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Copyright ©The Author(s) 2016.
World J Gastroenterol. Jan 21, 2016; 22(3): 933-948
Published online Jan 21, 2016. doi: 10.3748/wjg.v22.i3.933
Table 1 Vitamin D and mouse models of inflammatory bowel disease
StrainModelVitamin D metabolite/analogDose, routeTreatment window and durationSerum vit D measureOutcomeRef.
Vitamin D Supplementation
Protection
Il10-/-Spontaneous1,25(OH)2D3 and D30.005 μg 1,25(OH)2D3/d or 5 μg D3/d, diet3 wk of age; maintained throughout studyNDAmeliorated IBD[40]
0.2 μg 1,25(OH)2D3/d, dietAt the first sign of IBD (diarrhea), lasted for 2 wkEffective at blocking the progression and ameliorating the symptoms in established disease
Il10-/-Spontaneous1,25(OH)2D320 ng/d, diet4 wk of age; maintained throughout studyNDSignificantly reduced spontaneous colitis. More effective protection with combined treatment with calcium[113]
C57BL/6DSS (0.5-3.5%), 5 d1,25(OH)2D350 ng/d, diet or 10 ng, intrarectallyDiet given 1 wk prior to DSS treatment; maintained throughout study. Intrarectal administration given 1 d prior to DSS; given every other dayNDDecreased DSS-induced colitis. Intrarectal administration more effective than dietary delivery[106]
Balb/cDSS (3%), 7 dZK191784 (1,25(OH)2D3 analog)100 μg/kg per day, orally3 d prior or at the start of DSS treatment; given dailyNDSignificantly decreased DSS-induced colitis[115]
C57BL/6DSS (3%), 7 d1,25(OH)2D30.5 μg/kg, IP1 d prior to DSS treatment; given daily up to 11 dNDDecreased inflammation and tissue damage following DSS treatment; Increased weight loss likely due to hypercalcemia[41]
C57BL/6DSS (2%), 7 d1,25(OH)2D30.2 μg/25 g BW/d, oral gavageAfter DSS treatmentNDDecreased clinical disease, colonic inflammation and intestinal permeability following DSS treatment[117]
Cyp27b1-/- and Vdr-/-DSS (3.5%), 5 d1,25(OH)2D350 ng/d, diet2 wk prior to DSS treatment; maintained throughout studyNDCyp27b1-/- mice more susceptible to DSS-induced colitis; supplementation with 1,25(OH)2D3 partially ameliorated disease[91]
C57BL/6DSS (3%), 7 dNAAdoptive transfer of CYP27B1 over-expressing monocytesAdoptive transfer on 5th day of DSS treatmentNDCD11b+/Gr1+ monocytes overexpressing CYP27B1 trafficked to the inflamed colon and ameliorated DSS-induced colitis[114]
C57BL/6DSS (2%), 5 d of treatment followed by 2 d of regular water throughout study1,25(OH)2D30.2 μg/25 g BW/d, oral gavage2 wk after initiation of DSS treatment; maintained throughout studyNDVitamin 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 bilisD31000 IU or 5000 IU per kg diet, diet2 wk prior to H. bilis infection; maintained throughout study25(OH)DHigher vitamin D significantly decrease colonic inflammation[39]
Balb/cTNBS (100 mg/kg)1,25(OH)2D30.2 μg/kg, IPGiven 2 h before and 3 d post (acute) or 3, 4 and 5 d post TNBS (interventional)NDSignificantly reduced colitis; greater protection with concurrent treatment with dexamethasone[140]
C57BL/6TNBS (100 mg/kg)Paracalitriol (1,25(OH)2D3 analog)0.5 μg/kg, IPGiven 30 min before and 1, 3 and 5 d post TNBSNDAmeliorated TNBS colitis and protected against epithelial barrier disruption[116]
Neutral
Il10-/-Spontaneous colitisD325 IU or 5000 IU per kg diet, dietBefore conception; maintained throughout study25(OH)DNo significant difference in inflammation score[109]
Rag-/-Adoptive transfer of Il10-/- T cells + piroxicam (7 d)D31000 IU or 5000 IU per kg diet, dietAfter peroxicam treatment ends; for 12 d1,25(OH)2D, 25(OH)DVitamin D supplementation during active colitis did not alter colonic inflammation; increased trabecular bone deterioration[108]
Exacerbation
C57BL/6Citrobacter rodentium1,25(OH)2D30.5 μg/kg, IP1 d prior to treatment; dailyNDIncreased colonic ulceration and bacterial burdens compared to controls[41]
Vitamin D Deficiency
Il10-/-SpontaneousNAVit D deficient dietMaintain throughout studyNDIncreased mortality and more rapid disease development compared to vitamin D sufficient animals[40]
C57BL/6DSS (2.5%), 6 dNAVit D deficient diet6 wk prior to DSS treatment; maintained throughout study25(OH)DExacerbated DSS colitis and increased bacterial loads within the colonic tissue[105]
Il10-/-AOM + DSS (2%), 7 dNAVit D deficient diet3 wk of age; maintained throughout study25(OH)DIncreased mortality and disease severity in AOM/DSS colitis[141]
Smad3-/-Helicobacter bilisNAVit D deficient diet2 wk prior to infection; maintain throughout study25(OH)DDid not alter IBD development or severity[39]
Il10-/-DSS (2%), 9 days or E. coliNAVit D deficient dietMaintain throughout experiment1,25OH)2D and 25(OH)DDecreased survival and increased intestinal permeability following DSS treatment; increased susceptibility to infection with invasive E. coli[103]
Other (genetically altered VDR)
hVDR TgTNBS, DSS, and adoptive T cell transferNANANANDOverexpression of VDR in the intestinal epithelial cells protected against TNBS, DSS and adoptive T cell transfer -induced colitis[77]
hVDR Tg Il10-/-SpontaneousNANANANDOverexpression of VDR in the intestinal epithelial cells protected against spontaneous disease in Il10-/- mice[142]
Vdr-/-DSS (0.5%-3.5%), 5 dNANANANDIncreased sensitivity, mortality and disease severity in response to DSS[107]
Vdr-/-DSS (2%-2.5%), 7 dNANANANDMore sensitive to DSS inducted colitis resulting in severe mucosal ulcerations, impaired mucosal wound healing, decreased epithelial barrier function and increased mortality[102]
Vdr-/-Salmonella typhimuriumNANANANDAdministration 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]
VDRΔIECDSS (5%), 7 dNANANANDLoss 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 SpontaneousNANANANDIl10-/-/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-/-SpontaneousNANANANDIl10-/-/Vdr-/- mice developed more severe IBD compared to IL10-/- mice[106]
Il10-/-/Vdr-/-Spontaneous and Adoptive T cell TransferNANANANDAdoptive 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 TransferNANANANDAdoptive transfer of Il10-/-/Vdr-/- CD8 T cells into Rag-/- mice induces severe colitis. Vdr-/- CD8 T cells exacerbate CD4/CD45RBhigh cell-induced colitis[144]
Table 2 Vitamin D and mouse models of colitis-associated colon cancer
StrainModelVitamin D metabolite/analogDose, routeTreatment window and durationSerum vit D measureOutcomeRef.
Vitamin D Supplementation
A/JAOM + DSS (3%), 7 dRo26-2198 (analog)0.01 μg/kg per day, subcutaneous pump1 wk prior to AOMNDDelayed onset of clinical colitis, decreased cellular proliferation and decreased dysplasia following AOM/DSS[43]
CF1AOM + DSS (2.5%) × 7 dD3, 25(OH)D, 1,25(OH)2D3 and 1,25(OH)2D5500 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 diet1 wk prior to AOM + DSS treatment and maintained throughout studyNDD3, 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/6AOM + DSS (2%), 4 d × 3 cyclesD3100, 400, 1000, 2500 or 5000 IU/kg diet, diet2.5 wk prior to AOM + DSS treatment25(OH)DVitamin D supplementation significantly decreased dysplasia in a dose dependent manner[42]
Smad3-/-Helicobacter bilisD31000 IU or 5000 IU/kg diet, diet1 wk prior to infection; maintain throughout study25(OH)DHigher vitamin D significantly decreased tumor incidence[39]
Vitamin D Deficiency
Smad3-/-Helicobacter bilisNAVit D deficient diet2 wk prior to infection; maintain throughout study25(OH)DNo change in dysplasia score or tumor incidence[39]
Other (VDR Knockout)
Vdr-/-AOM + DSS (1.5%), 5 d × 3 cyclesNANANANDIncreased inflammation and tumor burdens; increased activation of EGFR and ErbB2 signaling[145]