disease activity at 50–59 ng/mL	Not linked to true MH
Supplementation dose	Clinical studies/guidelines91,92	Upper limits: 4000–10,000 IU/day	No defined dose to achieve MH
Absorption in IBD	CD-specific studies93,94	Reduced absorption, higher doses required	High inter-individual variability
Outcome measures	Multiple studies (as discussed)	Mostly based on clinical indices (DAI, HBI)	Limited use of validated MH indices (e.g., MES/UCEIS, SES-CD) as primary endpoints, with most studies relying on surrogate clinical measures.

This table highlights the distinction between objective MH and surrogate clinical endpoints, as well as current uncertainties.

CD, Crohn’s disease; DAI, disease activity index; HBI, Harvey–Bradshaw index; IBD, inflammatory bowel disease; MES, Mayo Endoscopic Score; MH, mucosal healing.

Figure 2.

Impact of VD levels on intestinal epithelium and immune modulation. Under normal VD conditions (left), 1,25(OH)2D3 enters epithelial cells and regulates epithelial integrity and immune homeostasis. TJ proteins, such as occludin, claudin, and zonula occludens, are maintained, ensuring epithelial barrier function. Normal VD levels promote cytokine regulation, including upregulation of anti-inflammatory mediators such as IL-10 and TGF-β, macrophages and regulatory T cells differentiation, and inhibition of dendritic cell maturation, contributing to immune tolerance and MH. In contrast, VD deficiency (right) leads to epithelial barrier disruption, increased permeability, and loss of the mucus layer. This allows bacterial translocation and triggers an inflammatory cascade characterized by elevated pro-inflammatory cytokines, including TNF-α, IL-6, and IL-17. These changes promote immune cell recruitment and perpetuate a chronic inflammatory cycle, further compromising intestinal integrity.

Source: Created with BioRender.

MH, mucosal healing; TJ, tight junctions; VD, vitamin D.

Immunological mechanisms of VD in MH

Following intestinal injury, rapid healing is essential to prevent sepsis and preserve function. In IBD, MH is clinically defined as the resolution of visible mucosal inflammation and ulceration, typically assessed by endoscopic evaluation and associated with improved clinical outcomes. Barrier establishment involves epithelial migration and immune cell activity, including clearance of debris and microbes and release of growth factors that promote repair. ⁵² In this context, VD has been demonstrated to modulate immune cell function in vitro and in vivo.

Neutrophils are rapidly recruited after injury and are essential for tissue healing, as depletion increases mortality and worsens colitis in animal models. Kühl et al. ⁵³ indicated that neutrophil depletion increases mortality in a colitis model induced with Trinitrobenzene sulfonic acid/dinitrobenzene sulfonic acid in rats. ⁵³ Neutrophils also promote mucosal recovery by inducing amphiregulin via TGF-β release, according to Chen et al. ⁵⁴ in 2018, who also demonstrated that the depletion of neutrophils results in a more severe colitis after DSS treatment in mice. The role of VD in neutrophil function remains unclear; however, the study by Subramanian et al. ⁵² suggests it enhances bacterial clearance by upregulating Toll-like receptors, while also limiting excessive inflammation by reducing neutrophil migration. ⁵⁵ These findings indicate that VD may modulate neutrophil efficacy during intestinal injury. Taken together, these data suggest that VD may optimize neutrophil function by enhancing microbicidal activity while limiting excessive, tissue-damaging recruitment.

Macrophages and monocytes also contribute to MH. In DSS-induced colitis, macrophages are essential for limiting inflammation and tissue damage. ⁵⁶ Although the link between VD and macrophage function is not fully understood, evidence shows that VD alters the transcriptome of human monocyte-derived macrophages during differentiation, ⁵⁷ and macrophage function is impaired when the VD receptor is depleted in mice, ⁵⁸ underscoring a potential role of VD in MH.

DCs are key antigen-presenting cells that support MG by coordinating immune responses and promoting epithelial repair through IL-22 and TGF-β production. ⁵⁹ VD drives DCs toward a tolerogenic phenotype, reducing co-stimulatory molecules, enhancing IL-10, and promoting Treg inductions while limiting effector T cell activation.^60,61 Thus, VD-modulated DCs may contribute to both immune regulation and epithelial repair in IBD.

B cells are immune cells that can differentiate into plasma cells and produce Ig. They play an active role in gut homeostasis by controlling microbiota and modulating inflammation in affected tissues. A recent study by Frede et al. ⁶² induced colitis in mice by administering DSS for 7 days and characterized immune cells using flow cytometry, finding that B cells expanded during the recovery phase. Depletion of B cells at this stage improved MH, likely because B cells impair crosstalk between stromal and epithelial cells. ⁶² These findings suggest that VD may reduce inflammation mediated by B cells, indirectly benefiting MH. However, there is currently no direct evidence linking VD-mediated modulation of B cells to MH in human IBD, and this remains a hypothesis primarily derived from preclinical studies.

T cells also participate in gut homeostasis. These cells can differentiate into T helper (Th) cells according to their cytokine profile and eliminate bacteria. VD has been reported to inhibit T cell differentiation into Th1 and Th17 profiles, decreasing the production of IL-17 and IFN-γ. ⁶³ This shift from pro-inflammatory Th1/Th17 responses toward a more regulatory profile can reduce cytokine-driven epithelial injury and thereby support mucosal repair. T regulatory cells inhibit T cell activity through direct contact and the release of anti-inflammatory cytokines such as TGF-β or IL-10, playing a crucial role in maintaining intestinal tolerance and controlling over-inflammation produced by microbiota. ⁶⁴ VD enhances the tolerogenic capacity of T regulatory cells, acting directly on T cells to upregulate Foxp3 and promote their development in human peripheral blood mononuclear cells. ⁶⁵ In mice, VD analog treatment in a model of autoimmune diabetes similarly expanded T regulatory cells in pancreatic lymph nodes and halted disease progression. ⁶⁶ These findings suggest that VD exerts an anti-inflammatory effect on T cells by enhancing T regulatory cell activity and inhibiting pro-inflammatory Th cell responses, indicating possible mechanisms through which VD may indirectly benefit MH (Figure 2).

Clinical evidence of VD in IBD patients

Clinical data indicates a strong association between low VD levels and increased disease activity in IBD. VD deficiency has been linked to higher rates of relapse, increased risk of hospitalization, and worse clinical outcomes. ⁶⁷ In contrast, VD supplementation has beneficial effects, including reduced relapse risk and improved quality of life.^68,69 A meta-analysis of 8316 adult IBD patients found that low 25(OH)D levels were associated with a higher risk of active disease and relapses in both UC (odds ratio (OR) of 0.47 and 1.20) and CD (OR 1.66 and 1.35). ⁶⁷ Nevertheless, the observational nature of the included studies precludes causal inference. This pattern is also observed in pediatric populations, with a recent systematic review identifying a strong association between VD deficiency and IBD in children. ⁷⁰ Moreover, VD deficiency has been linked with disease activity in CD and anemia in UC patients, as shown in a retrospective cohort study of 384 IBD patients. ⁷¹ Given its retrospective design, however, causality cannot be inferred from these associations.

VD plays a protective role in the pathogenesis of IBD, as suggested by clinical evidence. In a large retrospective cohort of 5021 veterans with IBD, with a median serum 25-hydroxyvitamin D of ~23 ng/mL and ~41% of patients receiving supplementation, VD supplementation was associated with 34% fewer IBD-related emergency department visits, 53% fewer hospitalizations, and a trend to 25% lower corticosteroid use, compared to untreated patients. ⁷² However, because this observational study relies strictly on healthcare utilization records rather than objective mucosal evaluation, these findings cannot establish causality between VD supplementation and improved outcomes. Another study involving healthy volunteers showed that VD3 supplementation improved the gut microbiome in the upper gastrointestinal tract, potentially providing protection against IBD development. ⁷³ In a clinical trial, Jørgensen et al. ⁶⁸ demonstrated that oral VD3 supplementation (1200 IU daily) significantly reduced the risk of relapse in CD patients, from 29% to 13%; however, as success was measured exclusively by the CDAI, these findings reflect purely clinical and subjective symptom improvement rather than confirmed mucosal repair. Similarly, Karimi et al. ⁶⁹ observed that administering 2000 IU/day of VD for 12 weeks increased serum 25-OHD levels, improved quality of life, and reduced disease activity assessed solely by clinical indices (such as the Partial Mayo Score) in adults with mild to moderate UC without endoscopic follow-up.

In contrast, a dose of 100 IU/day over the same period improved quality of life but did not impact disease activity. ⁶⁹ Supporting these findings, Guzman-Prado et al. ⁷⁴ conducted a systematic review and meta-analysis, concluding that higher VD doses were particularly effective in improving disease activity scores, such as the HBI, and reducing C-reactive protein, a key marker of systemic inflammation. Crucially, while these systemic markers are valuable, they remain indirect surrogates that do not necessarily mirror endoscopic tissue healing. In CD patients, low VD levels were linked to increased mucosal inflammation and diminished quality of life. ⁷⁴ Notably, mucosal inflammation can impair VD absorption, making VD deficiency a potential biomarker of inflammation in CD. This occurs because VD malabsorption reflects minor bowel inflammation, a feature specific to CD and not observed in UC. ⁶⁷ Furthermore, VD deficiency reduces calcium uptake, thereby impairing anti-inflammatory pathways. This, in turn, exacerbates mucosal inflammation, further hindering calcium absorption and perpetuating the cycle of deficiency. These mechanisms align with geographic and lifestyle patterns observed in IBD prevalence. ⁷⁵

It is worth noting that the clinical studies discussed in this section rely on disease activity indices and biochemical markers rather than on objective mucosal assessments. To date, no VD supplementation trial in IBD has evaluated MH as a primary outcome using endoscopic or histologic confirmation. This represents a significant gap in the literature, and further trials should prioritize these objective endpoints to determine whether VD supplementation translates into true MH in IBD patients.

While observational data link low VD to adverse IBD outcomes, these findings must be interpreted cautiously due to potential reverse causation and key confounding factors. It remains debated whether VD deficiency drives inflammation or results from it. Severe disease activity and extensive intestinal involvement (disease extent) often impair VD absorption. Furthermore, active IBD prompts dietary restrictions and reduced outdoor activities, limiting sun exposure and seasonal VD synthesis. Additionally, concurrent steroid use accelerates VD catabolism, and higher BMI can sequester VD in adipose tissue. Consequently, low VD may partly serve as a biomarker of severe systemic inflammation rather than a strictly independent pathogenic factor. ⁷⁶

All the above suggest that VD supplementation plays a pivotal role in preserving the integrity of the intestinal mucosal barrier, regulating gut microbiota, and modulating the intestinal immune response. Emerging data indicate that VD holds significant therapeutic potential for managing IBD. Restoring normal VD levels in IBD patients has been shown to reduce disease activity and improve long-term outcomes, including enhanced quality of life and mental health. ⁷⁷ This is particularly relevant given the higher incidence and prevalence of psychiatric disorders among IBD patients compared to the general population. ⁷⁸ Although British guidelines acknowledge VD deficiency in IBD, more recent guidelines from the European Crohn’s and Colitis Organization ⁷⁹ do not provide specific recommendations. The 2017 ECCO guidelines highlighted the importance of VD supplementation, especially for patients on steroids, but did not offer detailed management strategies for VD in IBD. ⁸⁰ Interestingly, this recommendation was omitted in the 2020 update. ⁸¹ The variability in study outcomes, particularly regarding dosing regimens and patient population, illustrates the challenges of achieving consistent results. These findings emphasize the importance of personalized approaches to VD therapy in IBD management, tailoring treatment to individual patients to optimize therapeutic outcomes.

Optimal dosing and formulations of VD for MH

VD levels are influenced by numerous factors, such as sun exposure, seasonal variations, geographic latitude, skin pigmentation, genetic factors, inadequate dietary intake, coexisting conditions, and drug interactions. ⁸² Due to these variables, establishing a universal guideline for optimal serum concentrations and determining deficiency thresholds, as well as appropriate supplementation doses, has proven challenging. ⁸³ Nonetheless, the scientific consensus considers 25(OH)D serum levels <20 ng/mL to be a deficiency. ⁸⁴ It should be noted that variability in 25(OH)D measurement methods may influence the interpretation of serum thresholds. Despite being the method of choice for its high analytical specificity, liquid chromatography-tandem mass spectrometry is not universally applied. Instead, immunoassays are widely used, though with notable inter-assay variability and potential bias. These differences can affect the classification of VD status and, consequently, have relevant implications when applying threshold-based dosing strategies. ⁸⁵ Given this uncertainty, the optimal VD serum concentration in IBD remains unclear, and several studies have sought to establish the necessary doses to achieve optimal serum levels. Additionally, genetic variability may contribute to differences in individual responses to VD supplementation. Polymorphisms in genes involved in VD signaling, particularly the VDR, as well as in enzymes related to its metabolism, have been associated with altered VD activity, bioavailability, and immune responses. These variations may partly explain the heterogeneity observed in clinical outcomes among IBD patients receiving VD supplementation and highlight the potential relevance of personalized approaches in optimizing therapeutic strategies. ⁸⁶

The potential of VD3 to repair mucosal injury has been assessed in murine models, such as the study by Wibowo et al., ⁸⁷ in which treatment with 0.6 μg of VD3 per 25 g body weight increased the expression of intestinal stem marker Lgr5+ and cell proliferation marker Ki67 in a dose-dependent manner, as well as the improvement of DAI, colon length, and histopathological index scores in the DSS-induced colitis model. ⁸⁷ In another study, Goswami et al. ⁸⁸ found that injections of either 1,25(OH)2D3 or dietary VD 20,000 IU/kg provided protection against disease progression and decreased crypt hyperplasia. These protective effects were attributed, at least in part, to the inhibition of intestinal pro-inflammatory cytokines and reduced NF-κB abundance in intestinal epithelia. However, no universal daily intake recommendation or upper limit exists for individuals with increased VD needs, such as those with malabsorption or deficiency. ⁸⁸ Therefore, establishing a specific dosage parameter to achieve true MH remains elusive. Consequently, studies evaluating the effects of VD in IBD can be broadly categorized into those assessing objective MH (endoscopic or histological) and those relying on surrogate clinical markers. Most studies have relied on the latter, aiming to determine serum levels that reduce clinical scores (such as DAI or HBI), which may not accurately reflect objective mucosal tissue repair.

Clinical trials addressing these endpoints have employed highly heterogeneous regimens, ranging from daily maintenance protocols (400–2000 IU/day) to high-dose weekly or monthly boluses. Consequently, the target thresholds used to guide these interventions differ significantly. Available clinical data are most robust regarding the therapeutic benefit of correcting absolute deficiency to sustain a baseline threshold above 20–30 ng/mL, a range that consistently correlates with reduced clinical relapse and lower systemic inflammation. In contrast, evidence supporting ultra-high target thresholds—such as maintaining levels between 50 and 100 ng/mL—remains weak, highly conflicting, and primarily limited to observational findings. For example, a cohort study including 141 patients with CD and 79 with UC found that disease activity was the lowest at VD concentrations of 50–59 ng/mL, with supplementation doses ranging from 400 to 1000 IU daily, depending on patients’ weight. However, they could not correlate a specific daily dose intake with the achievement of these serum levels. ⁸⁹ Crucially, while these elevated metrics (50–59 ng/mL) have been observed to be associated with lower clinical scores, there is currently no prospective interventional evidence demonstrating that raising serum levels beyond the standard 30–40 ng/mL threshold translates into superior clinical outcomes or objective mucosal tissue repair. The Institute of Medicine of the National Academies has recommended a tolerable upper limit of 4000 IU/day for adults and children over 8, while the Endocrine Society suggests a higher upper limit of 10,000 IU/day for individuals over 8 to correct deficiency.^90,91 Research indicates that VD absorption in patients with CD is approximately 30% lower than in healthy individuals, implying that daily VD doses for this group should be increased by 1.5 times the standard recommendations for the general population. ⁹² The oral dose of 25(OH)D3 necessary to elevate serum concentrations to 40 ng/mL in CD patients was investigated by Yang et al., ⁹³ where 18 patients were treated with an initial dose of 1000 IU/day, measuring serum levels every 2 weeks and increasing the dosage until serum levels reached the desired levels. Even though serum levels were raised, 14 patients required the maximum dosage, and after 24 weeks of supplementation, half of the patients still did not achieve the desired VD levels. ⁹³ Another study conducted by Pappa et al. ⁹⁴ on pediatric IBD patients found that serum levels increased from 0.8 to 1.1 ng/mL for every 10,000 IU of VD2 and 2 ng/mL for every 10,000 IU of VD3. Little is known about the turnover of VD, although it is theorized that this vitamin has a half-life of up to 20 days. Therefore, 6–12 weeks of supplementation should yield adequate serum concentration. Table 1 includes a more detailed review of the most extensive trials conducted on IBD patients and serum VD concentrations after supplementation.

Table 1.

Overview of studies assessing VD supplementation, serum levels, and intestinal MH effects in IBD patients. ^a

Study	Patients	VD daily dose (IU)	Supplementation period	Baseline VD levels (ng/mL)	Final VD levels (ng/mL)	Endoscopic/histologic endpoint assessment	Clinical or endoscopic improvement	ClinicalTrial.gov ID
67	18 CD	2000	3 months	<30	5.00 ± 3.12	Yes	No	NCT01877577
		4000			16.80 ± 9.15		Yes
77	108 CD	Placebo	12 months	27.6	38.4	No	No	NCT00122184
		1200					Yes
78	50 UC	1000	3 months	<20	>25	No	Yes	n.a.
		2000					Yes
76	2912 UC	1000	3 months	23	n.a.	Yes	No	n.a.
	1958 CD	2000
94	18 adult CD	5000	6 months	16 ± 10	45 ± 19	No	No	NCT00742781
103	61 IBD (5–21 years of age)	2000 D2	8 months	<20	9.3 ± 1.8	No	n.a.	NCT00621257
		50,000 D2			16.4 ± 2.0
		2000 D3			25.4 ± 2.5
98	141 CD	400–1000	3 months	<20	50–59	No	Yes	n.a.
	79 UC

Key findings from clinical trials evaluating the impact of different amounts of VD supplementation on IBD patients. Most studies primarily report clinical remission (reduction of disease activity indices) rather than objective endoscopic or histological MH.

^aMost of the interventional trials compiled in this table primarily report clinical remission and improvement based on subjective disease activity indices (such as the CDAI, Harvey–Bradshaw Index, or Partial Mayo Score) or indirect biomarkers (C-reactive protein and fecal calprotectin) rather than objective tissue healing. To date, these studies lack direct, standalone endoscopic or histological confirmation of tissue repair, representing a critical limitation when assessing true MH in the current literature.

CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; IBD, inflammatory bowel diseases; MH, mucosal healing; n.a., not available; UC, ulcerative colitis; VD, vitamin D.

VD supplementation is modulated by its forms of administration as well, as it can be administered in several oral or parental forms, including 25(OH)D3, 25(OH)D2, 1,25(OH)2D3, or a VD agonist (e.g., calcipotriol). ⁹⁵ The most used forms are D2 or D3 supplements. Numerous studies comparing their effectiveness have shown that 25(OH)D3 is the most effective form of VD to restore serum levels and reduce DAI, with D2 being less than one-third as effective as VD3. ⁹⁶ While excessive exogenous VD intake can lead to toxicity, manifested as hypercalcemia (>320 ng/mL, as reported by Garg et al. ³⁸ ), excessive sunlight exposure does not pose a risk in terms of VD production. ⁹⁵ Nevertheless, various studies have proven that VD supplementation is exceptionally safe, as hypercalcemic levels are far above those typically administered for IBD. Notably, serum levels associated with toxicity (e.g., >320 ng/mL) are well above the therapeutic targets commonly pursued in IBD (~20–50 ng/mL), reinforcing the wide safety margin when supplementation is appropriately monitored. A review of 25 RCTs found that only 24 patients experienced hypercalcemia, and most cases were asymptomatic and resolved with fasting. ⁹⁷ Furthermore, safe upper limits for VD intake have been established, with recommendations of up to 10,000 IU/day for healthy adults. ⁹⁸

From a clinical standpoint, VD supplementation in IBD should be highly individualized, taking into account several clinical and physiological determinants. Beyond disease activity and intestinal malabsorption, optimal dosing depends on the patient’s baseline VD status, as severe deficiency requires higher initial doses. Furthermore, concomitant therapies, such as corticosteroids, can alter VD metabolism. Physiological factors must also be considered; for instance, higher adiposity (BMI) can sequester this fat-soluble vitamin, and ethnicity-related skin pigmentation affects UV-B-dependent VD synthesis. Although deficiency is defined as serum 25(OH)D <20 ng/mL, optimal target levels for MH remain uncertain, and current evidence is largely based on surrogate clinical outcomes. Therefore, careful monitoring of serum levels is recommended, particularly in patients requiring higher or prolonged supplementation.

To facilitate interpretation of current evidence and remaining uncertainties, a summary of key aspects related to VD thresholds, dosing, and outcome assessment in IBD is presented in Table 2.

Conclusion

The multifaceted role of VD in the pathogenesis and treatment of IBD highlights its importance as a potential therapeutic agent. Preclinical and translational data demonstrate that VD exhibits meaningful anti-inflammatory and barrier-protective properties by modulating components of the immune response, improving intestinal barrier integrity, and influencing gut microbiota composition. Clinical evidence strongly supports the association between VD deficiency and worsening IBD outcomes, including higher relapse rates, increased hospitalizations, and decreased quality of life. In contrast, VD supplementation has been shown to improve disease activity indices and reduce systemic inflammation, thereby supporting pathways that facilitate MH and restore intestinal homeostasis. However, definitive proof that VD supplementation independently induces endoscopic or histologic MH or alters long-term structural outcomes is still lacking, as most evidence derives from observational studies and clinical trials relying on symptom-based indices rather than confirmed tissue-level remission.

Nevertheless, challenges remain in establishing optimal dosing regimens tailored to individual needs, as well as addressing variations in VD metabolism among IBD patients, given that dysregulated intestinal absorption frequently hinders the achievement of adequate serum levels. Further difficulty lies in accurately measuring MH and evaluating the bioavailability of VD at the intestinal level. Despite these promising findings, it is important to note that there is currently a lack of large-scale RCTs designed to evaluate VD as a monotherapy, as most available evidence derives from studies where VD is used as an adjunctive therapy, which limits our ability to isolate its independent therapeutic effect.

Future studies must move beyond mere symptomatic assessment and incorporate systematic endoscopic, histological, and potentially transmural evaluations to accurately quantify the impact of VD on deep tissue remission. In this context, randomized, adequately powered trials comparing different VD targets (e.g., 20–30 vs 40–60 ng/mL), with MH (endoscopic ± histologic) as a primary endpoint, and stratified by disease type (CD vs UC), disease location, and concomitant biologic therapy, are needed to better define optimal therapeutic strategies. As the global prevalence of IBD continues to increase, harnessing the therapeutic potential of VD offers a promising avenue to improve patient outcomes and reduce disease burden. Integrating VD optimization into clinical guidelines for IBD treatment could represent a paradigm shift in addressing this complex and debilitating disease.

This review underscores the importance of maintaining adequate VD levels as a fundamental strategy to improve outcomes in patients with IBD. Regular monitoring of VD status should be integrated into routine clinical practice, particularly for individuals with active disease or those at high risk of deficiency. When tailored to individual physiological needs, targeted VD supplementation provides a safe and effective adjunctive strategy to support the clinical management of MH, mitigate chronic inflammation, and significantly improve the overall quality of life for these patients. Pending further high-quality evidence, VD optimization should be considered a safe adjunctive measure in IBD, particularly in patients with documented deficiency, but not a replacement for established anti-inflammatory and biologic therapies.

Appendix

Abbreviations

1,25(OH)D 1,25-hydroxy vitamin D

25(OH)D 25-hydroxy vitamin D

CD Crohn’s disease

DAI disease activity index

HBI Harvey–Bradshaw index

IBD inflammatory bowel disease

IEC intestinal epithelial cells

MH mucosal healing

RXR retinoid X receptor

UC ulcerative colitis

UVB ultraviolet B light

VDR vitamin D receptor

VDRE vitamin D response elements