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Review article: vitamin d and inflammatory bowel diseases

Alimentary Pharmacology and Therapeutics Review article: vitamin D and inflammatory bowel diseases V. P. Mouli* & A. N. Ananthakrishnan†,‡ *Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
† Harvard Medical School, Boston, Vitamin D is traditionally associated with bone metabolism. The immuno- ‡Division of Gastroenterology, logical effects of vitamin D have increasingly come into focus.
Massachusetts General Hospital,Boston, MA, USA.
AimTo review the evidence supporting a role of vitamin D in inflammatory Correspondence to: bowel diseases.
Dr A. N. Ananthakrishnan, Crohn's &Colitis Centre, Massachusetts General Hospital, 165 Cambridge Street, 9th A comprehensive search was performed on PubMed using the terms Floor, Boston, MA 02114, USA.
crohn's disease' ‘ulcerative colitis' and ‘vitamin D'.
ResultsVitamin D deficiency is common in patients with inflammatory bowel dis- eases (IBD) (16–95%) including those with recently diagnosed disease. Evi- Submitted 27 September 2013 dence supports immunological role of vitamin D in IBD. In animal models, First decision 15 October 2013 Resubmitted 26 October 2013 deficiency of vitamin D increases susceptibility to dextran sodium sulphate Accepted 28 October 2013 colitis, while 1,25(OH)2D3 ameliorates such colitis. One prospective cohort EV Pub Online 17 November 2013 study found low predicted vitamin D levels to be associated with anincreased risk of Crohn's disease (CD). Limited data also suggest an associ- This commissioned review article wassubject to full peer review and the ation between low vitamin D levels and increased disease activity, particu- authors received an honorarium from larly in CD. In a large cohort, vitamin D deficiency (<20 ng/mL) was Wiley on behalf of AP&T.
associated with increased risk of surgery (OR 1.8, 95% CI 1.2–2.5) in CDand hospitalisations in both CD (OR 2.1, 95% CI 1.6–2.7) and UC (OR 2.3,95% CI 1.7–3.1). A single randomised controlled trial demonstrated thatvitamin D supplementation may be associated with reduced frequency ofrelapses in patients with CD compared with placebo (13% vs. 29%,P = 0.06).
ConclusionThere is growing epidemiological evidence to suggest a role for vitamin Ddeficiency in the development of IBD and also its influence on diseaseseverity. The possible therapeutic role of vitamin D in patients with IBDmerits continued investigation.
Aliment Pharmacol Ther 2014; 39: 125–136 ª 2013 John Wiley & Sons Ltd


V. P. Mouli and A. N. Ananthakrishnan ciation with pathogenesis and natural history of these Ulcerative colitis (UC) and Crohn's disease (CD) consti- tute chronic idiopathic inflammatory bowel diseases(IBD). The key underlying pathogenic mechanisms for both diseases is a dysregulated host immune response to A comprehensive literature search on Pubmed was con- commensal intestinal flora in genetically susceptible indi- ducted using the following search terms: ‘Crohn's dis- viduals.1, 2 Known genetic variants incompletely explain ease' ‘ulcerative colitis' and ‘vitamin D' to identify the variance in disease incidence, suggesting a strong role relevant English language articles published between for environmental factors, supported by epidemiological 1966 and 2013. In addition, bibliographies of the retrieved articles were searched to identify additional rel- Vitamin D has long been recognised as a major regu- evant articles.
lator of calcium and phosphorus metabolism and key inmaintaining bone health.5–7 However, several recent studies have yielded new insights into the role of vitaminD in various other physiological processes. In particular, Vitamin D synthesis vitamin D appears to play important roles in immune The main source of vitamin D is endogenous production regulation, particularly involving the innate immune in the skin where ultraviolet B energy in the sunlight system, cardiovascular and renal physiology, and devel- converts 7-dehydrocholestrol to cholecalciferol (vitamin opment of cancer.6 Importantly, an increasing body of D3) (Figure 1).5, 14 Dietary contribution to vitamin D literature supports an important role of vitamin D in the status includes foods such as egg yolk, beef liver, cod pathogenesis as well as potential therapy of IBD.8–13 The liver oil, fatty fish, fortified milk and milk products.5 current review examines the evidence linking vitamin D Vitamin D from the endogenous production on exposure to IBD, both through its effect on bone health and asso- to sunlight as well as that absorbed from diet is 7-dehydro cholesterol UV exposure (Sunlight) Dietary vitamin D Major circulating form 25-hydroxy vitamin D3 (bound to vitamin D bindingprotein) + Parathormone (PTH) (proximal tubules of kidney) – Fibroblast growth factor 23 Figure 1 Metabolism of Biologically active form 1,25-dihydroxyvitamin D3 Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd Review: vitamin D and inflammatory bowel diseases metabolised within the liver to 25-hydroxyvitamin D (25 related to the underlying bowel disease, while others are (OH)D) by the enzyme vitamin D 25-hydroxylase. 25 in common with the non-IBD population. These include (OH)D is the major circulating form of vitamin D and is inadequate exposure to sunlight either related to lifestyle also used to determine the status of vitamin D in clinical or persistent symptoms of active disease restricting phys- practice. 25(OH)D is biologically inactive and is activated ical activity, inadequate dietary intake due to symptoms within the proximal tubules of nephrons in the kidneys of bowel disease, impaired absorption, impaired conver- by the enzyme 25-hydroxyvitamin D-1alpha-hydroxylase sion of vitamin D to its active products, increased catab- (also known as CYP27B1) to 1,25-dihydroxyvitamin D olism and increased excretion.5, 7 That inadequate (1,25(OH)2D). The renal synthesis of the active biologi- exposure to sunlight is an important cause of vitamin D cal product of vitamin D (1,25(OH)2D) is regulated by deficiency in patients with IBD is supported by evidence.
various factors including serum calcium and phosphorus Several studies, particularly from northern climates, have levels, parathormone and fibroblast growth factor 23.15 consistently demonstrated an association between vita-min D deficiency and winter season, a period of likely Prevalence of vitamin D deficiency in IBD low sunlight and UVB exposure.13, 21, 22 Insufficient die- While it is relatively easy to ascertain macronutrient tary consumption also contributes to low vitamin D in deficiency clinically, micronutrient deficiency may not some patients with IBD. In a detailed nutritional survey always be clinically evident and usually requires labora- of 126 IBD patients, inadequate vitamin D consumption tory testing. The best measure of an individual's vitamin was found in 36% of patients and suboptimal serum D status is serum 25(OH)D.5, 7, 16 Serum 25(OH)D lev- vitamin D levels were found in 18% of patients.23 Oral els of less than 20 ng/mL (50 nmol/L) indicate vitamin intake correlated significantly with serum levels in CD D deficiency. Serum 25(OH)D levels between 21 and and with all IBD in remission.23 While other small stud- 29 ng/mL (52.5 and 72.5 nmol/L) represent vitamin D ies suggested no correlation between dietary vitamin D insufficiency, while levels between 30 and 100 ng/mL (75 intake and serum 25(OH)D in CD patients, they may and 250 nmol/L) represent normal values.5, 7, 16 Several have been limited by lack of statistical power.24 studies have reported a high prevalence of vitamin D Fats and fat-soluble vitamins are absorbed after emul- deficiency in patients with IBD, although it has not been sification by bile acids. The bile acid pool is maintained universally established that this rate is higher than in by an enterohepatic circulation occurring from the ter- other chronic illnesses, inflammatory diseases, or even minal ileum. Interruption of the enterohepatic circulation health individuals in that region (Table 1). Levin et al.
(e.g., by terminal ileal resection) could theoretically con- reported vitamin D deficiency in 19% and insufficiency tribute to vitamin D deficiency. However, clinical data in in 38% of children with IBD in a cohort predominantly support of this are conflicting. Terminal ileal resection consisting of patients with CD.17 In contrast, Alkhouri was associated with vitamin D deficiency in some stud- et al. reported that the prevalence of vitamin D defi- ies.25, 26 In a study of 12 CD patients who underwent ciency in children with IBD (62%) was lower than the terminal ileal resection, absorption of vitamin D was rate in their controls (75%).18 In a large, retrospective reduced with the decline in absorption correlating with study of adult patients with IBD from Wisconsin (101 the length of the resected segment. However, other stud- UC, 403 CD), nearly 50% of the patients had vitamin D ies failed to identify an effect of ileal resection or active deficiency and about 11% of patients had severe vitamin disease.19 Malabsorption may theoretically contribute to D deficiency,19 a frequency estimate that is consistent low vitamin D in CD patients as vitamin D is absorbed with other published IBD cohorts.13 While most studies in the proximal part of small intestine. The prevalence of have examined prevalence in patients with well estab- vitamin D deficiency is higher in CD patients with upper lished IBD, deficiency of vitamin D does not appear to gastrointestinal tract involvement.27 However, when be consequent to long-standing disease alone. In a absorption of vitamin D was specifically tested, only 10% cohort of newly diagnosed IBD patients from Manitoba of patients with CD had decreased absorption of vitamin providence in Canada, only 22% were found to have suf- D compared to 50% of patients with pancreatic insuffi- ficient levels of vitamin D.20 ciency.28 There also appears to be a wide variation inabsorption of vitamin D in patients with CD even in Causes of vitamin D deficiency in patients with IBD those with quiescent disease.29 Protein-losing enteropa- There are several factors contributing to vitamin D defi- thy occurs in some patients with IBD. As vitamin D and ciency in patients with IBD, some causes specifically its metabolites circulate predominantly as bound forms Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd V. P. Mouli and A. N. Ananthakrishnan Table 1 Prevalence of vitamin D deficiency in unselected cohorts of patients with inflammatory bowel diseases 65% of patients had low serum 25(OH)D25% had levels below 10 ng/mL 27% of CD patients had 25(OH)D levels <30 nmol/L 15% of UC patients had 25(OH)D levels <30 nmol/L Mean 25(OH)D was lower in IBD patients (18.7 mcg/L) compared with controls (28.5 mcg/L) (P < 0.05) 16% of CD patients had vitamin D < 38 nmol/L 22% had 25(OH)D levels <40 nmol/L8% had 25(OH)D levels <25 nmol/L 27% of CD patients were deficient (25(OH)D < 10 ng/mL) compared to During late-summer, 5% of controls and 18% of CD patients were deficient During late-winter, 25% of controls and 50% of CD patients were deficient 50% were vitamin D deficient during winter (<50 nmol/L) and 19% were deficient during summer Prevalence of vitamin D deficiency (25(OH)D < 15 ng/mL) was 35% 88% had serum 25(OH)D levels below 75 nmol/L Mean 25(OH) levels were lower in CD patients (11 ng/mL) compared with those with UC (20 ng/mL) (P < 0.001) 25(OH)D levels were lower in CD patients (16 ng/mL) compared with controls 50% of patients had 25(OH)D < 30 ng/dL, 11% had levels below 10 ng/dL Vitamin D insufficiency (<20 ng/mL) was seen in 31% of patients with CD and 28% of UC patients 19% of patients were deficient in vitamin D (<51 nmol/L) 37% had vitamin D deficiency 63% of patients with CD were deficient (<50 nmol/L) 39% of the entire cohort had low vitamin D (<50 nmol/L); this was more frequent in 43% of CD and 37% of UC patients 30% of patients with CD had levels below 37.5 nmol/L compared to 37% of controls 95% of patients had deficient vitamin D levels (25(OH)D < 30 ng/mL) 28% had insufficient (20–30 ng/mL) and 32% had deficient (<20 ng/mL) levels 62% of patients had low vitamin D levels compared to 75% of controls IBD, inflammatory bowel diseases; CD, Crohn's disease; UC, ulcerative colitis, IC, indeterminate colitis.
* Paediatric cohorts.
to plasma vitamin D binding protein (DBP), the loss of tion study of nearly 30 000 individuals of European des- DBP along with the bound vitamin D could be an addi- cent, variants at three loci near the genes involved in tional plausible mechanism of vitamin D deficiency, par- cholesterol synthesis, vitamin D hydroxylation and vita- ticularly in those with severe disease. Finally, recent min D transport were associated with vitamin D insuffi- studies have suggested that genetic variants contribute ciency.30 The contribution of such genetic variants to both to development of vitamin D insufficiency and vitamin D status in patients with IBD has not yet been response to supplementation. In a genome-wide associa- Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd Review: vitamin D and inflammatory bowel diseases Role of vitamin D in bone turnover and mineral Vitamin D and innate immunity Vitamin D receptor is ubiquitously expressed in several Vitamin D helps to maintain calcium homoeostasis by human tissues including immune cells, keratinocytes, acting on the small intestine epithelium and osteoblasts.
pancreatic beta-cells, cardiac myocytes, central nervous 1,25(OH)2D acts mainly through the nuclear vitamin D system, renal tubules and the intestine. Many of these receptor (VDR), which forms a heterodimer with a reti- tissues also contain the enzymes for conversion of vita- noid X receptor, binds to the vitamin D response ele- min D to its active metabolites, supporting a widespread ment and recruits co-activators and enzymes with extraskeletal role of vitamin D.45 Vitamin D appears to histone acetylation activity, thereby regulating gene have an important role in innate immunity as well as expression.10, 31–33 25(OH)D interacts with the VDR in adaptive immunity.10, 33 It acts as a key link between the small intestinal epithelium and augments the toll-like receptor (TLR) activation and antibacterial absorption of calcium and phosphorus from the small responses in innate immunity. Activation of TLRs on intestine.34 1,25(OH)2D also interacts with the VDR on macrophages by a Mycobacterium tuberculosis derived osteoblasts and increases the surface expression of lipopeptide leads to upregulation of conversion of 25 Receptor Activator for Nuclear Factor jB ligand (OH)D to the active 1,25(OH)2D, upregulation of VDR (RANKL), which, after binding with RANK on pre-os- expression and induction of downstream targets of VDR teoclasts, converts them into osteoclasts.35, 36 Osteoclasts including cathelicidin, an antimicrobial peptide.46 1,25 function in dissolution of bone matrix and mobilise cal- (OH)2D also acts synergistically with activated NF-jB to cium stores into circulation, thus helping in the mainte- induce expression of b-defensin 4 gene.47 Supplementa- nance of calcium homoeostasis. Dissolution of bone tion with vitamin D in individuals with insufficient matrix by osteoclasts is an essential part of bone serum levels of 25(OH)D leads to induction of cathelici- din, thus enhancing the innate immune defences against Vitamin D deficiency leads to reduction in serum lev- microbial agents.48 els of ionised calcium leading to secondary hyperpara- Autophagy plays an important role in the pathogene- sis of CD, and several lines of evidence support the disproportionate increase in bone resorption, osteopenia hypothesis that the effect of vitamin D on IBD patho- and osteoporosis.37 In children, vitamin D deficiency genesis may be through this pathway. 1,25 (OH)2D helps results in poor mineralisation of the epiphyseal growth in autophagy in macrophages by enhancing the co-locali- plates leading to bone deformities and stunted longitudi- sation of pathogen harbouring phagosomes with auto- nal growth, which are the typical features of rickets. In adults with vitamin D deficiency, there is defective min- Similar induction of autophagy by vitamin D has also eralisation of the newly formed bone collagen matrix been demonstrated in several models of cancer cell lines.
resulting in osteomalacia which manifests as bone pain, Vitamin D3 has been hypothesised to regulate autophagy fractures and proximal muscle weakness.5, 7, 16 at several steps.50 Increased calcium absorption mediated There is a high prevalence of metabolic bone disease by the effect of vitamin D3 on the VDR can activate in patients with IBD. The prevalence of osteopenia autophagy through various calcium-dependent kinases ranges from 23% to 67% and osteoporosis from 7% to and phosphates, while vitamin D3 can itself downregu- 35% among patients with CD or UC.38–40 Active late the expression of mTOR, a negative regulator of inflammatory disease is a strong risk factor for low autophagy.50, 51 Vitamin D3 can also induce autophagy bone mineral density (BMD) in patients with IBD, with through increasing beclin-1 expression, a regulatory of BMD improving with increasing duration of remis- autophagy, and activating the PI3K signalling path- sion.41 This is supported by the known effect of TNF-a way.50–52 Vitamin D has been long used to treat myco- and other pro-inflammatory cytokines like IL-1, IL-6, infections46, 53, 54 IL-17 in activating osteoclasts.42, 43 In addition, gluco- supplementation may reduce likelihood of tuberculin corticoids use is an important risk factor for bone loss conversion.55, 56 In a randomised controlled trial, vita- in patients with IBD.39 However, the data linking vita- min D supplementation was associated with a reduced min D deficiency and impaired BMD in patients with rate of development of a positive tuberculin reaction, IBD have been conflicting, with some studies support- suggesting a protective effect against tuberculosis infec- tion in an endemic population.56 Low serum vitamin D effect.20, 39, 44 is also associated with reduced immunoreactivity to an Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd V. P. Mouli and A. N. Ananthakrishnan anergy panel, and supplementation with vitamin D in link between polymorphisms in the VDR gene region on anergic individuals with deficient levels restored delayed chromosome 12 to development of IBD,10, 68–70 although not all cohorts have yielded positive results. Variations Vitamin D also plays a role in preventing over-activa- in the DBP were also found to be associated with IBD.71 tion of pro-inflammatory responses. 1,25(OH)2D within Few studies have been able to examine the association the monocytes dose-dependently inhibits lipopolysaccha- between vitamin D status and incident IBD directly. One ride (LPS)-induced p38 phosphorylation and production such study was using the Nurses' Health Study, a cohort of IL-6 and TNF-a in LPS-stimulated monocytes.58 Anti- of female registered nurses in the United States, followed gen-presenting cells, including dendritic cells, express prospectively using biennial questionnaires, and compre- VDR.59 The action of 1,25(OH)2D on dendritic cells hensive assessment of diet and supplement intake and leads to a tolerogenic phenotype, thus protecting against physical activity during the cohort follow-up timeline.8 autoimmune type 1 diabetes in adult non-obese diabetic The vitamin D status of the participants was defined mice.60 Maturation of dendritic cells is prevented by the using a validated regression model incorporating race, interaction of 1,25(OH)2D with VDR on the dendritic diet, physical activity and region of residence. Over a 22-year follow-up, higher predicted plasma 25(OH)D le-ves was associated with a significant reduction in the risk Vitamin D and adaptive immunity of incident CD, but not UC.8 Compared to women with Vitamin D receptor is expressed in mitotically active T the lowest quartile of plasma vitamin D, those in highest and B lymphocytes.62 1,25(OH)2D acts on helper T cells quartile had a reduced risk of CD (HR 0.54, 95% CI (TH cells), inhibits production of IL-2 and immunoglob- 0.30–0.99).8 For each 1 ng/mL increase in the plasma ulin synthesis by TH cell regulated B lymphocytes.63 Reg- level of 25(OH)D, there was a 6% relative risk reduction ulatory T cells (Treg), which are responsible for for CD. There was also an inverse association between maintenance of tolerance to self-antigens, are also modu- vitamin D intake from dietary sources and supplement lated by 1,25(OH)2D.10, 33 Although the effect of vitamin and the risk for incident UC; each 100 IU/day increase D on B cells is predominantly through modulation of in total vitamin D intake was associated with a 10% rela- T-cell function, recent evidence suggests that 1,25 tive reduction in the risk of UC.8 (OH)2D may also act directly on the B cells, affectingthe proliferation of activated B cells and inhibiting the Relationship of vitamin D levels and IBD disease generation of plasma cells and post-switch memory B In tune with its immune-modulating effects, vitamin Dmay also influence severity of inflammation in IBD.
Role of vitamin D in the immunopathogenesis of IBD Vitamin D deficiency causes more severe growth retarda- Several lines of epidemiological and laboratory evidence tion and weight loss and also led to higher mortality in support a role for vitamin D in the pathogenesis of IBD.
IL-10 KO mice colitis.72 Disease severity correlated with First, there is a north–south gradient in IBD incidence, a vitamin D status in mice with DSS-induced colitis; both gradient that parallels UV exposure and consequently local as well as endocrine effects of 1,25 (OH)2D affect vitamin D levels. In a study by Khalili et al., residence in the disease severity.73 TNF-a plays a central role in Southern latitudes of the United States, particularly at inflammation. 1,25(OH)2D reduces the severity of colitis age 30 was associated with a significantly lower risk of in IL-10 KO mice by downregulating several genes asso- CD [Hazard ratio (HR) 0.48, 95% CI 0.30–0.77] and UC ciated with TNF-a.74 When mice with tri-nitro-benzene (HR 0.62, 95% CI 0.42–0.90).65 This has been supported sulphonic (TNBS) acid-induced colitis were treated with by other studies that have modelled residential UV expo- a combination of corticosteroids and 1,25 (OH)2D, the sure and shown an inverse correlation between UV improvement in disease activity paralleled downregula- exposure and IBD incidence.66 Mice lacking VDR are tion of TH1 inflammatory cytokines profile as well as more susceptible to dextran sodium sulphate (DSS)-in- TH17 effector functions along with the promotion of TH2 duced mucosal injury compared with the wild type and regulatory T-cell profiles.75 mice.67 The disruption in the epithelial junctions was Data supporting a clinical association between vitamin severe in mice lacking VDR and 1,25(OH)2D preserved D deficiency and disease activity in IBD are conflicting the integrity of the tight junctions in Caco-2 cells mono- (Table 2). Neither El-Matary et al. nor Levin et al. found layers.67 Genetic epidemiological studies have suggested a a correlation between vitamin D levels and disease Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd Review: vitamin D and inflammatory bowel diseases Table 2 Observational studies of the association between vitamin D levels and outcomes in Crohn's disease andulcerative colitis negatively correlatedwith disease activity(correlationco-efficient Vitamin D levels were not associated with Vitamin D deficiency was associated with l ower HRQoL( 2.2, 95% CI increased diseaseactivity (1.1, 95%CI 0.4–1.7) in CD,but not in UC Vitamin D deficiency (<20 ng/mL) was increased risk ofsurgery (OR 1.8,95% CI 1.2–2.5) inCD and hospitalisationsin both CD (OR 2.1,95% CI 1.6–2.7) andUC (OR 2.3, 95%CI 1.7–3.1) Patients with low within 3 months of anti-TNF initiation increased risk of early cessation of CD, Crohn's disease; UC, ulcerative colitis; IBD, inflammatory bowel disease; HBI, Harvey Bradshaw index; PCDAI, Paediatric Cro-hn's disease activity index; PUCAI, paediatric ulcerative colitis activity index; SCCAI, simple clinical colitis activity index.
activity in cross-sectional studies of IBD cohorts.17, 76 In increased risk of surgery [Odds ratio (OR) 1.76; 95% CI contrast, a retrospective study by Ulitsky et al. concluded 1.24–2.51] and hospitalisation (OR 2.07; 95% CI 1.59– that vitamin D deficiency was associated with lower heal- 2.68) compared with those with sufficient levels.13 Fur- th-related quality of life and increased disease activity in thermore, CD patients who normalised their plasma 25 patients with CD, but not with UC.19 Overcoming some (OH)D had a reduced likelihood of IBD-related surgery of the limitations engendered by cross-sectional assess- (OR 0.56; 95% CI 0.32–0.98) compared with those who ment of vitamin D and disease severity, we examined remained deficient.13 prospectively the association between vitamin D defi-ciency and need for IBD-related surgery or hospitalisa- Does vitamin D have a role in the treatment of IBD tions in a large cohort of 3217 patients with at least one There have been several studies examining the role of vita- measurement of plasma 25(OH)D.13 We found that min D as a therapeutic agent for IBD in animal models.77 plasma 25(OH)D < 20 ng/mL was associated with an Vitamin D-deficient IL-10 KO mice spontaneously Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd V. P. Mouli and A. N. Ananthakrishnan develop an accelerated and severe form of IBD. However, of anti-TNF treatment, with a more pronounced effect when such mice were fed high-calcium diet and 1,25 on patients with CD.79 Miheller et al. compared the (OH)2D, they developed only mild disease.72 Both in therapeutic effects of 1,25(OH)2D and 25(OH) D in TNBS- and DSS-induced colitis models, administration of patients with CD with respect to disease activity and 1,25(OH)2D led to an improvement in disease activity and bone health.80 There was a significant improvement in addition of 1,25(OH)2D to a steroid regimen had a syner- disease activity as well as bone metabolism in the short- gistic effect and this combination most effectively reduced term at 6 weeks with 1,25(OH)2D but not 25(OH)D.80 the disease severity.78 A novel vitamin D analogue withanti-proliferative effects and limited calcemic activity was also found to alleviate disease activity in mice withDSS-induced colitis.78 There have been few human studies (Table 3). Jorgen- Despite emerging promising data, there exist several lim- sen et al. conducted a multicentre, randomised, dou- itations in the literature regarding the role of vitamin D ble-blind, placebo-controlled trial in Denmark evaluating in IBD pathogenesis. First, while consistently supported the efficacy of 1,25(OH)2D as a maintenance therapy in by experimental animal models, the association between CD patients in remission.12 One hundred and eight low pre-diagnosis vitamin D and increased risk of CD patients were randomised to receive either 1200 IU of has been examined in a single prospective cohort study 1,25(OH)2D with 1200 mg of calcium or 1200 mg of cal- that used a regression model to predict an individual's cium alone daily over 1 year. Nearly one-third of the vitamin D status. Ongoing analysis of pre-diagnosis study population had vitamin D deficiency defined as banked specimens from ongoing prospective cohorts as serum 25(OH)D levels <50 nmol/L. Only 13% of well as additional high-risk IBD cohorts will provide a patients in the vitamin D group relapsed during the more definitive answer to this hypothesis as randomised 1-year study period compared to 29% in the placebo controlled trials of vitamin D in prevention of IBD are group (P = 0.06).12 A second study by Zator et al. exam- unlikely to be feasible, given relatively low incidence of ined the influence of vitamin D status on response to disease in the general population, and need for large anti-TNF therapy. In a single centre cohort of patients numbers of participants and long follow-up. The associa- with CD and UC, plasma 25(OH)D levels measured tion between low vitamin D and increased disease within 3 months of initiation of anti-TNF therapy dem- activity, particularly in CD, is also supported primarily onstrated a significant inverse association with durability Table 3 Interventional studies examining the effect of vitamin D supplementation on disease activity in Crohn'sdisease and ulcerative colitis Number of patients Mean CDAI decreased patients treated with of cholecalciferol 104 CD patients in Relapse rate was lower clinical remission in patients treated with compared to placebo(29%) (P = 0.06) Vitamin D supplementation mild-to-moderate CD reduced CDAI scores from 230 to 118 (P < 0.0001), and improved health-related serum 25(OH)Dof 40 ng/mL CD, Crohn's disease; CDAI, Crohn's disease activity index.
Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd Review: vitamin D and inflammatory bowel diseases cross-sectional and unable to differentiate effect of vita- three regimens for 6 weeks: 2000 IU daily of vitamin D2; min D on disease activity from that of disease course on 2000 IU daily of vitamin D3; or 50 000 IU weekly of vitamin D levels, more recent analyses of large cohorts vitamin D2.83 It was found that the 6-week regimens of have been able to prospectively demonstrate an associa- 50 000 IU of vitamin D2 per week and 2000 IU of vita- tion between low vitamin D levels and increased risk for min D3 daily were superior to vitamin D2 2000 IU daily.
surgery and hospitalisations, particularly in CD.13 How- Whereas the regimen of 50 000 IU per week of vitamin ever, only one randomised controlled trial has examined D2 improved the serum 25(OH)D levels to more than the role of vitamin D in preventing relapse, but was also 32 ng/mL in 75% of patients, only 38% of patients who limited by small numbers.12 Effect of vitamin D supple- received 2000 IU of vitamin D3 daily and 25% of patients mentation in ameliorating disease activity in CD has who received 2000 IU of vitamin D2 daily achieved been examined only in two open-label pilot studies, and serum 25(OH)D levels of more 32 ng/mL after 6 weeks no studies have evaluated this in UC. Consequently, of therapy. All the three regimens were found to be safe there is an urgent need for high-quality randomised and well tolerated.
intervention trials of vitamin D supplementation in bothCD and UC with disease activity as a treatment end Future directions Several unanswered question remain regarding the role ofvitamin D in IBD (Table 4). Further investigation is Clinical practice needed to understand the effects of dietary intake of vita- Patients with IBD are at risk of developing vitamin D min D and vitamin D supplementation in relation to poly- deficiency. The Endocrine Clinical Practice Guidelines morphisms of DBP or VDR to identify if there are Committee recommends screening of patients with IBD subgroups who may derive greater benefit from prophy- as well as patients who are on corticosteroids for vitamin laxis or who would require greater doses for treatment.
D status.16 While there is lack of professional guidelines With recent evidence pointing towards vitamin D defi- regarding subsequent assessments of vitamin D status, we ciency as associated with IBD risk, confirmation of such adopt the following in our practice. If the baseline vita- findings in other cohorts would establish the vitamin D as min D status is normal, it may be logical to consider one of the links in the gene-environment-gut micro- rechecking the status annually or biennially if there is biome-immune system interactions necessary for the active disease, if there is documented metabolic bone development of IBD. It also merits investigation whether disease or if there is continued use of systemic corticos-teroids. The Institute of Medicine and the Endocrine Table 4 Unanswered clinical questions regarding the Practice Guidelines Committee recommend a dietary role of vitamin D in inflammatory bowel diseases intake of 400 IU of vitamin D per day for infants, 600 IUof vitamin D per day for children beyond 1 year of age 1. Does low serum vitamin D cause Crohn's disease or ulcerative colitis, or is it a marker for other risk factors? and adults and 800 IU of vitamin D per day for the 2. Can supplementation with vitamin D in high-risk individuals elderly aged above 70 years.82 However, to consistently prevent or delay the onset of Crohn's disease or raise the level of 25(OH)D to more than 30 ng/mL, espe- ulcerative colitis? cially in patients who are at risk for vitamin D deficiency, 3. Does vitamin D deficiency cause a more severe phenotype or increased inflammatory activity in Crohn's disease, the Endocrine Practice Guidelines Committee recom- or is it merely a consequence of severity of disease? Is mended that a maintenance dose of at least 1000 IU per vitamin D status predictive of recurrence of Crohn's day would be required.16 To treat documented vitamin D deficiency, it is recommended to use either vitamin D2 or 4. What is the optimal role of vitamin D supplementation as a vitamin D3 in a dosage of 2000 IU per day for 6 weeks, therapeutic modality in patients with IBD? Induction of remission? or 50 000 IU once a week for 6 weeks in case of children Maintenance of remission and prevention of relapse? and vitamin D2 or vitamin D3 6000 IU per day for Prevention of post-operative recurrence? 8 weeks, or 50 000 IU once a week for 8 weeks for adults 5. What is the optimal serum 25(OH)D level for its effect to achieve serum 25(OH)D levels of more than 30 ng/ on inflammation in patients with IBD? mL. The optimal therapeutic regimen in IBD patients 6. What is the optimal dose and modality for treatment of was examined in a single clinical trial by Pappa et al. in vitamin D deficiency in IBD patients? which 71 patients with IBD aged 5–21 years with vitamin 7. Can vitamin D supplementation reduce risk of colorectal cancer in IBD? D deficiency were randomised to one of the following Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd V. P. Mouli and A. N. Ananthakrishnan vitamin D deficiency leads causally to increased disease severity or is merely a consequence of severe disease. Fur- Guarantor of the article: Ananthakrishnan.
thermore, it needs to be identified if there are high-risk Author contributions: Mouli and Ananthakrishnan per- groups of patients who may need to be screened for vita- formed literature review. Mouli wrote the first draft of min D deficiency and preemptively treated to prevent the the manuscript. Ananthakrishnan provided supervision onset of IBD. Further high-quality studies are needed to and both authors approved the final version of the evaluate if correction of vitamin D deficiency or if vitamin D supplementation can prevent disease relapses, whetherit can be used to induce remission in active disease, and whether it has a role in prevention of long-term dis- Declaration of personal interests: Dr Ananthakrishnan ease-related complications like colorectal cancer as has has served on the scientific advisory board of Cubist been identified in non-IBD patients. Continued and fertile interactions between biochemists, nutritional epidemiolo- Declaration of funding interests: Dr Ananthakrishnan is gists, laboratory scientists and clinical researchers will help supported in part by a grant from the National Insti- address many of these unanswered questions, improve our tutes of Health (K23 DK097142). This work is also sup- understanding of the role of the complex panoply of ported by the National Institutes of Health (NIH) (P30 functions of vitamin D, and its application into clinical DK043351) to the Center for Study of Inflammatory Bowel Diseases.
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ameliorates symptoms of experimental randomized clinical trial comparing Aliment Pharmacol Ther 2014; 39: 125-136 ª 2013 John Wiley & Sons Ltd

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A community-based factorial trial on Alzheimer's disease. Effects of expectancy, recruitment methods, co- morbidity and drug use. The Dementia Study in Northern Norway Fred Andersen, MD ‘Navigare necesse est. Vivere non est necesse' Pompeius 56 f. Kr Contents