Protective links between vitamin D, inflammatory bowel disease and colon cancer

Table 1 Vitamin D and mouse models of inflammatory bowel disease

Strain	Model	Vitamin D metabolite/analog	Dose, route	Treatment window and duration	Serum vit D measure	Outcome	Ref.
Vitamin D Supplementation
Protection
Il10-/-	Spontaneous	1,25(OH)2D3 and D3	0.005 μg 1,25(OH)2D3/d or 5 μg D3/d, diet	3 wk of age; maintained throughout study	ND	Ameliorated IBD	[40]
			0.2 μg 1,25(OH)2D3/d, diet	At the first sign of IBD (diarrhea), lasted for 2 wk		Effective at blocking the progression and ameliorating the symptoms in established disease
Il10-/-	Spontaneous	1,25(OH)2D3	20 ng/d, diet	4 wk of age; maintained throughout study	ND	Significantly reduced spontaneous colitis. More effective protection with combined treatment with calcium	[113]
C57BL/6	DSS (0.5-3.5%), 5 d	1,25(OH)2D3	50 ng/d, diet or 10 ng, intrarectally	Diet given 1 wk prior to DSS treatment; maintained throughout study. Intrarectal administration given 1 d prior to DSS; given every other day	ND	Decreased DSS-induced colitis. Intrarectal administration more effective than dietary delivery	[106]
Balb/c	DSS (3%), 7 d	ZK191784 (1,25(OH)2D3 analog)	100 μg/kg per day, orally	3 d prior or at the start of DSS treatment; given daily	ND	Significantly decreased DSS-induced colitis	[115]
C57BL/6	DSS (3%), 7 d	1,25(OH)2D3	0.5 μg/kg, IP	1 d prior to DSS treatment; given daily up to 11 d	ND	Decreased inflammation and tissue damage following DSS treatment; Increased weight loss likely due to hypercalcemia	[41]
C57BL/6	DSS (2%), 7 d	1,25(OH)2D3	0.2 μg/25 g BW/d, oral gavage	After DSS treatment	ND	Decreased clinical disease, colonic inflammation and intestinal permeability following DSS treatment	[117]
Cyp27b1-/- and Vdr-/-	DSS (3.5%), 5 d	1,25(OH)2D3	50 ng/d, diet	2 wk prior to DSS treatment; maintained throughout study	ND	Cyp27b1-/- mice more susceptible to DSS-induced colitis; supplementation with 1,25(OH)2D3 partially ameliorated disease	[91]
C57BL/6	DSS (3%), 7 d	NA	Adoptive transfer of CYP27B1 over-expressing monocytes	Adoptive transfer on 5th day of DSS treatment	ND	CD11b+/Gr1+ monocytes overexpressing CYP27B1 trafficked to the inflamed colon and ameliorated DSS-induced colitis	[114]
C57BL/6	DSS (2%), 5 d of treatment followed by 2 d of regular water throughout study	1,25(OH)2D3	0.2 μg/25 g BW/d, oral gavage	2 wk after initiation of DSS treatment; maintained throughout study	ND	Vitamin D decreased clinical disease and colonic inflammation following DSS treatment. Vitamin D treatment significantly decreased mononuclear cell infiltrates present in the spleen and mesenteric lymph node following DSS	[139]
Smad3-/-	Helicobacter bilis	D3	1000 IU or 5000 IU per kg diet, diet	2 wk prior to H. bilis infection; maintained throughout study	25(OH)D	Higher vitamin D significantly decrease colonic inflammation	[39]
Balb/c	TNBS (100 mg/kg)	1,25(OH)2D3	0.2 μg/kg, IP	Given 2 h before and 3 d post (acute) or 3, 4 and 5 d post TNBS (interventional)	ND	Significantly reduced colitis; greater protection with concurrent treatment with dexamethasone	[140]
C57BL/6	TNBS (100 mg/kg)	Paracalitriol (1,25(OH)2D3 analog)	0.5 μg/kg, IP	Given 30 min before and 1, 3 and 5 d post TNBS	ND	Ameliorated TNBS colitis and protected against epithelial barrier disruption	[116]
Neutral
Il10-/-	Spontaneous colitis	D3	25 IU or 5000 IU per kg diet, diet	Before conception; maintained throughout study	25(OH)D	No significant difference in inflammation score	[109]
Rag-/-	Adoptive transfer of Il10-/- T cells + piroxicam (7 d)	D3	1000 IU or 5000 IU per kg diet, diet	After peroxicam treatment ends; for 12 d	1,25(OH)2D, 25(OH)D	Vitamin D supplementation during active colitis did not alter colonic inflammation; increased trabecular bone deterioration	[108]
Exacerbation
C57BL/6	Citrobacter rodentium	1,25(OH)2D3	0.5 μg/kg, IP	1 d prior to treatment; daily	ND	Increased colonic ulceration and bacterial burdens compared to controls	[41]
Vitamin D Deficiency
Il10-/-	Spontaneous	NA	Vit D deficient diet	Maintain throughout study	ND	Increased mortality and more rapid disease development compared to vitamin D sufficient animals	[40]
C57BL/6	DSS (2.5%), 6 d	NA	Vit D deficient diet	6 wk prior to DSS treatment; maintained throughout study	25(OH)D	Exacerbated DSS colitis and increased bacterial loads within the colonic tissue	[105]
Il10-/-	AOM + DSS (2%), 7 d	NA	Vit D deficient diet	3 wk of age; maintained throughout study	25(OH)D	Increased mortality and disease severity in AOM/DSS colitis	[141]
Smad3-/-	Helicobacter bilis	NA	Vit D deficient diet	2 wk prior to infection; maintain throughout study	25(OH)D	Did not alter IBD development or severity	[39]
Il10-/-	DSS (2%), 9 days or E. coli	NA	Vit D deficient diet	Maintain throughout experiment	1,25OH)2D and 25(OH)D	Decreased survival and increased intestinal permeability following DSS treatment; increased susceptibility to infection with invasive E. coli	[103]
Other (genetically altered VDR)
hVDR Tg	TNBS, DSS, and adoptive T cell transfer	NA	NA	NA	ND	Overexpression of VDR in the intestinal epithelial cells protected against TNBS, DSS and adoptive T cell transfer -induced colitis	[77]
hVDR Tg Il10-/-	Spontaneous	NA	NA	NA	ND	Overexpression of VDR in the intestinal epithelial cells protected against spontaneous disease in Il10-/- mice	[142]
Vdr-/-	DSS (0.5%-3.5%), 5 d	NA	NA	NA	ND	Increased sensitivity, mortality and disease severity in response to DSS	[107]
Vdr-/-	DSS (2%-2.5%), 7 d	NA	NA	NA	ND	More sensitive to DSS inducted colitis resulting in severe mucosal ulcerations, impaired mucosal wound healing, decreased epithelial barrier function and increased mortality	[102]
Vdr-/-	Salmonella typhimurium	NA	NA	NA	ND	Administration of probiotics (Lactobacillus rhamnosus and Lactobacillus plantarum) increased VDR protein expression in colon epithelial cells. Probiotic administration protected against Salmonella-induced colitis in wild type but not Vdr-/- mice	[138]
VDRΔIEC	DSS (5%), 7 d	NA	NA	NA	ND	Loss of intestinal epithelial VDR exacerbated DSS colitis, altered paneth cell development and changed autophagy gene expression	[137]
Vdr-/- and Il10-/-/Vdr-/-	Adoptive T Cell Transfer and Spontaneous	NA	NA	NA	ND	Il10-/-/Vdr-/- mice developed more severe IBD and increased mortality compared to Il10-/- mice. Adoptive transfer of Vdr-/- CD4 T cells into Rag-/- mice induced severe IBD	[143]
Il10-/-/Vdr-/-	Spontaneous	NA	NA	NA	ND	Il10-/-/Vdr-/- mice developed more severe IBD compared to IL10-/- mice	[106]
Il10-/-/Vdr-/-	Spontaneous and Adoptive T cell Transfer	NA	NA	NA	ND	Adoptive transfer of Il10-/-/Vdr-/- CD4 T cells into Rag-/- mice induced severe colitis. Loss of VDR results in decreased T cell homing to the gut and decreased CD4/CD8αα intraepithelial lymphocytes	[89]
Vdr-/- Il10-/-/Vdr-/-, and Rag-/-	Adoptive T Cell Transfer	NA	NA	NA	ND	Adoptive transfer of Il10-/-/Vdr-/- CD8 T cells into Rag-/- mice induces severe colitis. Vdr-/- CD8 T cells exacerbate CD4/CD45RBhigh cell-induced colitis	[144]

AOM: Azoxymethane; BW: Body weight; Cyp27b1: 1α-hydroxylase; D₃: Vitamin D₃; DSS: Dextran sodium sulfate; IBD: Inflammatory bowel disease; IP: Intraperitoneal; NA: Not applicable; ND: Not done; TNBS: 2,4,6-Trinitrobenzenesulfonic acid; Vit: Vitamin; VDR: Vitamin D receptor.

Table 2 Vitamin D and mouse models of colitis-associated colon cancer

Strain	Model	Vitamin D metabolite/analog	Dose, route	Treatment window and duration	Serum vit D measure	Outcome	Ref.
Vitamin D Supplementation
A/J	AOM + DSS (3%), 7 d	Ro26-2198 (analog)	0.01 μg/kg per day, subcutaneous pump	1 wk prior to AOM	ND	Delayed onset of clinical colitis, decreased cellular proliferation and decreased dysplasia following AOM/DSS	[43]
CF1	AOM + DSS (2.5%) × 7 d	D3, 25(OH)D, 1,25(OH)2D3 and 1,25(OH)2D5	500 μg D3/kg diet , - 500 μg 25(OH)D/kg diet, 2.5 μg 1,25(OH)2D3/kg diet and 25 μg 1,25(OH)2D5/kg diet	1 wk prior to AOM + DSS treatment and maintained throughout study	ND	D3, 25(OH)D, and 1,25(OH)2D5 significantly decreased tumor incidence. 1,25(OH)2D3 induced significant weight loss compared to other treatments; not included in final analysis	[118]
C57BL/6	AOM + DSS (2%), 4 d × 3 cycles	D3	100, 400, 1000, 2500 or 5000 IU/kg diet, diet	2.5 wk prior to AOM + DSS treatment	25(OH)D	Vitamin D supplementation significantly decreased dysplasia in a dose dependent manner	[42]
Smad3-/-	Helicobacter bilis	D3	1000 IU or 5000 IU/kg diet, diet	1 wk prior to infection; maintain throughout study	25(OH)D	Higher vitamin D significantly decreased tumor incidence	[39]
Vitamin D Deficiency
Smad3-/-	Helicobacter bilis	NA	Vit D deficient diet	2 wk prior to infection; maintain throughout study	25(OH)D	No change in dysplasia score or tumor incidence	[39]
Other (VDR Knockout)
Vdr-/-	AOM + DSS (1.5%), 5 d × 3 cycles	NA	NA	NA	ND	Increased inflammation and tumor burdens; increased activation of EGFR and ErbB2 signaling	[145]

AOM: Azoxymethane; D₃: Vitamin D₃; DSS: Dextran sodium sulfate; EGFR: Epidermal growth factor receptor; ErbB2: Receptor tyrosine-protein kinase erbB-2; NA: Not applicable; ND: Not done; Vit: Vitamin.