Vitamin D and Inflammatory Bowel Disease

Table 3

Therapeutic studies in experimental and human IBD (chronological order).

Author	Year	Species/cells	Investigational agent	Methodology	Main findings
Animal and in vitro studies
Cantorna et al. [96]	2000	IL-10 KO mice	1,25(OH)2D3 p.o.	Exp. 1. Vit. D-deficient IL-10 KO mice versus vit. D-sufficient mice (treated with cholecalciferol); Exp. 2. Vit. D-deficient IL10 KO mice versus 1,25(OH)2D3- treated; Exp. 3. Vit. D treatment after onset of GI symptoms	Vitamin D sufficiency prevents enterocolitis in IL-10 KO mice up to 13 weeks; 1,25(OH)2D3 treatment ameliorates inflammation
Daniel et al. [97]	2006	BALB/c mice	TNBS colitis; 22-ene-25-oxa-vitamin D (ZK156979) i.p.; (vitamin D analogue)	Treatment with ZK156979 versus 1,25(OH)2D3 before or after induction of colitis with TNBS; investigation of tissue MPO, TNF-, IFN-, T-bet, IL-10, and IL-4	ZK156979 versus 1,25(OH)2D3 prevents or ameliorates TNBS colitis decreasing pro-inflammatory and increasing anti-inflammatory cytokines
Laverny et al. [98]	2010	C57BL/6 mice	DSS-colitis, 1,25(OH)2-16-ene-20-cyclopropyl-vitamin D3 (BXL-62) (=VDR agonist) intrarectally	Daily administration of BXL-62 versus 1,25(OH)2D3; Macro- and microscopic scoring; mucosal concentrations of TNF-, IL-12/23p40, IL-6, and IFN- and assessment of mRNA	Higher potency of BXL-62 versus 1,25(OH)2D3 in reducing tissue inflammation
Verlinden et al. [99]	2013	C57BL/6 mice	DSS- colitis 1,25(OH)2-19-nor-14,20-bisepi-23-yne-vitamin D3 (TX527)	Histological examination; measurement of transcript levels of cytokines (IL-1, IL-6, IFN-, and TNF-)	TX527 reduced “clinical” disease scores and attenuated histological scores, downregulation of transcript levels of inflammatory cytokines
Ooi et al. [100]	2013	C57BL/6 mice; Cyp KO; VDR KO	1,25(OH)2D3 p.o.	DSS colitis; characterization of gut microbiota, and; gut macrophages; E-cadherin expression	Lower expression of E cadherin and tolerogenic macrophages; Less beneficial microbiota in KO mice; Vitamin D treatment ameliorates colitis and reduces Helicobacteraceae
Wu et al. [21]	2014	Conditional VDR KO and IL-10 KO mice; DSS-colitis; cells: MEF, SKCO15, HCT116; human tissue	DSS colitis; BUT feeding in IL-10 KO	VDR KO: colitis evaluation, pyrosequencing for microbiota, Paneth cells, lysozyme production, autophagy; MEF (VDR^−/− VDR^+/− VDR^+/+) and VDR knockdown in SKCO15 with evaluation of ATG16L1 and LC3B proteins; IL-10 KO: VDR and ATG16L1 expression with or w/o BUT feeding; Human tissue (UC, inflamed versus normal) VDR, ATG16L1, Bacteroides concentration (FISH); HCT116 and HIEC: VDR expression with and w/o incubation with BUT	Conditional VDR KO mice: worse colitis, increased E. coli and Bacteroides (B. fragilis), and decreased BUT-producing bacteria; less and abnormal Paneth cells and reduced lysozyme and ATG16L1 protein; in SKCO15 and MEF reduced expression of ATG16L1 and LC3B proteins; In UC: reduced expression of VDR and ATG16L1, increase of Bacteroides; BUT increases VDR expression in HIEC and HCT116
Tao et al. [102]	2014	C57BL/6 mice	TNBS-colitis; Vitamin D sufficient or deficient diet	At week 14, assessment of ECM and total collagen production, together with determination in isolated colonic SEMF, of expression of VDR, -SMA, and Collagen I in normal SEMF	Histological scoring, ECM, and collagen production in the colon reduced in vitamin D supplemented mice; in SEMF decreased levels of TGF-1, Smad-3, p-Smad3, and Collagen I and induced VDR expression and decreased TGF-1-induced -SMA and Collagen I expression
Assa et al. [101]	2015	Caco cells; C57BL/6 mice	DSS- colitis; Vitamin D sufficient or deficient diet; 1,25(OH)2D3 for Caco	Caco cells incubated with or w/o 1,25(OH)2D3 challenged with AIEC; C57BL/6 mice on normal or low 1,25(OH)2D3 diet infected with AIEC	1,25(OH)2D3 protects Caco cells against AIEC induced loss of TER and TJ protein redistribution; 1,25(OH)2D3 reduces DSS colitis and AIEC invasion; low vitamin D diet and DSS colitis increased Bacteroides
In vivo and ex vivo studies in IBD patients
Stio et al. [105]	2007	4 CD and 4 HC	TX 527 [19-nor-14,20-bisepi-23-yne-1,25(OH)2D3], Vitamin D analogue	Single-center, ex vivo study; experimental study on PBMC of CD patients	TX 527 inhibits TNF- mediated effects on PBMC and the activation of NF-κB; its action is mediated by VDR
Miheller et al. [107]	2009	37 CD	Group A treated with aVD versus group B treated with pVD	Single-center study; evaluation of bone parameters and CDAI, CRP, and SIBDQ after 6, 12, 52 weeks	In aVD, after 6 weeks (but not at 52 weeks) a significant reduction of CDAI, IBDQ, and CRP together with a significant change of bone parameters
Ardizzone et al. [103]	2009	9 UC, 8 CD	1,25(OH)2D3	Single-center ex vivo study; PBMC with or without calcitriol; determination of TNF-, IFN-, IL-2, and IL-10	In UC PBMC 1,25(OH)2D3 reduced IFN- and enhanced IL-10 production; In CD PBMC 1,25(OH)2D3 reduced TNF- production
Jørgensen et al. [108]	2010	94 CD	Vitamin D3 versus placebo	Multi-center randomized double-blind placebo-controlled study; 1200 IU vit D3/day or placebo; estimation of clinical relapse rate	Vit. D3 significantly increased; serum vit. D levels, but the decrease of relapse was not significant (13% versus 29%, = 0.06)
Bendix-Struve et al. [104]	2010	108 CD	Vitamin D3 versus placebo	Randomized, placebo-controlled, clinical trial; After 0, 36, and 52 weeks, PBMC tested in 10 patients treated with Vitamin D3 (1200 IU/day) and in 10 patients treated with placebo for cytokine production and proliferation	Vit. D3 treatment of CD patients increased the IL-6 levels and enhance the CD4^+ T-cell proliferation
Laverny et al. [98]	2010	22 CD, 21 UC	1,25(OH)2-16-ene-20-cyclopropyl-vitamin D3 (BXL-62)	Ex vivo preparations of PBMC (+LPS) and (CD2/CD28 activated)-LPMCs incubated with or without BXL-62.; Determination of mRNA and protein concentrations of TNF-, IL-12/23p40, IL-6, and IFN-	Higher anti-inflammatory potency compared to 1,25(OH)2D3 demonstrated by the significantly more potent inhibition in PBMC and in LPMCs of the proinflammatory cytokines TNF-, IL-12/23p40, IL-6, and IFN-
Yang et al. [109]	2013	18 CD	Vitamin D3	Open-label prospective clinical trial over 24 weeks, multi-center study; vitamin D3 at 1000 IU/day; dose increase every two week of 1000 IU/day up to 5000 IU/day to achieve serum 25(OH)D3 >40 ng/mL	Vit. D3 supplementation significantly raised serum 25(OH)D3, reduced CDAI scores, and improved IBDQ scores
Bartels et al. [106]	2014	10 CD	Vitamin D3	Single-center study, oral vitamin D supplementation (or placebo) and assessment of maturation marker expression and cytokine production of monocyte-derived dendritic cells	Dendritic cells from vitamin supplemented CD patients exhibited reduced expression of CD80 and reduced production of the cytokines IL-10, IL-1, and IL-6
Ham et al. [93]	2014	PBMC	Incubation of CD4^+ with vit D 50 nM	Determination of CD25^+ and CD39^+ cells	3-fold increase of CD25^+ cells, CD39^+ unchanged

CD: Crohn’s disease; UC: ulcerative colitis; HC: healthy controls; vit: vitamin; p.o.: per os; GI: gastrointestinal; KO: knock-out; TNBS: 2,4,6-trinitrobenzene sulfonic acid; i.p.: intraperitoneal; DSS: dextran sodium sulfate; 25(OH)D: 25-hydroxycholecalciferol; 1,25(OH)₂D₃: 1,25-dihydroxycholecalciferol; vitamin D3 (vit D3): cholecalciferol; VDR: vitamin D receptor; MEF: mouse embryonic fibroblasts; AIEC: adherent-invasive Escherichia coli; TER: transepithelial electrical resistance; TJ: tight-junction; aVD: active vitamin D (1,25(OH)₂D₃); pVD: plain vitamin D (25(OH)vitamin D); CDAI: Crohn’s disease activity index; CRP: C-reactive protein; SIBDQ: Short IBD questionnaire; PBMC: peripheral blood mononuclear cells; LPS, lipopolysaccharide; LPMCs: lamina propria mononuclear cells; IBDQ: IBD questionnaire; IL: interleukin; Cyp: Cyp27b1 gene; IFN: interferon; TNF: tumor necrosis factor; BUT butyrate; SEMF: subepithelial myofibroblasts; ECM: extracellular matrix; α-SMA: alpha smooth muscle actin; FISH: fluorescent in situ hybridization; HIEC: human intestinal epithelial cells; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); LC3B: autophagy-related protein LC3B; SKCO15: human colorectal adenocarcinoma cells; HCT116: human colon cancer cell.