Association between Inflammatory Bowel Disease and Vitamin D Deficiency: A Systematic Review and Meta-Analysis

Abstract

Background

Vitamin D plays a role in several immune-mediated diseases, but its association with inflammatory bowel disease (IBD) is unclear. We conducted a systematic review and meta-analysis to assess the association between IBD and vitamin D deficiency.

Methods

We searched electronic databases from inception to December 2014 for observational studies reporting the presence of vitamin D deficiency (defined as serum 25-hydroxycholecalciferol [25(OH)D] level of ≤20 ng/ml) in IBD patients and having a control group without IBD. Odds ratios (OR) were combined using a random effects model. Meta-regression was performed using latitude as a moderator. Study quality was assessed using the Newcastle-Ottawa scale.

Results

Out of 816 citations, 14 eligible studies were identified, comprising 1891 participants (938 IBD cases and 953 controls). Meta-analysis showed that patients with IBD had 64% higher odds of vitamin D deficiency when compared to controls (OR = 1.64; 95% CI: 1.30, 2.08; I² = 7%; p < 0.0001). UC patients had more than double the odds of vitamin D deficiency when compared to normal controls (OR = 2.28; 1.18, 4.41; I² = 41%; p=0.01). Latitude did not influence the association between IBD and vitamin D deficiency (p = 0.34). Generalizability of our results might be limited as we summarized unadjusted ORs, due to non-availability of adjusted ORs in individual studies.

Conclusions

IBD is significantly associated with having higher odds of vitamin D deficiency. Well-designed RCTs and longitudinal studies are needed to further clarify the role of vitamin D in IBD pathogenesis and its therapy.

INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic, relapsing-remitting systemic disease that includes two major forms, Crohn’s disease (CD) and Ulcerative colitis (UC). CD primarily involves the ileum and colon, but it may affect any region of the gastrointestinal tract, while UC is mostly limited to the colon and/or rectum. The prevalence of IBD is increasing worldwide, with approximately 3 million people affected in Europe and 1.5 million in the USA and rapidly increasing trends observed in the Asia-Pacific regions^1–4. IBD has a significant impact on health related quality-of-life⁵. It poses a significant economic burden, with estimated annual direct medical costs of nearly 3 billion US dollars^{6, 7}.

The exact etiology of IBD has not been fully elucidated; however, it is thought to result from an inappropriate and ongoing activation of the immune system against environmental triggers in genetically predisposed individuals^{8, 9}. Risk factors associated with IBD include altered intestinal flora^{9, 10}, a diet rich in carbohydrates and fats¹¹, oral contraceptives¹² and living in urban areas¹³. A stressful lifestyle is considered to exacerbate the disease¹⁴. In this setting, an aberrant innate immune response to gut luminal agents, possibly facilitated by an impaired mucosal barrier function, results in the stimulation of dendritic cells and subsequent activation of the inflammatory cascade, leading to intestinal inflammation^{15, 16}.

Vitamin D is a pleiotropic hormone with a diverse range of effects ranging from immune modulation to cell differentiation and intercellular adhesion. Several in vivo and in vitro studies have examined the role of vitamin D in immune-mediated diseases like IBD^17–19. The consequences of vitamin D deficiency on the gastrointestinal tract include, but are not limited to, decreased colonic bacterial clearance²⁰, reduced expression of tight junctions in the intestinal epithelium²¹, and elevated Th1-driven inflammation at the gut level²².

Hypovitaminosis D is reported to be as high as 60% in IBD patients²³, although it is not clear whether it results from IBD-related malabsorption due to intestinal mucosal damage²⁴, or whether it is a possible contributor to disease onset and progression^{25, 26}. Evidence from observational studies remains questionable, as some studies report lower circulating vitamin D levels in IBD^27–43, while others^44–53 do not. Given the lack of clarity regarding the association of vitamin D deficiency with IBD, we decided to conduct a systematic review and meta-analysis of observational studies looking at the association of IBD and its subtypes with vitamin D deficiency.

MATERIALS AND METHODS

Study protocol

This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines⁵⁴. A comprehensive search of major electronic databases was conducted for articles from inception through December 2014. The following databases were included: 1) PubMed, 2), the COCHRANE library 3) EMBASE, and 4) CINAHL. The search utilized the terms ‘Vitamin D’, ‘ergocalciferol’, ‘Inflammatory bowel disease’, ‘Crohn’s disease’ and ‘Ulcerative colitis’ in several combinations. The detailed search strategy is presented in the online appendix. In addition, review articles on the topic were searched for eligible articles. The search strategy was not limited by language. We did not attempt to contact the authors of the articles for retrieving additional information or clarifications.

Inclusion and exclusion criteria

Two authors (RDP and DP) independently reviewed abstracts and articles for eligibility. Conflicts were resolved in consultation with a senior author (FC)⁵⁵. Inclusion of studies was limited to case-control, cohort and cross-sectional studies with a control group that reported dichotomous outcomes of vitamin D deficiency in adult or pediatric subjects. Vitamin D deficiency was defined as circulating 25(OH)D ≤20 ng/ml (≤50 nmol/L), according to the Endocrine Society Guidelines⁵⁶. We did not exclude studies on the basis of disease parameters (IBD activity, severity, duration of disease or region/extent of involvement), previous or current IBD therapy (including use of corticosteroids, salicylates and biologics), history of IBD-related surgery and vitamin D supplementation.

The following data were extracted (Table 1):

• Study characteristics: primary author, year of publication, time period of study, country, latitude of the area where the study was conducted, seasonality data, number of patients with IBD and in the control group

• Patient characteristics: age, sex, race/ethnicity, BMI, smoking status, serum vitamin D levels, current IBD-related therapy, prior IBD-related surgery, vitamin D supplementation and tanning habits

• Disease characteristics: distribution of IBD subtypes (CD vs. UC), disease activity, site/s and extent of involvement and disease duration

• Assay characteristics: type of assay used for circulating vitamin D assessment (such as RIA or ELISA) and inter/intra-assay coefficients of variability

• Outcome measures: Prevalence of vitamin D deficiency in participants with and without IBD, as defined by the number or percentage of participants with circulating vitamin D levels ≤20 ng/ml or adjusted ORs and a measure of variability such as 95% confidence interval (CI) or standard error (SE).

Table 1.

Characteristics of the included studies.

Author, year	Country, latitude (°)1	Time period of study	25(OH)D assay	IBD/control	N.	Sex (M/F)	Race/Ethnicity (%)	Age (years) (SD)	Mean 25(OH)D (SD or CI)§,*
Grunbaum 2013	Canada, Montréal 45.46	March 2009–April 2011	RIA	IBD (CD/UC)	55 (34/21)	21/34	Caucasian-95%. Jewish-51%	CD: 39.9 (12.3) UC: 44.2 (13.7)	71.2 (32.8)§
				Non-IBD	48	10/38	Caucasian-79%. Jewish-42%	39.6 (13.8)	68.3 (26.2)§
Souza 2008	Brasil, Curitiba 25.42	N/A	RIA	IBD (CD/UC)	76 (39/37)	33/43	N/A	CD: 32.1 (8.7) UC: 35.0 (8.5)	CD: 25.9 (8.2)* UC: 21.8 (8.0)*
				Non-IBD	40	16/24	N/A	34 (7)	34.4 (12.8)*
Silvennoinen 1996	Finland, Oulu 65.01	April–May 1993	RIA	IBD (CD/UC)	150 (76/67)	79/71	N/A	40 (9.3)	28.4 (12.0)§
				Non-IBD	73	35/38	N/A	40.8 (9.3)	36.1 (16.7)§
Suibhne 2012	Irland, Dublin 53.34	All seasons	RIA	IBD (CD/UC)	81 (81/−)	33/48	Caucasian-100%	36.4 (11)	47.76 (27.27)§
				Non-IBD	70	28/42	Caucasian-100%	36.3 (9.5)	51.86 (24.53)§
Garg 2013	Australia, Melbourne 37.86	All seasons	ECLA	IBD (CD/UC)	71 (40/31)	39/32	Australian/NZ-72%, European-18%, Other-8%	CD: 41 (23–76) UC: 44 (22–82)	CD: 70 (61–78)§ UC: 70 (58–81)§
				Non-IBD	23	10/13	Australian/NZ-70%, European-9%, Other-26%	39 (22–68)	66 (55–76)§
Gilman 2006	Irland, Cork 51.89	All seasons	ELISA	IBD (CD/UC)	73 (47/26)	ns	N/A	CD: 36.0 (11.6) UC: 40.5 (11.0)	CD: 71.6 (33)§ UC: 63.9 (20.5)§
				Non-IBD	73	ns	N/A	CD ctr: 35.9(11.5) UC ctr: 40.3(11.2)	CD ctr: 133 (69.2)§ UC ctr: 109 (50.8)§
Duggan 2004	Irland, Cork 51.89	September–October 2002	ELISA	IBD (CD/UC)	44 (44/−)	15/29	N/A	36.9 (11)	75 (28.7)§
				Non-IBD	44	15/29	N/A	36.7 (11)	105.3 (55.5)§
Prosnitz 2013	Pennsylvania, Philadelphia 40.00	All seasons	RIA	IBD (CD/UC)	78 (78/−)	44/34	Black-10%, Non-Black-90%	12.7 (2.8)	Black: 10.5 (4.6)* Non-Black: 23.5 (9.2)*
				Non-IBD	221	112/109	Black-28%, Non-Black-72%	13.5 (4.4)	Black: 15.8 (7.9)* Non-Black: 25.3 (8.7)*
Laakso¥ 2012	Finland, Helsinki 60.17	June 2004–December 2005	HPLC	IBD (CD/UC)	80 (49/28)	37/43	N/A	14.9 (5.1–20.1)	N/A
				Non-IBD	80	37/43	N/A	14.4 (7.4–18.8)	N/A
Tajika 2004	Japan, Nagoya 35.16	December 2001–January 2002	CPBA	IBD (CD/UC)	44 (33/11)	31/13	Asian-100%	CD: 37.6 (7.5) UC: 47.6 (12.4)	CD: 15.2 (6.5)* UC: 17.6 (4.7)*
				Non-IBD	15	8/7	Asian-100%	37.7 (10)	16.9 (5.2)*
De Bruyn 2014	Netherlands, Amsterdam 52.37	September–December 2012	CLIA	IBD (CD/UC)	101 (101/−)	31/70	Caucasian-83%	41 (30–50)	51.6 (26.6)§
				Non-IBD	41	8/33	Caucasian-88%	28 (24–39)	60.8 (27.6)§
Veit 2014	Massachussets, Worcester 42.27	January 2007–June 2013	CLIA	IBD (CD/UC)	58 (40/18)	31/27	White-88%, Black-3%, Multiethnicity-3%, Unknown-5%	CD: 16.6 (2.2) UC: 16.1 (1.9)	CD: 61.69 (24.43)§ UC: 53.26 (25.51)§
				Non-IBD	116	49/67	White-80%, Black-8%, Multiethnicity-5%, Unknown-4%	14.5 (4.3)	65.32 (27.97)§
Dumitrescu 2014	Romania, Iasi 47.13	March 2011–June 2012	HPLC	IBD (CD/UC)	47 (14/33)	25/22	N/A	CD: 36 (9) UC: 42 (14)	24 (10)¶
				Non-IBD	94	50/44	N/A	42 (12)	31 (13)¶
Salacinski 2013	Pennsylvania, Pittsburgh 41.94	October–November	HPLC	IBD (CD/UC)	19 (19/−)	9/10	N/A	44.16 (10.28)	32.0 (9.1)*
				Non-IBD	19	9/10	N/A	41.68 (11.19)	35.3 (11.1)*

¹degrees of latitude as reported by the included studies or, if data not available, derived from the region where research was conducted (see text)

N/A = not available

^§circulating 25(OH)D expressed as nmol/l

^*circulating 25(OH)D expressed as ng/ml

^¶circulating 25(OH)D expressed as mcg/l

^¥winter values were used (IBD: n=41; non-IBD: n=76).

RIA: radio-immuno assay

ECLA: electro-chemiluminescence assay

ELISA: enzyme linked immuno-sorbent assay

CPBA: competitive-protein binding assay

HPLC: high-performance liquid chromatography

NZ: New Zealander

Assessment of study quality

Quality of included articles was assessed using the Newcastle-Ottawa Scale for case-control studies⁵⁷. The following items were assessed:

1. Adequacy of definition of cases: IBD cases had to be confirmed by clinical, histological and radiographic confirmation

2. Representativeness of the defined cases

3. Criteria used for selection of controls

4. Comparability of cases and controls. Age/sex were considered the most important matching factors, and an additional star was awarded if the study controlled for at least one additional confounder such as race, BMI, sun exposure, vitamin D supplementation, smoking, socioeconomic status or absence of bone pathology

5. Method of ascertainment of exposure, i.e. assessment of vitamin D levels in cases and controls.

Statistical Analysis

Using a random effects model, studies were pooled to calculate the odds of vitamin D deficiency in the IBD group in comparison to the control group. We used adjusted ORs whenever available, otherwise dichotomous data were used to calculate unadjusted ORs. Heterogeneity between studies was assessed by the I² statistic as defined by the Cochrane handbook for systematic reviews⁵⁸. Accordingly, an I² value of 50% or more was considered to represent a substantial heterogeneity. Review manager 5 was used to generate forest plots, and generated funnel plots were used to test for publication bias⁵⁸. Since studies reported the prevalence of vitamin D deficiency by specific groups, namely adults or children, we conducted stratified meta-analyses based on these groups. We also conducted stratified analysis based on the two IBD subtypes, CD and UC. Since latitude affects sunlight exposure and thereby serum vitamin D levels as well, we decided to perform meta-regression using latitude as a moderator. The ‘metafor’ package⁵⁹ in R software was used to perform random-effects meta-regression and plot the graph⁶⁰. We also performed sensitivity analysis based on two different cut-offs for vitamin D deficiency (i.e. ≤20 ng/ml and <15 ng/ml).

RESULTS

Out of 816 citations, 14 articles with a total of 1891 patients met our predefined inclusion and exclusion criteria. The study flow is presented in Figure 1. The descriptive characteristics of the included studies are presented in Table 1. Women comprised 50.7% of the total IBD population. Thirteen studies reported on previous surgery and 22% of 788 IBD patients had had a history of bowel resection. Thirteen studies reported on vitamin D supplementation and 24.3% of 862 IBD cases and 14.3% of 913 controls were on vitamin D supplements (Supplementary Table 1). Data on disease location and extent and seasonality are reported in Supplementary Table 2.

Figure 1.

PRISMA flow diagram.

The methodological quality of these studies based on the Newcastle-Ottawa scale is described in Supplementary Table 3. Three studies matched for age/sex and at least one other a priori defined confounding variable, while 8 studies only matched for age/sex. Studies had a quality score between 6 and 9 stars.

Description of excluded studies

The study by Alkhouri et al. was excluded as a higher cut-off for vitamin D deficiency was used (30 ng/ml)⁴⁷. The study by McCarthy et al. was excluded as the prevalence of vitamin D deficiency was examined in two different seasons resulting in unit-of-analysis errors when combined²⁹. The study by Sylvester et al. was excluded, as events were not observed in the examined groups³². Two studies^{42, 43} where the control group participants comprised of persons with functional gastrointestinal disorders were excluded. Three other studies^{30, 33, 51} that reported extractable data for only one of the two groups, i.e. either for cases or controls only, were also excluded.

Results of the meta-analysis

Vitamin D deficiency in IBD cases vs. non-IBD controls

Meta-analysis of 14 studies including 1891 patients (938 IBD cases and 953 controls) showed that patients with IBD had 64% higher odds of vitamin D deficiency when compared to controls (OR = 1.64; 95% CI: 1.30, 2.08; p<0.0001) (Figure 2). Heterogeneity between studies was low (I² = 7%). We did not assess for publication bias using funnel plots due to the lack of sufficient studies.

Figure 2.

Meta-analysis of Vitamin D deficiency in IBD cases compared to non-IBD controls. Stratified analysis based on adult versus pediatric participants.

Stratified analysis based on adult vs. pediatric participants

Of the 14 included studies, 11 reported on adult participants, whereas 3 were on pediatric participants. Therefore, we conducted a stratified meta-analysis based on age (adult vs. pediatric). Meta-analysis of the 11 studies reporting on adults showed that 761 adult participants with IBD had nearly double the odds of vitamin D deficiency when compared to 540 controls (OR = 1.81; 95% CI: 1.37, 2.40; I² = 1%; p < 0.0001). Meta-analysis of the 3 studies reporting on children showed that 177 pediatric cases with IBD had a higher, though not significant odds of vitamin D deficiency compared to 413 non-IBD controls (OR = 1.36; 95% CI: 0.91, 2.04; I² = 18%; p = 0.14) (Figure 2).

Vitamin D deficiency in CD and UC cases vs. controls

We also conducted meta-analysis of studies that reported vitamin D deficiency by type of IBD. Meta-analysis of 12 studies reporting on vitamin D deficiency in CD showed that 570 participants with CD had a significantly higher odds of vitamin D deficiency compared to 778 controls (OR = 1.63; 95% CI: 1.24, 2.13; p = 0.0004) (Figure 3). Heterogeneity between studies was not detected (I² = 0%). Meta-analysis of 7 studies reporting on prevalence of vitamin D deficiency in UC showed that 177 participants with UC had more than double the odds of vitamin D deficiency compared to 362 controls (OR = 2.28; 95% CI: 1.18, 4.41; p = 0.01) (Figure 4). Heterogeneity between studies was moderate (I² = 41%).

Figure 3.

Stratified meta-analysis of Vitamin D deficiency in CD cases compared to controls.

Figure 4.

Stratified meta-analysis of Vitamin D deficiency in UC cases compared to controls.

Meta-regression using latitude as a moderator

Whenever latitude data was available in studies, we extracted this information. When studies did not provide latitude data, we used the region of the hospital where the study was conducted (or using the region of the source of cases and controls) to obtain the latitude as we felt that this would be a reasonable approximation of the true latitude. We performed meta-regression analysis on the main meta-analysis (IBD vs. controls), which showed that latitude had no effect on the association between IBD and serum vitamin D status (p = 0.34) (Supplementary Figure 1).

Sensitivity analysis based on Vitamin D deficiency cut-offs

Out of the 14 studies, 5 studie^{27, 35, 40, 46, 50} reported on vitamin D deficiency using a more stringent cut-off of 15 ng/ml⁶¹. Therefore, we conducted sensitivity analyses to check if the exclusion of these studies would change the effect estimate. Exclusion of these 5 studies from the meta-analysis did not substantially influence the summary estimate (OR = 1.65; 95% CI: 1.25, 2.19; I² = 11%; p = 0.0004).

DISCUSSION

Our meta-analysis shows that vitamin D deficiency is significantly higher in IBD patients, as well as its subtypes, when compared to non-IBD subjects. UC, in particular, was found to be associated with more than double the odds of vitamin D deficiency compared to the absence of the disease. Stratified analysis based on age showed that adult IBD patients had nearly twice the odds of vitamin D deficiency when compared to healthy adult controls, whereas a similar comparison in the pediatric population showed a higher odds of vitamin D deficiency in the presence of IBD, but didn’t reach statistical significance, likely due to a small sample size. Latitude did not seem to moderate the association between IBD and serum vitamin D. Sensitivity analysis after excluding studies that used a lower cut-off of 15 ng/ml did not substantially influence the pooled effect estimate. All studies were of moderate-high quality as assessed by the Newcastle-Ottawa scale, with a rating between 6 and 9 stars.

Prior studies^62–64 have reviewed the scientific evidence regarding the role of vitamin D in IBD and concluded that crucial aspects of this relationship are still to be elucidated. In particular, whether effective preventive or therapeutic strategies with vitamin D supplementation can be adopted in IBD, and how they should be conducted to obtain meaningful clinical results, still remains an open question. Therefore, we believe that our meta-analysis evaluating vitamin D status in a relatively large cohort of 1891 patients might provide useful information for future investigations.

Hypovitaminosis D in IBD may have several explanations. It is of significance that both conditions are associated with common environmental factors such as air pollution, industrialization, high latitude, and seasonality¹³. Hypovitaminosis D in the context of IBD may be the consequence of malabsorption, due to bowel inflammation or surgical resection²⁴; reduced outdoor activities with less UV exposure, as a consequence of IBD symptomatology⁶³; or increased uptake of vitamin D by inflammatory cells in the affected sites⁴⁴. Consistent with the latter point, enhanced 25(OH)D uptake has been demonstrated in peripheral monocyte/macrophages from HIV-infected patients with hypovitaminosis D after in vitro stimulation with the viral envelope protein gp120 or lipopolysaccharide (LPS)⁶⁵. Low vitamin D levels may also negatively affect the gut barrier and immune system functions, thus potentially impacting IBD onset and progression. In particular, vitamin D has been demonstrated to inhibit several pro-inflammatory pathways^{66, 67}, modulate autophagy⁶⁷, decrease oxidative stress⁶⁸, reduce white cells differentiation and activation^{67, 69, 70}, and enhance expression of tight junctions in the intestinal epithelium, thereby influencing mucosal permeability and tissue integrity²¹. In vivo studies show that vitamin D receptor (VDR) knockout mice are more susceptible to bowel inflammation⁷¹, and genetic studies have also linked VDR and vitamin D binding protein (VDBP) polymorphisms to IBD^{72, 73}.

The Nurses’ Health Study, a large longitudinal study of 72,719 adult women in the United States followed from 1986 to 2008 showed that higher pre-diagnosis vitamin D levels were associated with a significant reduction in risk of incident CD and a nonsignificant reduction in risk of incident UC in the examined cohort²⁶. A retrospective study of 504 IBD patients not only demonstrated the high prevalence of vitamin D deficiency (defined as serum vitamin D<20 ng/ml) in the study population (~50%), but also showed that vitamin D deficiency is independently associated with greater disease activity, as well as lower quality-of-life in CD patients⁷⁴. Low plasma 25(OH)D levels have been shown to be associated with an increased risk of IBD-related surgery, as well as increased hospitalizations⁷⁵. Vitamin D might also enhance the durability of anti-TNF therapy in IBD and its insufficiency has been found to be associated with earlier cessation of anti-TNFα therapy, particularly in CD⁷⁶. A recent randomized, double-blind placebo-controlled study on 94 CD patients with inactive disease, assigned to either 1200 IU vitamin D3 daily or placebo for 12 months, showed that the IBD relapse rate had a trend towards being lower in the treatment group (p = 0.06)⁷⁷. Other authors have observed short-term beneficial effect on disease activity in CD patients treated with vitamin D, and this was particularly true for those patients receiving the active form of the vitamin⁷⁸. Similarly, a recent prospective randomized controlled trial on 18 patients with UC and hypovitaminosis D showed that vitamin D3 supplementation improved quality-of-life and reduced UC disease activity, especially at higher doses (4000 IU daily vs. 2000 IU daily)⁷⁹.

Our meta-analysis demonstrated an association between IBD and low serum vitamin D levels only in adults, but not in the pediatric population. There could be several reasons for this, including, but not limited to shorter disease duration, more frequent outdoor activities leading to increased sunlight exposure, and greater use of vitamin D fortified foods when compared to adults. Furthermore, a physiological decline in cutaneous levels of the vitamin D precursor, 7-dehydrocholesterol, associated with aging, may profoundly affect the skin’s vitamin D production capability, particularly when sun exposure is limited, which might explain the significantly higher vitamin D deficiency in adults⁸⁰.

Our meta-analysis produced an interesting finding in that UC patients had a higher odds of vitamin D deficiency than CD patients. This is likely a sample size issue as there were fewer total patients and fewer events in the UC meta-analysis in comparison to the CD meta-analysis. However, there might be other pathophysiological mechanisms; particularly, alterations in the vitamin D metabolic pathway that could potentially explain our findings. These include vitamin D activation and deactivation processes mediated by cytochromes (CYP2R1 and CYP27B1 for activation and CYP24A1 for deactivation), its transportation in blood and across cell membranes mediated by proteins (DBP, megalin/cubulin) and its genetic effects mediated by cellular complexes such as VDR/RXR and transcriptional activators/repressors⁸¹. In addition, genetic polymorphisms^{25, 73, 82} and disease related impairments (altered protein turnover⁸³, protein-losing enteropathies^{84, 85} and dysbiosis^{86, 87}) might also modify the association between IBD and serum vitamin D levels.

Our meta-regression analysis seemed to indicate that latitude does not moderate the association between IBD and vitamin D levels. However, it would be simplistic to dismiss this association as the relationship between latitude, vitamin D levels and IBD is likely more complex. Secondly, the effect of latitude could also not be measured precisely because most studies did not provide the latitude of the region where they conducted the study. Nevertheless, we felt that using the region of the hospital where the studies were conducted (or using the region of the source of cases and controls) was a reasonable approximation of the true latitude. Most importantly, because of the variable nature of seasonality data (as different studies were conducted in different seasons), the effect of latitude, if any, might have been suppressed. Finally, it should be noted that meta-regression itself typically has low power to detect statistically significant relationships⁸⁸ and hence, the lack of such a relationship should be interpreted with caution.

Despite considerable diagnostic and therapeutic achievements in recent years, IBD still represents a challenge in terms of treatment⁸⁹. The available therapies are not curative and their side effects may considerably impact patients’ general health. Current drug research is therefore highly oriented towards the study of novel therapies that target specific pathogenetic pathways⁹⁰. In parallel with disease-modifying agents, there are promising results from other approaches aimed at modulating the gut environment. Intestinal microbiota and the innate immune system have therefore become interesting targets for complementary therapies, such as probiotic formulations. Vitamin D as a therapeutic agent, in particular, has also shown promise in lowering relapse rates and bettering quality-of-life in IBD, but larger, well-designed randomized controlled trials investigating the long-term effectiveness of vitamin D in IBD are needed to substantiate these findings from early trials.

This meta-analysis had several strengths. First, the number of included studies (n=14) provided a sufficiently large sample size. Second, study quality was systematically assessed using the Newcastle-Ottawa scale⁵⁷ and the included studies were of reasonably high quality. Third, subgroup and sensitivity analyses were conducted, the results of which were congruent with our findings in the main meta-analysis. Finally, heterogeneity was moderate or not present in all the meta-analyses we conducted. Our study was not without limitations. The entire body of evidence was observational, which is often biased due to unmeasured confounders. Included studies, with the exception of one³⁹, did not provide baseline adjusted data; therefore, in the absence of adjusted measures of risk, unadjusted measures (unadjusted ORs) were used, which limits generalizability of our results. In that study, even after adjusting for several confounders like age, sex, race, season, and vitamin D supplementation, the odds of vitamin D deficiency was still twice as high in IBD cases in comparison to healthy controls. Few studies reported stratified results on vitamin D deficiency based on important parameters such as surgery, disease location or disease activity and hence, stratified meta-analyses based on these criteria were not possible. Different 25(OH)D assays were also used in the studies (table 1); consequently, inter-assay variability is possible, due to different sensitivity of each assay method to vitamin D2 or D3.

In summary, this meta-analysis shows that IBD is associated with a higher odds of vitamin D deficiency compared to the absence of the disease. Further studies, particularly longitudinal studies in different settings, are needed for corroborating our findings. Well-designed, large randomized controlled trials using variable doses of vitamin D supplementation in different IBD statuses can help us better understand the therapeutic significance of vitamin D in IBD.

Supplementary Material

Legacy Manuscript File

Supplemental methods: Search strategies. PubMed search strategy; COCHRANE search strategy; EMBASE search strategy; CINAHL search strategy.

Supplementary Table 1: Use of vitamin D supplementation, smoking status, mean BMI, mean disease duration, previous IBD-related surgery, disease activity, and use of medications as reported in the included studies.

Supplementary table 2: Disease location and extent, seasonality, and tanning habits in the included studies.

Supplementary Table 3: Methodological quality of the included studies based on the Newcastle-Ottawa Quality Assessment Scale for case-control studies.

Supplementary Figure 1_1

Supplementary Figure 1: Meta-regression analysis on the association between IBD and serum vitamin D levels using latitude as a moderator. Red solid line represents the linear model, whereas blue dashed line represents the polynomial fractional best fitting model. No interaction was found between serum vitamin D levels and latitude.