Vitamin D and inflammatory bowel diseases

Abstract

Crohn’s disease and ulcerative colitis are the two main gastrointestinal disorders that constitute inflammatory bowel diseases (IBD). Their etiology is still unknown; however, their pathogenesis is believed to be rooted in a disorganized immune response. Targeted research was conducted in the PubMed, Scopus and EMBASE databases, including relevant peer-reviewed articles published from November 1994 to June 2025. In the past decade, vitamin D (VD) has been established as a major regulator of the immune system, including the specific environment of the digestive system, beyond its role in calcium and phosphate homeostasis. There is strong evidence that VD supports epithelial barrier integrity by influencing gut microbiome composition. On the other hand, VD deficiency is very common among patients with IBD and may contribute to disease activity, morbidity (including the need for surgery and risk for colorectal cancer), and impaired health-related quality of life. Moreover, VD deficiency seems to increase the risk of malignancy in patients with IBD. However, it remains controversial whether VD deficiency is a consequence of the disease or is implicated in its pathogenesis. Finally, the therapeutic role of VD in IBD remains to be established.

Key Words: Vitamin D; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Pathogenesis; Review; Immune modulation; Vitamin D receptor signaling; Disease activity; Vitamin D supplementation

Core Tip: Vitamin D (VD) is a main regulator of immune-mediated diseases, including inflammatory bowel disease. The VD-VD receptor signaling pathway plays a pivotal role in maintaining the integrity of the intestinal epithelial barrier and gastrointestinal microbiota. Lower VD levels seem to play a part to the pathogenesis of inflammatory bowel disease and reflect the disease activity. VD deficiency is linked to a higher risk of colorectal cancer. In contrast, increased VD levels are associated with reduced bowel resection risk and fewer hospitalizations. Finally, there is promising evidence that VD administration could act as a therapeutic factor.

INTRODUCTION

Crohn’s disease (CD) and ulcerative colitis (UC) are the two main gastrointestinal disorders that constitute inflammatory bowel diseases (IBD). Their etiology remains unknown; however, their pathogenesis is believed to involve a dysregulated immune response of the host against the intestinal mucosa, influenced by environmental and genetic factors. The result is a chronic inflammatory condition of the gastrointestinal tract. Vitamin D (VD) is well known for its role in calcium and phosphate homeostasis, and in recent years, emerging evidence suggests that it is a main regulator of immune-mediated diseases, including IBD[1]. Moreover, VD deficiency is very common in patients with IBD, especially those with CD, and it is believed to contribute not only to pathogenesis but also to treatment outcomes.

This article evaluates new evidence regarding the relationship between VD (and its deficiency) and IBD, and explores the potential benefits of VD in IBD treatment strategies by reviewing research conducted over the last 10 years, thereby providing updated and comprehensive knowledge on the subject.

METHODOLODY

The literature search was conducted in the PubMed, Scopus, and EMBASE databases from November 1994 to June 2025 using the following Medical Subject Headings terms: (1) “Vitamin D” AND “inflammatory bowel disease”; (2) “Vitamin D” AND “Crohn’s disease”; and (3) “Vitamin D” AND “ulcerative colitis.” The search was limited to articles written in English. Emphasis was placed to clinical human studies with consideration of translational and experimental data. Conflicting evidence in the literature was identified and explicitly reported and discussed to ensure transparency and provide a balanced interpretation of the findings (Figure 1)[2].

Figure 1 Preferred Reporting Items for Systematic reviews and Meta-Analyses flow diagram of study selection. Records were identified through database searching (PubMed, Scopus, EMBASE) and screened according to predefined inclusion and exclusion criteria. The numbers of records identified, excluded, and included at each stage are shown.

PATHOPHYSIOLOGY

The immune system

VD is a fat-soluble protein whose active circulating metabolite is 1,25- dihydroxyvitamin D (1,25-vitD), derived after two sequential modifications of its inactive form in the liver and kidneys, respectively. Its sources include predominantly ultraviolet-mediated skin synthesis and minor dietary intake[3]. VD binds to the VD receptor (VDR), a nuclear receptor, and stimulates multiple metabolic pathways by regulating the expression of specific target genes. VDR has been shown to be expressed not only in tissues associated with calcium and bone homeostasis but also in many other cell types, particularly immune-related cells such as T cells, B cells, neutrophils, dendritic cells, and macrophages[4,5].

Notably, VD and its associated signaling pathways inhibit the differentiation of B-cells into memory and plasma cells, thereby limiting uncontrolled inflammation. Regarding T-cell regulation, VD suppresses T helper 1 (Th1) and Th17 responses while favoring Th2 and anti-inflammatory cytokine responses. In summary, elucidating the mechanisms underlying VD-mediated immune regulation is increasingly recognized as important in the management of various diseases, especially autoimmune disorders[6].

VD exerts anti-inflammatory effects by enhancing the chemotactic and phagocytic responses of macrophages and increasing the production of antimicrobial peptides, such as cathelicidin. Conversely, the production of pro-inflammatory cytokines, including interleukin 1 (IL-1), IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) is downregulated by 1,25-vitD[7].

Sharifi et al[8] in a randomized, double-blind, placebo-controlled trial, found that a single injection of 7.5 mg cholecalciferol in 90 patients with mild-to-moderate UC decreased CD40 ligand gene expression, an essential mediator of inflammatory pathways. However, the sample and study duration were limited. In a prospective observational study Schardey et al[9] enrolled 200 outpatients with IBD, isolated T cells from peripheral blood and intestinal tissue, and incubated them with VD. The incubation resulted in markedly reduced populations of pro-inflammatory CD4+ and CD8+ T cells.

Gut health

VD has various effects on gut health. Gut epithelial cells express VDR mainly in specific regions of the crypts. The VD/VDR signaling pathway plays a pivotal role in maintaining the integrity of the intestinal epithelial barrier and the gastrointestinal microbiota[10].

Vernia et al[11] reported that VD appears to influence gut microbiome composition through the expression of junctional proteins and antimicrobial peptides, such as defensins and mucins. Studies have shown that VD supplementation in patients with IBD increases concentrations of beneficial enterobacteriaceae such as Alistipes and Faecalibacterium[12]. More recently, a link between seasonal serum VD levels and microbiome variations in IBD has been reported, with higher levels of strains such as Pediococcus spp., Clostridium spp., and Escherichia/Shigella spp. correlating with higher VD levels during summer and autumn. However, distinct seasonal exacerbations of disease activity have not been confirmed[11].

McGillis et al[13] found that VD deficiency in mice increased microRNA-142-3p, which suppresses ileal autophagy. Patients with IBD with low VD levels had increased microRNA-142-3p in affected colonic areas, suggesting that VD may play a significant role in intestinal autophagy dysregulation.

Moreover, VDR is a vital component of gut homeostasis by regulating autophagy and Paneth cell function. Mice lacking VDR exhibited altered gut microbiota and were more susceptible to developing colitis and severe inflammation. Importantly, these changes in intestinal flora were partially reversed by administration of 1,25-vitD[14-16]. VDR activation is also responsible for the beneficial effects of ginseng in UC, a widely used herb in traditional Chinese medicine[17].

Cause or effect

Emerging data suggests that VD deficiency is associated with the clinical course of IBD. Although low serum 25(OH)D levels are common in patients with IBD, it remains controversial whether this represents a consequence or the cause of the disease[18,19].

Regarding pathogenesis and natural history, it is understandable why VD deficiency may be a consequence of IBD. Apart from malabsorption of fat-soluble vitamins, including VD, patients often reduce physical activity and sunlight exposure during disease exacerbations, resulting in lower VD levels. Avoidance of sunlight exposure is sometimes recommended in patients with IBD due to the increased skin cancer risk from immunosuppressive therapy[10,20-22].

Furthermore, the role of dairy foods, a rich source of VD, remains debated. Many patients with IBD avoid milk and dairy products, although evidence suggests there may be no need for such dietary restriction[23]. Finally, VD is primarily absorbed in the jejunum. Therefore, when the jejunum is affected or resected, VD deficiency may occur more frequently. This hypothesis of small intestine disease could explain why VD deficiency is more common in CD than UC[24].

Considering VD deficiency as a causative factor, Ananthakrishnan et al[25] in a prospective observational study of women participating in the Nurses’ Health Study, reported significantly lower CD incidence in the highest predicted VD quartile. However, this cohort was limited by small case numbers and reliance on self-reported data.

Studies across Europe have shown increased IBD incidence in areas with lower ultraviolet exposure, raising the question of whether VD deficiency is an independent risk factor in IBD pathogenesis[26-28]. Higher IBD prevalence in northern regions was not fully explained by differences in tobacco consumption or education, although data on these and other potential cofounders were limited. A recent meta-analysis of 63 studies reported a possible association between latitude and CD prevalence, supporting the previous hypothesis[29]. Nevertheless, only one cohort study was included and further research is needed.

EPIDEMIOLOGY OF VD DEFICIENCY AMONG PATIENTS WITH IBD

VD, iron and zinc deficiencies are common in patients with IBD[30]. The prevalence of VD deficiency (serum 25(OH) < 25 ng/mL) among patients with IBD is reported at 38.1% in CD and 31.6% in UC[31]. VD levels appear similar between UC and CD patients[32], although some studies suggest that patients with CD are more prone to deficiency. Nevertheless, both groups remain more vulnerable compared to the general population[10]. Female sex and early age at diagnosis have been identified as statistically significant risk factors for deficiency after multivariate adjustment[33].

Domislović et al[34], in a 2020 cross-sectional study of 185 patients with IBD, recommended tactical measurement of VD even in patients receiving supplementation, due to the high prevalence of untreated or undertreated deficiency. Additionally, patients who underwent ileal or ileocolonic resection experienced VD deficiency or insufficiency in up to 58.4% and 32.4% of cases, respectively.

DISEASE ACTIVITY

A recent systematic review and meta-analysis of 27 studies including over 8000 patients with IBD, supports that VD deficiency is linked with increased disease activity and may predict poor clinical outcomes. This research, however, included only observational studies and lacked complete information on VD supplementation or diet[35].

Recent findings show an inverse correlation between serum VD levels and intestinal inflammation markers such as fecal calprotectin in patients with both UC and CD, suggesting VD could serve as an adjunct biomarker[36,37]. Two cross-sectional studies also found that elevated systemic inflammatory markers, including C-reactive protein (CRP) were associated with low serum VD levels[38,39]. That said, these reports were limited to single time points and did not include endoscopic results.

Blanck and Aberra[40], in a retrospective study of 34 patients with UC, reported that 68% were VD-deficient. Lower VD levels correlated with higher UC activity (Mayo score) and increased steroid intake. The small sample, still, prevents drawing definitive conclusions.

A systematic review and meta-analysis including 20 previous studies from 2010 to 2019 by Guzman-Prado et al[41] concluded that VD supplementation corrected serum 25(OH)D levels and was associated with improved disease activity scores (Harvey Bradshaw Index and CRP). Key constraints of this review included heterogeneous dosages and treatment durations, limited data on objective disease activity, and differences by disease subtype, progression, surgery history, or diet.

A recent clinical controlled trial reported that CRP and erythrocyte sedimentation rate, as markers of inflammation, decreased 3 months after VD administration in UC patients with VD deficiency[42]. These findings should be interpreted in light of a relatively small sample size (90 patients), short follow-up, and concurrent immunomodulatory therapies. Similarly, a Canadian retrospective study suggested that improving VD status was associated with lower inflammation and CD activity. This could illustrate a possible anti-inflammatory benefit of VD in patients with IBD and warrants further research[43].

Other studies continue to suggest a relationship between severe VD deficiency and a more aggressive clinical course of IBD. Ham et al[44] conducted a cohort study of 711 patients with CD and 764 patients with UC, finding that higher CD Activity Index, partial Mayo scores, and CRP correlated with lower 25(OH)D levels. Severe deficiency appeared linked to greater disease extent in UC.

Lastly, Meckel et al[45] in 230 patients with UC, after having adjusted for race, sex, 5-aminosalicylic acid use, smoking status, and season of enrollment, reported that each 1 ng/mL increase in VD decreased the odds of Mayo endoscopic score > 1 and total Mayo score > 5 decreased 5% and 7%, respectively. Nevertheless, the investigators acknowledge the fact that they could not establish the causative role of low VD levels, because this may be secondary to a more severe disease activity.

SURGICAL APPROACH OF PATIENTS WITH VD DEFICIENCY

Ananthakrishnan et al[46], in a cohort of 3217 patients (55% CD) found that VD deficiency (< 20 ng/mL) increased the odds of surgery [odds ratio (OR) = 1.76, 95% confidence interval (CI): 1.24-2.59] and hospitalization (OR = 2.07, 95%CI: 1.59-2.68). Additionally, patients with CD receiving substitution therapy were less likely to undergo surgery (OR = 0.56, 95%CI: 0.32-0.98). That said, the authors noted that VD levels were not measured in all patients, and tested patients were systematically sicker, limiting causal inference.

Furthermore, Venkata et al[47], in a retrospective cohort study of 196 patients with CD observed for at least 1 year, reported that patients with VD deficiency with CD were 1.5 times more likely to be hospitalized over a year. The authors came to the conclusion that sufficient VD levels may be protective in the clinical course of CD. Still, this role needs to be further clarified.

A longitudinal cohort study of 5474 patients with IBD, during a mean follow-up of 13 years, suggested that higher 25(OH)D levels were associated with reduced bowel resection risk in IBD, particularly in UC[48]. By contrast, severe deficiency was considered to be an independent risk factor for surgery in both CD (hazard ratio = 1.93, 95%CI: 1.38-2.70) and UC (hazard ratio = 2.77, 95%CI: 1.14-6.74)[44].

Finally, Yamada et al[49] in a retrospective cohort study of 89 patients with VD deficiency with CD who underwent intestinal surgery, concluded that increased VD level was linked with a lower risk of postoperative endoscopic CD recurrence at 6-12 months postoperatively.

HEALTH-RELATED QUALITY OF LIFE

Another issue that has been raised is the impact of VD deficiency on patients’ health-related quality of life (HRQOL).

Hlavaty et al[50] in their cohort research, including 220 patients with IBD (79 UC and 141 CD), whose HRQOL was assessed using the short IBD questionnaire, reported that low serum VD, particularly during winter/spring, correlated with poorer QOL. Similar results were observed in patients with CD by Ulitsky et al[51] (504 patients with IBD with a mean disease duration over 10 years).

Conversely, a cross-sectional study of 133 patients (85 UC and 48 CD) found no HRQOL differences between patients with deficient and sufficient VD levels[52]. Moreover, 529 deaths (198 in CD and 331 in UC) were documented among 5222 individuals with IBD, whereas a nonlinear correlation was observed between VD concentrations and overall mortality[53].

It should be noticed that the relationship between VD levels and HRQF can be interpreted in more than one plausible way. Both HRQOF and VD levels may be negatively affected in patients with severe symptoms (e.g., malnutrition, recurrent diarrhea), those requiring hospitalization or those undergoing repeated surgical interventions. Conversely, patients with milder disease or better overall well-being may be more physical active, spend more time outdoors, maintain a better diet, and use supplements more consistently, resulting in higher VD levels.

Johansen et al[54] analyzed data from 573 adult patients diagnosed with IBD to investigate symptom clusters, defined as groups of symptoms that co-occur, are related to each other, and often share an underlying mechanism. They noticed that VD deficiency was the only factor associated with the impaired energy cluster, which affected 28.2% of patients and comprised three symptoms: (1) Lack of energy; (2) Drowsiness; and (3) Difficulty sleeping.

MALIGNANT POTENTIAL

Regarding cancer development in IBD, a recent longitudinal study of 2809 patients demonstrated VD deficiency was associated with an increased risk of colorectal cancer. Moreover each 1 ng/mL increase in serum VD levels was linked to an 8% reduction in malignancy risk[55]. The investigators acknowledge that, despite the adequate sample size, important data were missing, including body mass index and smoking status. In addition, adjustments for disease activity and duration – both established risk factors for colorectal cancer – were not fully implemented.

O’Mahony et al[56] demonstrated in an experimental model that a high-fat diet can protect mice from developing acute and chronic colitis following dextran sulfate sodium administration (dextran sulfate sodium-induced colitis) as well as colitis-associated cancer by reducing tumor burden. This effect may be attributed to alterations in the gut microbiota and bile acid metabolism, which regulate VD signaling pathways. Two recent studies also reported that asperuloside and vitexin (two glycosides extracted from various plants) can attenuate the progression from chronic colitis to colorectal cancer via specific VDR signaling pathways. These findings suggest that VDR deficiency may accelerate the transition from chronic colitis to colorectal cancer[57,58]. Although the results from these experimental studies are promising, important translational challenges remain. Further research, particularly involving human subjects, is required to draw reliable conclusions.

VD AND MONOCLONAL ANTIBODIES

In recent years, emerging research has investigated the potential role of VD status in the effectiveness of biological agents in the treatment of IBD.

Cusato et al[59] identified correlations between VD-related single nucleotide polymorphisms (SNPs), clinical response to vedolizumab and ustekizumab, and IBD phenotype and localization. In a cohort of 103 patients with IBD (40 receiving vedolizumab and 63 receiving ustekinumab), specific SNPs were negative predictors of achieving fecal calprotectin levels below 250 mg/kg, a marker suggestive of inactive bowel inflammation and mucosal healing. Moreover, certain SNPs were associated with a higher prevalence of CD compared with UC, as well as with non-ileal CD. Regarding the VDR-related SNPs, a recent survey reported a possible association with disease phenotype, progression, and response to biological agents in CD[60]. Both of these studies, however, were limited by small sample sizes.

In a retrospective study of 88 patients (44 with CD and 44 with UC) receiving vedolizumab, higher pre-treatment VD levels were linked with greater endoscopic improvement in patients with UC. Among patients with CD, higher baseline VD levels were linked to significantly increased vedolizumab concentrations following treatment[61].

Chanchlani et al[62] measured 25(OH)D concentrations in 659 patients with CD receiving infliximab and 448 receiving adalimumab. In contrast to other studies, they concluded that pretreatment VD levels were not associated with primary non-response to anti-TNF treatment at week 14 or with lack of remission at week 54.

Lastly, recent experimental research has shown that VD inhibits TNF-α production by reducing lipid synthesis in intestinal epithelial cells. Given the fact that the dose of infliximab, an anti-TNF-α antibody, is weight-based, VD may enhance the therapeutic efficacy of infliximab in overweight patients with IBD[63]. Nevertheless, considering the experimental nature of this evidence, additional investigation is required to confirm these findings.

ROLE OF VD AS A TREATMENT

Given the high incidence of VD deficiency in IBD and its potential association with disease activity and progression, there has been growing interest in VD supplementation as a therapeutic strategy.

A recent retrospective cohort study of 5021 patients with IBD in the United States Veterans Health Administration system (2000-2023), reported that VD supplementation was associated with reduced IBD-related emergency department visits, hospitalizations, and corticosteroid use[64]. Despite the large sample size, the study lacked standardized dosing protocols and did not account for several potential confounders, highlighting the need for prospective, controlled clinical trials to confirm these findings

Gisbert-Ferrándiz et al[65] analyzed intestinal resections from 24 patients, including damaged mucosa from 12 patients with CD and healthy mucosa from 10 controls with colorectal cancer. They also investigated the effects of VD on intestinal fibrosis in a mouse model. The study demonstrated that VDR expression was reduced in fibroblasts isolated from damaged human mucosa. VD treatment increased VDR protein levels and inhibited the enhanced migration observed in these cells in mice. While this study provides valuable mechanistic insight into VDR expression in intestinal fibroblasts from patients with CD and suggests a potential antifibrotic role of VD in vitro and in vivo, its clinical implications should be interpreted with caution.

Metabolic bone disease is common in patients with IBD, with an increased incidence of osteopenia and osteoporosis over time. This is likely due to impaired absorption of bone minerals and the use of corticosteroid therapy. Consequently, VD supplementation is essential in high-risk patients[66,67]. However, while the role of VD in maintaining bone health is well established, its anti-inflammatory effects in IBD remain unclear[68]. Emerging evidence suggest that VD may also improve iron deficiency in IBD by downregulating hepcidin and upregulating ceruloplasmin, thereby enhancing intestinal iron absorption[69].

A recent review of 22 randomized controlled trials, including 1874 participants, evaluated VD in the treatment of IBD. The analysis indicated that VD supplementation was associated with fewer clinical relapses compared with placebo. However, there is insufficient evidence to draw definitive conclusions regarding differences in clinical response, QOL, or treatment withdrawals[70].

Zepeda et al[71] published a narrative review in 2022 examining VD supplementation in adult patients with IBD. The review included 43 primary studies published between 2015 and 2020 in English and Spanish. After discussing the immunomodulatory effects of VD, as well as its role in maintaining intestinal barrier integrity and microbiota composition, the authors suggested that supplementation above 2000 IU/day may benefit patients with inactive IBD, while higher doses (5000-10000 IU/day) may be considered for those with active disease.

Regarding the role of VD supplementation in IBD prevention, a cross-sectional study including 3591 participants from the 2009-2010 National Health and Nutrition Examination Survey, reported that higher VD intake may be associated with reduced risk of IBD. Specifically, each 1 μg increase in VD intake was linked to an approximately 51% lower risk of IBD. Nevertheless, is should be noted that these findings were based on self-reported dietary recall and IBD status, which may limit their reliability[72].

Finally, regarding pediatric patients with IBD, a 2023 systematic review and meta-analysis evaluating 16 papers, did not identify a clear association between VD and pediatric IBD. Nevertheless, the authors suggested that VD supplementation may help improve disease activity. That said, the authors acknowledged significant heterogeneity in study designs, adolescence populations and supplementation dosing across the included studies[73].

CONCLUSION

VD has been implicated in the pathogenesis of IBD, and its deficiency may adversely affect immune regulation and contribute to disease exacerbations. Interest in the association between VD deficiency and IBD has increased substantially over the past decade. Most of the studies conducted, reveal a significant and multifaceted relationship between VD status and IBD, encompassing disease activity, relapse rates, complications, and HRQOL. However, to date, only a limited number of randomized clinical trials have been conducted, and none have included sufficiently large sample sizes to establish causality. Therefore, further well-designed, adequately powered clinical trials are needed to clarify whether VD repletion can play a definitive therapeutic role in IBD (Table 1)[8,9,25,29,30,33-48,50-55,61,62,64,66,67,69-73].

Table 1 Key findings.

Ref.	Study design	Population/sample size	VD assessment	IBD type	Association between VD and IBD
Sharifi et al[8], 2020	Randomized, double-blinded, placebo-controlled trial	90 patients with UC	Serum 25(OH)D levels	UC	VD supplementation decreases the CD40 L gene expression in patients with mild-to-moderate UC
Schardey et al[9], 2019	Prospective cohort study	200 outpatients with IBD	Serum 25(OH)D levels	UC, CD	The incubation VD resulted in remarkably reduced populations of pro-inflammatory CD4+ and CD8+ T cells
Ananthakrishnan et al[25], 2012	Prospective cohort study	122 CD women	Serum 25(OH)D levels	CD	Higher levels of VD reduce the risk of incident CD in women
Sadeghian et al[29], 2016	Meta-analysis	63 studies	Serum 25(OH)D levels	CD	Patients with CD had lower VD levels compared with their healthy counterparts. There was an inverse correlation between VD levels and severity of CD
Topalova-Dimitrova et al[39], 2023	Cross-sectional study	92 patients with IBD, 14 health controls	Serum 25(OH)D levels	UC, CD	Reverse correlation between VD and inflammatory markers
Andres et al[30], 2024	Retrospective cohort study	204 patients with IBD	Serum 25(OH)D levels	UC, CD	In younger patients, VD was associated with adverse clinical outcomes, but the same trend was not seen in older patients
Yang et al[33], 2024	Prospective observational study	106 patients with IBD	Serum 25(OH)D levels	UC, CD	Female sex and early age at diagnosis were identified as statistically significant risk factors for VD deficiency
Domislović et al[34], 2020	Cross-sectional study	185 patients with IBD	Serum 25(OH)D levels, VD supplement	UC, CD	VD deficiency common in IBD patients but the proportion of untreated and undertreated patients is also considerably high
Gubatan et al[35], 2019	Systematic review and meta-analysis	27 studies, 8316 patients with IBD	Serum 25(OH)D levels	UC, CD	Low VD levels are associated with increased odds of disease activity, mucosal inflammation, low quality of life, and future clinical relapse
Yeaman et al[36], 2023	Retrospective observational study	325 patients with IBD	Serum 25(OH)D levels	UC, CD	VD level is negatively correlated with FCP and may be considered an adjunct biomarker at this stage
Koureta et al[37], 2025	Cross-sectional observational study	325 patients with IBD	Serum 25(OH)D levels	UC, CD	In CD, higher CRP and stool calprotectin are usually detected in patients with low than normal VD levels, rendering VD a possible activity marker, something that cannot be supported for patients with UC.
Song et al[38], 2024	Retrospective, cross-sectional observational study	1989 patients with IBD	Serum 25(OH)D levels	UC, CD	There was a negative association between CRP levels and VD in hospitalized patients with IBD
Blanck and Aberra[40], 2013	Cross-sectional study	34 patients with UC	Serum 25(OH)D levels	UC	VD deficiency is common among patients with active UC, particularly those requiring corticosteroids
Guzman-Prado et al[41], 2020	Systematic review and meta-analysis	12 randomized controlled trials and 4 observational studies	VD supplement	UC, CD	VD supplementation is effective at correcting VD levels and is associated with improvement in clinical and biochemical disease activity scores
Sharifi et al[42], 2016	Clinical controlled trial	90 patients with UC	VD supplement	UC	CRP and erythrocyte sedimentation rate were lower at 3 months after the administration of VD in patients with UC and VD deficiency
Alrefai et al[43], 2017	Retrospective cohort study	201 patients with CD	Serum 25(OH)D levels	CD	VD concentrations showed a significant inverse association with both high-sensitivity-CRP level and disease activity levels
Ham et al[44], 2021	Retrospective cohort study	711 patients with CD, 764 patients with UC	Serum 25(OH)D levels	UC, CD	Higher CD activity index, partial Mayo scores, and CRP levels were linked with decreased levels of VD. Severe VD deficiency seems to correlate to the disease extent in UC
Meckel et al[45], 2016	Prospective cohort study	230 patients with UC	Serum 25(OH)D levels	UC	In patients with UC, VD concentration is inversely correlated with mucosal inflammation and disease activity
Ananthakrishnan et al[46], 2013	Retrospective cohort study	3217 patients with IBD	Serum 25(OH)D levels	UC, CD	Low VD is associated with increased risk of surgery and hospitalization in both CD and UC, and normalization of VD status is associated with a reduction in the risk of CD-related surgery
Venkata et al[47], 2017	Retrospective cohort study	196 patients with CD	Serum 25(OH)D levels	CD	Normal or adequate VD stores may be protective in the clinical course of CD
Dan et al[48], 2024	Longitudinal cohort study	5474 patients with IBD	Serum 25(OH)D levels	UC, CD	Increased VD levels are independently associated with reduced bowel resection risk in IBD. This association was significant in UC but may not be stable in CD
Hlavaty et al[50], 2014	Retrospective cohort study	220 patients with IBD	Serum 25(OH)D levels	UC, CD	VD low levels were correlated with poorer quality of life
Ulitsky et al[51], 2011	Retrospective cohort study	504 patients with IBD	Serum 25(OH)D levels	UC, CD	VD deficiency is associated with lower quality of life in CD, but not UC
Torki et al[52], 2015	Cross-sectional study	133 patients with IBD	Serum 25(OH)D levels	UC, CD	No difference regarding health-related quality of life between patients with deficient and sufficient VD
Dan et al[53], 2022	Prospective cohort study	5222 patients with IBD 529 deaths	Serum 25(OH)D levels	UC, CD	Nonlinear correlation was observed between VD concentrations and overall mortality
Johansen et al[54], 2023	Prospective cohort study	573 patients with IBD	Serum 25(OH)D levels	UC, CD	VD deficiency is the only factor related with impaired energy cluster (lack of energy, feeling drowsy, difficulty in sleeping)
Ananthakrishnan et al[55], 2014	Multi-institutional cohort study	2089 patients with IBD	Serum 25(OH)D levels	UC, CD	Patients with IBD with VD deficiency has an increased risk of developing colorectal cancer
Abraham et al[61], 2023	Retrospective cohort study	88 patients with IBD	Pretreatment 25(OH)D levels	UC, CD	Higher pre-treatment VD levels were linked with profound endoscopic improvement in patients with UC. Regarding CD patients, those with high pre-treatment VD levels had significantly higher vedolizumab levels after treatment
Chanchlani et al[62], 2023	Prospective cohort study	1107 patients with IBD	Pretreatment 25(OH)D levels	CD	Pretreatment VD concentration is not associated with primary non-response to anti-tumor necrosis factor treatment at week 14 or non-remission at week 54
Sninsky et al[64], 2025	Retrospective cohort study	5021 patients with IBD	VD supplement	UC, CD	VD supplementation was linked to fewer IBD-related emergency department visits, hospitalizations, and corticosteroid use
Yin et al[66], 2022	Retrospective cross-sectional study	639 patients with IBD	VD supplement	UC, CD	Supplementation of VD is crucial in patients with high-risk of developing osteopenia and osteoporosis
Tulewicz-Marti et al[67], 2022	Prospective, one-centre study	187 patients with IBD	Serum 25(OH)D levels, VD supplement	UC, CD	Bone mineral alterations were common in patients with IBD, mostly in patients with CD. VD supplementation remains crucial, especially when taking corticosteroids
Stallhofer et al[69], 2022	Cross-sectional observational study	104 patients with IBD	Serum 25(OH)D levels	UC, CD	VD can improve iron deficiency in IBD contributing in higher iron absorption from the intestine
Wallace et al[70], 2023	Systematic review	22 randomized controlled trials, 1874 patients with IBD	VD supplement	UC, CD	Lesser clinical relapses observed when comparing VD with placebo, but there is no enough evidence to draw any conclusions on differences in clinical response, quality of life, or withdrawals
Zepeda et al[71], 2022	Narrative review	43 primary studies published from 2015 to 2020	VD supplement	UC, CD	VD administration above 2000 IU per day to inactive patients with inflammatory bowel disease, and higher doses (between 5000 IU per day and 10000 IU per day) to those in the active stage, could possibly benefit the disease
Li et al[72], 2025	Cross-sectional study	3591 subjects	VD supplement	UC, CD	Increased VD intake may reduce the risk of IBD
Sun et al[73], 2023	Systematic review and meta-analysis	16 papers	Serum 25(OH)D levels, VD supplement	UC, CD	No obvious relationship between pediatric IBD and VD was noticed. VD supplementation can improve disease activity

CD: Crohn’s disease; CD40 L: Cluster of differentiation ligand; CRP: C-reactive protein; FCP: Fecal Calprotectin; IBD: Inflammatory bowel diseases; UC: Ulcerative colitis; VD: Vitamin D.