Vitamin D activity is associated with the modulation of a wide variety of biological systems, in addition to its roles in calcium homeostatic mechanisms. While vitamin D is well known to promote gastrointestinal calcium absorption, vitamin D also plays a role in attenuating and/or preventing the progression of several gastrointestinal diseases including Crohn’s disease, ulcerative colitis, and colorectal cancer, and may also play a role in chemotherapy-induced intestinal mucositis. The pro-differentiation, immunomodulatory, and anti-inflammatory effects of vitamin D, which has been reported in numerous circumstances, are key potential mechanisms of action in the prevention of gastrointestinal disorders. While the debate of the effectiveness of vitamin D to treat bone pathologies continues, the clinical importance of vitamin D therapy to prevent gastrointestinal disorders should be investigated given current evidence, using both nutritional and pharmaceutical intervention approaches.
Impact statement
The non-skeletal functions of vitamin D play an important role in health and disease. The anti-inflammatory properties and maintenance of intestinal function fulfilled by vitamin D impact other systems in the body though downstream processing. This review provides insight into the mechanisms underpinning the potential benefits of vitamin D in both maintaining intestinal homeostasis and associated diseased states.
XueYFleetJC.Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology2009;
136:1317–2 7, e1–2.
2.
AsprayTJChadwickTFrancisRMMcCollEStampEPrenticeAvon Wilamowitz-MoellendorffASchoenmakersI.Randomized controlled trial of vitamin D supplementation in older people to optimize bone health. Am J Clin Nutr2019;
109:207–17
3.
TanXLiYLiuY.Therapeutic role and potential mechanisms of active vitamin D in renal interstitial fibrosis. J Steroid Biochem Mol Biol2007;
103:491–6
4.
BikleDD.Vitamin D and the skin: physiology and pathophysiology. Rev Endocr Metab Disord2012;
13:3–19
5.
BikleDDOdaYXieZ.Calcium and 1,25(OH)2D: interacting drivers of epidermal differentiation. J Steroid Biochem Mol Biol2004;
89-90:355–60
6.
CuiXGoochHPettyAMcGrathJJEylesD.Vitamin D and the brain: genomic and non-genomic actions. Mol Cell Endocrinol2017;
453:131–43
7.
NitsaAToutouzaMMachairasNMariolisAPhilippouAKoutsilierisM.Vitamin D in cardiovascular disease. In Vivo2018;
32:977–81
8.
PeregrinaKHoustonMDaroquiCDhimaESellersRSAugenlichtLH.Vitamin D is a determinant of mouse intestinal Lgr5 stem cell functions. Carcinogenesis2015;
36:25–31
9.
KabeyaTQiuSHibinoMNagasakiMKodamaNIwaoTMatsunagaT.Cyclic AMP signaling promotes the differentiation of human induced pluripotent stem cells into intestinal epithelial cells. Drug Metab Dispos2018;
46:1411–9
BarbáchanoAFernández-BarralAFerrer-MayorgaGCostales-CarreraALarribaMJMuñozA.The endocrine vitamin D system in the gut. Mol Cell Endocrinol2017;
453:79–87
12.
RafteryTO'SullivanM.Optimal vitamin D levels in Crohn's disease: a review. Proc Nutr Soc2015;
74:56–66
13.
Ferrer-MayorgaGLarribaMJCrespoPMunozA.Mechanisms of action of vitamin D in colon cancer. J Steroid Biochem Mol Biol2018;185:1–6
14.
OosteromNDirksNFHeilSGde JongeRTissingWJEPietersRvan den Heuvel-EibrinkMMHeijboerACPluijmS.A decrease in vitamin D levels is associated with methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia. Support Care Cancer2018;27:183–190
15.
GoltzmanD.Functions of vitamin D in bone. Histochem Cell Biol2018;
149:305–12
16.
BouillonRMarcocciCCarmelietGBikleDWhiteJHDawson-HughesBLipsPMunnsCFLazaretti-CastroMGiustinaABilezikianJ.Skeletal and extra-skeletal actions of vitamin D: Current evidence and outstanding questions. Endocr Rev2018;
40:1109–1151
17.
FudgeNJKovacsCS.Pregnancy up-regulates intestinal calcium absorption and skeletal mineralization independently of the vitamin D receptor. Endocrinology2010;
151:886–95
18.
RummensKvan CromphautSJCarmelietGvan HerckEvan BreeRStockmansIBouillonRVerhaegheJ.Pregnancy in mice lacking the vitamin D receptor: normal maternal skeletal response, but fetal hypomineralization rescued by maternal calcium supplementation. Pediatr Res2003;
54:466–73
19.
Van CromphautSJRummensKStockmansIVan HerckEDijcksFAEderveenAGCarmelietPVerhaegheJBouillonRCarmelietG.Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle through vitamin D receptor-independent mechanisms. J Bone Miner Res2003;
18:1725–36
20.
LeeSMRileyEMMeyerMBBenkuskyNAPlumLADeLucaHFPikeJW.1,25-Dihydroxyvitamin D3 controls a cohort of vitamin D receptor target genes in the proximal intestine that is enriched for calcium-regulating components. J Biol Chem2015;
290:18199–215
21.
SongYPengXPortaATakanagaHPengJBHedigerMAFleetJCChristakosS.Calcium transporter 1 and epithelial calcium channel messenger ribonucleic acid are differentially regulated by 1,25 dihydroxyvitamin D3 in the intestine and kidney of mice. Endocrinology2003;
144:3885–94
22.
LiYCPirroAEAmlingMDellingGBaronRBronsonRDemayMB.Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci USA1997;
94:9831–5
23.
Van CromphautSJDewerchinMHoenderopJGStockmansIVan HerckEKatoSBindelsRJCollenDCarmelietPBouillonRCarmelietG.Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects. Proc Natl Acad Sci USA2001;
98:13324–9
24.
YoshizawaTHandaYUematsuYTakedaSSekineKYoshiharaYKawakamiTAriokaKSatoHUchiyamaYMasushigeSFukamizuAMatsumotoTKatoS.Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet1997;
16:391–6
25.
BriniMCarafoliE.The plasma membrane Ca(2)+ ATPase and the plasma membrane sodium calcium exchanger cooperate in the regulation of cell calcium. Cold Spring Harb Perspect Biol2011;
3:a004168
26.
CaiQChandlerJSWassermanRHKumarRPennistonJT.Vitamin D and adaptation to dietary calcium and phosphate deficiencies increase intestinal plasma membrane calcium pump gene expression. Proc Natl Acad Sci USA1993;
90:1345–9
27.
GhijsenWVan OsCH.1α,25-dihydroxy-vitamin D-3 regulates ATP-dependent calcium transport in basolateral plasma membranes of rat enterocytes. Biochim Biophys. Acta, Biomembr1982;
689:170–2
28.
BennBSAjibadeDPortaADhawanPHedigerMPengJBJiangYOhGTJeungEBLiebenLBouillonRCarmelietGChristakosS.Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. Endocrinology2008;
149:3196–205
29.
KutuzovaGDDelucaHF.Gene expression profiles in rat intestine identify pathways for 1,25-dihydroxyvitamin D(3) stimulated calcium absorption and clarify its immunomodulatory properties. Arch Biochem Biophys2004;
432:152–66
30.
FujitaHSugimotoKInatomiSMaedaTOsanaiMUchiyamaYYamamotoYWadaTKojimaTYokozakiHYamashitaTKatoSSawadaNChibaHNusratA.Tight junction proteins claudin-2 and -12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. MBoC2008;
19:1912–21
31.
DeLucaHF.Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr2004;
80:1689s–96s
32.
MarksJSraiSKBiberJMurerHUnwinRJDebnamES.Intestinal phosphate absorption and the effect of vitamin D: a comparison of rats with mice. Exp Physiol2006;
91:531–7
33.
SegawaHKanekoIYamanakaSItoMKuwahataMInoueYKatoSMiyamotoK.Intestinal Na-P(i) cotransporter adaptation to dietary P(i) content in vitamin D receptor null mice. Am J Physiol Renal Physiol2004;
287:F39–47
34.
WilliamsKBDeLucaHF.Characterization of intestinal phosphate absorption using a novel in vivo method. Am J Physiol Endocrinol Metab2007;
292:E1917–21
35.
ChristakosSLiebenLMasuyamaRCarmelietG.Vitamin D endocrine system and the intestine. Bonekey Rep2014;
3:496
36.
XuHBaiLCollinsJFGhishanFK.Age-dependent regulation of rat intestinal type IIb sodium-phosphate cotransporter by 1,25-(OH)(2) vitamin D(3). Am J Physiol, Cell Physiol2002;
282:C487–93
37.
KanekoISegawaHFurutaniJKuwaharaSAranamiFHanabusaETominagaRGiralHCaldasYLeviMKatoSMiyamotoK.Hypophosphatemia in vitamin D receptor null mice: effect of rescue diet on the developmental changes in renal Na+ -dependent phosphate cotransporters. Pflugers Arch2011;
461:77–90
38.
MasuyamaRNakayaYKatsumataSKajitaYUeharaMTanakaSSakaiAKatoSNakamuraTSuzukiK.Dietary calcium and phosphorus ratio regulates bone mineralization and turnover in vitamin D receptor knockout mice by affecting intestinal calcium and phosphorus absorption. J Bone Miner Res2003;
18:1217–26
39.
BernsteinCNFriedMKrabshuisJHCohenHEliakimRFedailSGearryRGohKLHamidSKhanAGLeMairAWMalfertheinerOuyangQReyJFSoodASteinwurzFThomsenOOThomsonAWatermeyerG.World Gastroenterology Organization Practice Guidelines for the diagnosis and management of IBD in 2010. Inflamm Bowel Dis2010;
16:112–24
40.
CantornaMTYuSBruceD.The paradoxical effects of vitamin D on type 1 mediated immunity. Mol Aspects Med2008;
29:369–75
41.
CantornaMTMcDanielKBoraSChenJJamesJ.Vitamin D, immune regulation, the microbiota, and inflammatory bowel disease. Exp Biol Med (Maywood)2014;
239:1524–30
42.
OpsteltenJLChanSSMHartARvan SchaikFDMSiersemaPDLentjesEKhawKTLubenRKeyTJBoeingHBergmannMMOvervadKPalliDMasalaGRacineACarbonnelFBoutron-RuaultMCTjonnelandAOlsenAAndersenVKaaksRKuhnTTuminoRTrichopoulouAPeetersPHMVerschurenWMMWittemanBJMOldenburgB.Prediagnostic serum vitamin D levels and the risk of Crohn's disease and ulcerative colitis in European populations: a nested case-control study. Inflamm Bowel Dis2018;
24:633–40
43.
AnanthakrishnanANKhaliliHHiguchiLMBaoYKorzenikJRGiovannucciELRichterJMFuchsCSChanAT.Higher predicted vitamin D status is associated with reduced risk of Crohn's disease. Gastroenterology2012;
142:482–9
44.
Del PintoRPietropaoliDChandarAKFerriCCominelliF.Association between inflammatory bowel disease and vitamin D deficiency: a systematic review and meta-analysis. Inflamm Bowel Dis2015;
21:2708–17
45.
FarrayeFANimitphongHStucchiADendrinosKBoulangerABVijjeswarapuATanennbaumABiancuzzoRChenTCHolickMF.Use of a novel vitamin D bioavailability test demonstrates that vitamin D absorption is decreased in patients with quiescent Crohn's disease. Inflamm Bowel Dis2011;
17:2116–21
46.
FroicuMCantornaMT.Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury. BMC Immunol2007;
8:5
47.
KongJZhangZMuschMWNingGSunJHartJBissonnetteMLiYC.Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier. Am J Physiol Gastrointest Liver Physiol2008;
294:G208–16
48.
LiuTShiYDuJGeXTengXLiuLWangEZhaoQ.Vitamin D treatment attenuates 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis but not oxazolone-induced colitis. Sci Rep2016;
6:32889
49.
CantornaMTMunsickCBemissCMahonBD.1,25-Dihydroxycholecalciferol prevents and ameliorates symptoms of experimental murine inflammatory bowel disease. J Nutr2000;
130:2648–52
50.
FroicuMWeaverVWynnTAMcDowellMAWelshJECantornaMT.A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol Endocrinol2003;
17:2386–92
51.
FroicuMZhuYCantornaMT.Vitamin D receptor is required to control gastrointestinal immunity in IL-10 knockout mice. Immunology2006;
117:310–8
52.
ChenJBruceDCantornaMT.Vitamin D receptor expression controls proliferation of naive CD8+ T cells and development of CD8 mediated gastrointestinal inflammation. BMC Immunol2014;
15:6
53.
YuSBruceDFroicuMWeaverVCantornaMT.Failure of T cell homing, reduced CD4/CD8alphaalpha intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice. Proc Natl Acad Sci USA2008;
105:20834–9
54.
MihellerPMuzesGHritzILakatosGPregunILakatosPLHerszenyiLTulassayZ.Comparison of the effects of 1,25 dihydroxyvitamin D and 25 hydroxyvitamin D on bone pathology and disease activity in Crohn's disease patients. Inflamm Bowel Dis2009;
15:1656–62
55.
YangLWeaverVSmithJPBingamanSHartmanTJCantornaMT.Therapeutic effect of vitamin d supplementation in a pilot study of Crohn's patients. Clin Transl Gastroenterol2013;
4:e33
56.
JorgensenSPAgnholtJGlerupHLyhneSVilladsenGEHvasCLBartelsLEKelsenJChristensenLADahlerupJF.Clinical trial: vitamin D3 treatment in Crohn's disease – a randomized double-blind placebo-controlled study. Aliment Pharmacol Ther2010;
32:377–83
57.
PappaHMGrandRJGordonCM.Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease. Inflamm Bowel Dis2006;
12:1162–74
58.
FerlayJShinH-RBrayFFormanDMathersCParkinDM.Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer2010;
127:2893–917
59.
EganJBThompsonPAVitanovMVBartikLJacobsETHausslerMRGernerEWJurutkaPW.Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate beta-catenin activity in colon cancer cells. Mol Carcinog2010;
49:337–52
60.
NusseRCleversH.Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell2017;
169:985–99
61.
BarbáchanoALarribaMJFerrer-MayorgaGGonzález-SanchoJMMuñozA.Vitamin D and colon cancer. In: FeldmanD (ed.) Vitamin D, Volume II: health, disease and therapeutics2018, Elsevier; London, pp.837–62
62.
BerkovichLSintovACBen-ShabatS.Inhibition of cancer growth and induction of apoptosis by BGP-13 and BGP-15, new calcipotriene-derived vitamin D3 analogs, in-vitro and in-vivo studies. Invest New Drugs2013;
31:247–55
63.
TangprichaVSpinaCYaoMChenTCWolfeMMHolickMF.Vitamin D deficiency enhances the growth of MC-26 colon cancer xenografts in Balb/c mice. J Nutr2005;
135:2350–4
64.
HobausJTennakoonSHeffeterPGroeschelCAggarwalAHummelDMThiemUMarculescuRBergerWKallayE.Impact of CYP24A1 overexpression on growth of colorectal tumour xenografts in mice fed with vitamin D and soy. Int J Cancer2016;
138:440–50
65.
UrashimaMOhdairaHAkutsuTOkadaSYoshidaMKitajimaMSuzukiY.Effect of vitamin D supplementation on relapse-free survival among patients with digestive tract cancers: the AMATERASU randomized clinical trial. JAMA2019;
321:1361–9
66.
NgKNimeiriHSMcClearyNJAbramsTAYurgelunMBClearyJMRubinsonDASchragDMiksadRBullockAJAllenJZuckermanDChanEChanJAWolpinBMConstantineMWecksteinDJFaggenMAThomasCAKourniotiCYuanCGanserCWilkinsonBMackintoshCZhengHHollisBWMeyerhardtJAFuchsCS.Effect of high-dose vs standard-dose vitamin D3 supplementation on progression-free survival among patients with advanced or metastatic colorectal cancer: the SUNSHINE randomized clinical trial. JAMA2019;
321:1370–9
67.
BarryELPeacockJLReesJRBostickRMRobertsonDJBresalierRSBaronJA.Vitamin d receptor genotype, vitamin d3 supplementation, and risk of colorectal adenomas: a randomized clinical trial. JAMA Oncol2017;
3:628–35
68.
BergerMDStintzingSHeinemannVCaoSYangDSunakawaYMatsusakaSNingYOkazakiSMiyamotoYSuenagaMSchirripaMHannaDLSoniSPucciniAZhangWCremoliniCFalconeALoupakisFLenzHJ.A polymorphism within the Vitamin D transporter gene predicts outcome in metastatic colorectal cancer patients treated with FOLFIRI/bevacizumab or FOLFIRI/Cetuximab. Clin Cancer Res2018;
24:784–93
69.
JiangXO'ReillyPFAschardH.Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nat Commun2018;
9:260
70.
Vaughan-ShawPGO'SullivanFFarringtonSMTheodoratouECampbellHDunlopMGZgagaL.The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis. Br J Cancer2017;
116:1092
71.
SutaloNTomicSBevandaMDragisicVMarijanovicIPetricevicJMikulicI.Immunohystochemical expression of vitamin D receptor in development stages of colorectal carcinoma. Psychiatr Danub2017;
29: Suppl 4:855–8
72.
LarribaMJMartín-VillarEGarcíaJMPereiraFPeñaCGarcía de HerrerosABonillaFMuñozA.Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer. Carcinogenesis2009;
30:1459–68
73.
PálmerHGLarribaMJGarcíaJMOrdóñez-MoránPPeñaCPeiróSPuigIRodríguezRde la FuenteRBernadAPollánMBonillaFGamalloCde HerrerosAGMuñozA.The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat Med2004;
10:917
74.
KhalekFJAGallicanoGIMishraL.Colon cancer stem cells. Gastrointestinal Cancer Res: GCR2010;S16–S23
75.
ZhouJ-YChenMMaLWangXChenY-GLiuS-L.Role of CD44(high)/CD133(high) HCT-116 cells in the tumorigenesis of colon cancer. Oncotarget2016;
7:7657–66
76.
LiMXLiLFZhangLXiaoZGShenJHuWZengQChoCH.Vitamin D and cancer stem cells in the gastrointestinal tract. Curr Med Chem2017;
24:918–27
77.
CorboCOrruSGemeiMNotoRDMirabelliPImperliniERuoppoloMVecchioLDSalvatoreF.Protein cross-talk in CD133+ colon cancer cells indicates activation of the Wnt pathway and upregulation of SRp20 that is potentially involved in tumorigenicity. Proteomics2012;
12:2045–59
78.
DengYSuQMoJFuXZhangYLinEH.Celecoxib downregulates CD133 expression through inhibition of the Wnt signaling pathway in colon cancer cells. Cancer Invest2013;
31:97–102
79.
KotlarzAPrzybyszewskaMSwobodaPMiloszewskaJGrygorowiczMAKutnerAMarkowiczS.Differential interference of vitamin D analogs PRI-1906, PRI-2191, and PRI-2205 with the renewal of human colon cancer cells refractory to treatment with 5-fluorouracil. Tumor Biol2016;
37:4699–709
80.
Ferrer-MayorgaGGomez-LopezGBarbachanoAFernandez-BarralAPenaCPisanoDGCanteroRRojoFMunozALarribaMJ.Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer. Gut2017;
66:1449–62
81.
GibsonRJKeefeDMLallaRVBatemanEBlijlevensNFijlstraMKingEEStringerAMvan der VeldenWJYazbeckREladSBowenJM.Mucositis Study Group Of The Multinational Association Of Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Support Care Cancer2013;
21:313–26
82.
Carneiro-FilhoBALimaIPAraujoDHCavalcanteMCCarvalhoGHBritoGALimaVMonteiroSMSantosFNRibeiroRALimaAA.Intestinal barrier function and secretion in methotrexate-induced rat intestinal mucositis. Dig Dis Sci2004;
49:65–72
83.
GibsonRJBowenJMAlvarezEFinnieJKeefeDM.Establishment of a single-dose irinotecan model of gastrointestinal mucositis. Chemotherapy2007;
53:360–9
84.
GibsonRJBowenJMCumminsAGKeefeDM.Relationship between dose of methotrexate, apoptosis, p53/p21 expression and intestinal crypt proliferation in the rat. Clin Exper Med2005;
4:188–95
85.
LoganRMGibsonRJBowenJMStringerAMSonisSTKeefeDM.Characterisation of mucosal changes in the alimentary tract following administration of irinotecan: implications for the pathobiology of mucositis. Cancer Chemother Pharmacol2008;
62:33–41
86.
SonisST.The biologic role for nuclear factor-kappaB in disease and its potential involvement in mucosal injury associated with anti-neoplastic therapy. Crit Rev Oral Biol Med2002;
13:380–9
87.
SonisST.A biological approach to mucositis. J Support Oncol2004;
2:21–32 discussion 5–6
88.
SonisSTO'DonnellKEPopatRBragdonCPhelanSCocksDEpsteinJB.The relationship between mucosal cyclooxygenase-2 (COX-2) expression and experimental radiation-induced mucositis. Oral Oncol2004;
40:170–6
89.
LoganRMStringerAMBowenJMGibsonRJSonisSTKeefeDM.Serum levels of NFkappaB and pro-inflammatory cytokines following administration of mucotoxic drugs. Cancer Biol Ther2008;
7:1139–45
90.
LoganRMStringerAMBowenJMGibsonRJSonisSTKeefeDM.Is the pathobiology of chemotherapy-induced alimentary tract mucositis influenced by the type of mucotoxic drug administered?Cancer Chemother Pharmacol2009;
63:239–51
91.
LoganRMStringerAMBowenJMYeohASGibsonRJSonisSTKeefeDM.The role of pro-inflammatory cytokines in cancer treatment-induced alimentary tract mucositis: pathobiology, animal models and cytotoxic drugs. Cancer Treat Rev2007;
33:448–60
92.
GibsonRJCumminsAGBowenJMLoganRMHealeyTKeefeDM.Apoptosis occurs early in the basal layer of the oral mucosa following cancer chemotherapy. Asia-Pacific J Clin Oncol2006;
2:39–49
93.
LoganRMGibsonRJSonisSTKeefeDM.Nuclear factor-kappaB (NF-kappaB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy. Oral Oncol2007;
43:395–401
94.
AranowC.Vitamin D and the immune system. J Investig Med2011;
59:881–6
95.
BakkeDSunJ.Ancient nuclear receptor VDR with new functions: microbiome and inflammation. Inflamm Bowel Dis2018;
24:1149–54
96.
WangFJohnsonRLDeSmetMLSnyderPWFairfaxKCFleetJC.Vitamin D receptor-dependent signaling protects mice from dextran sulfate sodium-induced colitis. Endocrinology2017;
158:1951–63
97.
HaagenJKrohnHRolligSSchmidtMWolframKDorrW.Effect of selective inhibitors of inflammation on oral mucositis: preclinical studies. Radiother Oncol2009;
92:472–6
98.
LimaVBritoGACunhaFQReboucasCGFalcaoBAAugustoRFSouzaMLLeitaoBTRibeiroRA.Effects of the tumour necrosis factor-alpha inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters. Eur J Oral Sci2005;
113:210–7
99.
MeloMLBritoGASoaresRCCarvalhoSBSilvaJVSoaresPMValeMLSouzaMHCunhaFQRibeiroRA.Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide. Cancer Chemother Pharmacol2008;
61:775–84
100.
FakihMGTrumpDLJohnsonCSTianLMuindiJSungaAY.Chemotherapy is linked to severe vitamin D deficiency in patients with colorectal cancer. Int J Colorectal Dis2009;
24:219–24
101.
HoltPRBresalierRSMaCKLiuKFLipkinMByrdJCYangK.Calcium plus vitamin D alters preneoplastic features of colorectal adenomas and rectal mucosa. Cancer2006;
106:287–96
102.
StringerAMGibsonRJBowenJMLoganRMAshtonKYeohASAl-DasooqiNKeefeDM.Irinotecan-induced mucositis manifesting as diarrhoea corresponds with an amended intestinal flora and mucin profile. Int J Exp Pathol2009;
90:489–99
103.
StringerAMGibsonRJLoganRMBowenJMYeohASHamiltonJKeefeDM.Gastrointestinal microflora and mucins may play a critical role in the development of 5-Fluorouracil-induced gastrointestinal mucositis. Exp Biol Med (Maywood))2009;
234:430–41
104.
StringerAMGibsonRJLoganRMBowenJMYeohASLaurenceJKeefeDM.Irinotecan-induced mucositis is associated with changes in intestinal mucins. Cancer Chemother Pharmacol2009;
64:123–32
105.
OoiJHLiYRogersCJCantornaMT.Vitamin D regulates the gut microbiome and protects mice from dextran sodium sulfate-induced colitis. J Nutr2013;
143:1679–86
106.
KuhneHSchutkowskiAWeinholzSCordesCSchierhornASchulzKKonigBStanglGI.Vitamin D receptor regulates intestinal proteins involved in cell proliferation, migration and stress response. Lipids Health Dis2014;
13:51
107.
AugenlichtLH.Environmental impact on intestinal stem cell functions in mucosal homeostasis and tumorigenesis. J Cell Biochem2017;
118:943–52
108.
KrausovaMKorinekV.Wnt signaling in adult intestinal stem cells and cancer. Cell Signal2014;
26:570–9
109.
GaoNWhitePKaestnerKH.Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2. Dev Cell2009;
16:588–99
110.
BonhommeCDulucIMartinEChawengsaksophakKChenardMPKedingerMBeckFFreundJNDomon-DellC.The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development. Gut2003;
52:1465–71
111.
YamamotoHMiyamotoKLiBTaketaniYKitanoMInoueYMoritaKPikeJWTakedaE.The caudal-related homeodomain protein Cdx-2 regulates vitamin D receptor gene expression in the small intestine. J Bone Miner Res1999;
14:240–7
112.
PulitoCTerrenatoIDi BenedettoAKoritaEGoemanFSacconiABiagioniFBlandinoGStranoSMutiPMottoleseMFalvoE.Cdx2 polymorphism affects the activities of vitamin D receptor in human breast cancer cell lines and human breast carcinomas. PLoS One2015;
10:e0124894
113.
SerranoDGnagnarellaPRaimondiSGandiniS.Meta-analysis on vitamin D receptor and cancer risk: focus on the role of TaqI, ApaI, and Cdx2 polymorphisms. Eur J Cancer Prev2016;
25:85–96
114.
RibiczeyPPappBHomolyaLEnyediAKovacsT.Selective upregulation of the expression of plasma membrane calcium ATPase isoforms upon differentiation and 1,25(OH)2D3-vitamin treatment of colon cancer cells. Biochem Biophys Res Commun2015;
464:189–94
115.
Ordonez-MoranPLarribaMJPalmerHGValeroRABarbachanoADunachMde HerrerosAGVillalobosCBercianoMTLafargaMMunozA.RhoA-ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells. J Cell Biol2008;
183:697–710
116.
PálmerHGGonzález-SanchoJMEspadaJBercianoMTPuigIBaulidaJQuintanillaMCanoAGarcía De HerrerosALafargaMMuñozA.Vitamin D3 promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of β-catenin signaling. J Cell Biol2001;
154:369–87
117.
ZhaoHZhangHWuHLiHLiuLGuoJLiCShihDQZhangX.Protective role of 1,25(OH)2 vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice. BMC Gastroenterol2012;
12:57
118.
ChenJWaddellALinYDCantornaMT.Dysbiosis caused by vitamin D receptor deficiency confers colonization resistance to Citrobacter rodentium through modulation of innate lymphoid cells. Mucosal Immunol2015;
8:618–26
119.
DuJChenYShiYLiuTCaoYTangYGeXNieHZhengCLiYC.1,25-dihydroxyvitamin D protects intestinal epithelial barrier by regulating the myosin light chain kinase signaling pathway. Inflamm Bowel Dis2015;
21:2495–506
120.
LiuZSunBQiLLiYZhaoXZhangDZhangY.Dickkopf-1 expression is down-regulated during the colorectal adenoma-carcinoma sequence and correlates with reduced microvessel density and VEGF expression. Histopathology2015;
67:158–66
121.
WangZSchuetzEGXuYThummelKE.Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol2013;
136:54–8
122.
AjouzHMukherjiDShamseddineA.Secondary bile acids: an underrecognized cause of colon cancer. World J Surg Oncol2014;
12:164
123.
EchchgaddaISongCSRoyAKChatterjeeB.Dehydroepiandrosterone sulfotransferase is a target for transcriptional induction by the vitamin D receptor. Mol Pharmacol2004;
65:720–9
124.
FanJLiuSDuYMorrisonJShipmanRPangKS.Up-regulation of transporters and enzymes by the vitamin D receptor ligands, 1alpha,25-dihydroxyvitamin D3 and vitamin D analogs, in the Caco-2 cell monolayer. J Pharmacol Exp Ther2009;
330:389–402
125.
JurutkaPWThompsonPDWhitfieldGKEichhorstKRHallNDominguezCEHsiehJCHausslerCAHausslerMR.Molecular and functional comparison of 1,25-dihydroxyvitamin D(3) and the novel vitamin D receptor ligand, lithocholic acid, in activating transcription of cytochrome P450 3A4. J Cell Biochem2005;
94:917–43
126.
LiuPTStengerSLiHWenzelLTanBHKrutzikSROchoaMTSchauberJWuKMeinkenCKamenDLWagnerMBalsRSteinmeyerAZugelUGalloRLEisenbergDHewisonMHollisBWAdamsJSBloomBRModlinRL.Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science2006;
311:1770–3
127.
PiemontiLMontiPSironiMFraticelliPLeoneBEDal CinEAllavenaPDi CarloV.Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol2000;
164:4443–51
128.
BhallaAKAmentoEPSerogBGlimcherLH.1,25-Dihydroxyvitamin D3 inhibits antigen-induced T cell activation. J Immunol1984;
133:1748–54
129.
DanielCSartoryNAZahnNRadekeHHSteinJM.Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J Pharmacol Exp Ther2008;
324:23–33
130.
TangJZhouRLugerDZhuWSilverPBGrajewskiRSSuS-BChanC-CAdoriniLCaspiRR.Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. J Immunol2009;
182:4624–32
131.
PennaGRoncariAAmuchasteguiSDanielKCBertiEColonnaMAdoriniL.Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+ Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood2005;
106:3490–7
132.
AlmerighiCSinistroACavazzaACiapriniCRocchiGBergaminiA.1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine2009;
45:190–7
133.
WeiRChristakosS.Mechanisms underlying the regulation of innate and adaptive immunity by vitamin D. Nutrients2015;
7:8251–60
134.
HewisonM.Vitamin D and immune function: an overview. Proc Nutr Soc2011;
71:50–61
135.
HooperLVStappenbeckTSHongCVGordonJI.Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat Immunol2003;
4:269–73
136.
PackeyCDSartorRB.Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr Opin Infect Dis2009;
22:292–301
137.
HoSPothoulakisCKoonHW.Antimicrobial peptides and colitis. Curr Pharm Des2013;
19:40–7
138.
SchepensMASchonewilleAJVinkCvan SchothorstEMKramerEHendriksTBrummerRJKeijerJvan der MeerRBovee-OudenhovenIM.Supplemental calcium attenuates the colitis-related increase in diarrhea, intestinal permeability, and extracellular matrix breakdown in HLA-B27 transgenic rats. J Nutr2009;
139:1525–33
139.
AokiTNarumiyaS.Prostaglandins and chronic inflammation. Trends Pharmacol Sci2012;
33:304–11
140.
KrishnanAVFeldmanD.Mechanisms of the anti-cancer and anti-inflammatory actions of vitamin D. Annu Rev Pharmacol Toxicol2011;
51:311–36
141.
QiaoLKozoniVTsiouliasGJKoutsosMIHanifRShiffSJRigasB.Selected eicosanoids increase the proliferation rate of human colon carcinoma cell lines and mouse colonocytes in vivo. Biochim Biophys Acta1995;
1258:215–23
142.
TsujiSKawanoSSawaokaHTakeiYKobayashiINaganoKFusamotoHKamadaT.Evidences for involvement of cyclooxygenase-2 in proliferation of two gastrointestinal cancer cell lines. Prostaglandins Leukot Essent Fatty Acids1996;
55:179–83
143.
MorenoJKrishnanAVSwamiSNonnLPeehlDMFeldmanD.Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer Res2005;
65:7917–25
144.
KalerPAugenlichtLKlampferL.Macrophage-derived IL-1beta stimulates Wnt signaling and growth of colon cancer cells: a crosstalk interrupted by vitamin D3. Oncogene2009;
28:3892–902
145.
ZhouAScogginSGaynorRBWilliamsNS.Identification of NF-kappa B-regulated genes induced by TNFalpha utilizing expression profiling and RNA interference. Oncogene2003;
22:2054–64
146.
BrozekWBisesGGirschTCrossHSKaiserHEPeterlikM.Differentiation-dependent expression and mitogenic action of interleukin-6 in human colon carcinoma cells: relevance for tumour progression. Eur J Cancer2005;
41:2347–54
147.
HsuCPChenYLHuangCCChouCCLiuCLHungCHKaoTYChungYC.Anti-interleukin-6 receptor antibody inhibits the progression in human colon carcinoma cells. Eur J Clin Invest2011;
41:277–84
148.
LippitzBE.Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol2013;
14:e218–28
149.
NonnLPengLFeldmanDPeehlDM.Inhibition of p38 by vitamin D reduces interleukin-6 production in normal prostate cells via mitogen-activated protein kinase phosphatase 5: implications for prostate cancer prevention by vitamin D. Cancer Res2006;
66:4516–24
150.
PeehlDMShinghalRNonnLSetoEKrishnanAVBrooksJDFeldmanD.Molecular activity of 1,25-dihydroxyvitamin D3 in primary cultures of human prostatic epithelial cells revealed by cDNA microarray analysis. J Steroid Biochem Mol Biol2004;
92:131–41
151.
MeekerSSeamonsAPaikJTreutingPMBrabbTGradyWMMaggio-PriceL.Increased dietary vitamin D suppresses MAPK signaling, colitis, and colon cancer. Cancer Res2014;
74:4398–408
152.
van Harten-GerritsenASBalversMGWitkampRFKampmanEvan DuijnhovenFJ.Vitamin D, inflammation, and colorectal cancer progression: a review of mechanistic studies and future directions for epidemiological studies. Cancer Epidemiol Biomarkers Prev2015;
24:1820–8
153.
MeltonACMelroseJAlajokiLPrivatSChoHBrownNPlavecAMNguyenDJohnstonEDYangJPolokoffMAPlavecIBergELO'MahonyA.Regulation of IL-17A production is distinct from IL-17F in a primary human cell co-culture model of T cell-mediated B cell activation. PLoS One2013;
8:e58966
154.
ChaeW-JGibsonTFZeltermanDHaoLHenegariuOBothwellA.Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis. Proc Nat Acad Sci2010;
107:5540–4
155.
TsengJ-YYangC-YLiangS-CLiuR-SYangS-HLinJ-KChenY-MWuY-CJiangJ-KLinC-H.Interleukin-17A modulates circulating tumor cells in tumor draining vein of colorectal cancers and affects metastases. Clin Cancer Res2014;
20:2885–97
156.
ChenSWWangPYZhuJChenGWZhangJLChenZYZuoSLiuYCPanYS.Protective effect of 1,25-dihydroxyvitamin d3 on lipopolysaccharide-induced intestinal epithelial tight junction injury in caco-2 cell monolayers. Inflammation2015;
38:375–83
157.
JinDWuSZhangYGLuRXiaYDongHSunJ.Lack of vitamin D receptor causes dysbiosis and changes the functions of the murine intestinal microbiome. Clin Ther2015;
37:996–1009.e7
158.
AssaAVongLPinnellLJRautavaJAvitzurNJohnson-HenryKCShermanPM.Vitamin D deficiency predisposes to adherent-invasive Escherichia coli-induced barrier dysfunction and experimental colonic injury. Inflamm Bowel Dis2015;
21:297–306
159.
RyzNRPattersonSJZhangYMaCHuangTBhinderGWuXChanJGlesbyAShamHPDutzJPLevingsMKJacobsonKVallanceBA.Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses. Am J Physiol Gastrointest Liver Physiol2012;
303:G1299–311
160.
BashirMPrietlBTauschmannMMautnerSIKumpPKTreiberGWurmPGorkiewiczGHogenauerCPieberTR.Effects of high doses of vitamin D3 on mucosa-associated gut microbiome vary between regions of the human gastrointestinal tract. Eur J Nutr2016;
55:1479–89
161.
BoraSAKennettMJSmithPBPattersonADCantornaMT.The gut microbiota regulates endocrine vitamin D metabolism through fibroblast growth factor 23. Front Immunol2018;
9:408
162.
SchafflerHHerlemannDPKlinitzkePBerlinPKreikemeyerBJasterRLamprechtG.Vitamin D administration leads to a shift of the intestinal bacterial composition in Crohn's disease patients, but not in healthy controls. J Dig Dis2018;
19:225–34
163.
CiubotaruIGreenSJKukrejaSBarengoltsE.Significant differences in fecal microbiota are associated with various stages of glucose tolerance in African American male veterans. Transl Res2015;
166:401–11
164.
WangJThingholmLBSkiecevicieneJRauschPKummenMHovJRDegenhardtFHeinsenFARuhlemannMCSzymczakSHolmKEskoTSunJPricop-JeckstadtMAl-DurySBohovPBethuneJSommerFEllinghausDBergeRKHubenthalMKochMSchwarzKRimbachGHubbePPanWHSheibani-TezerjiRHaslerRRosenstielPD'AmatoMCloppenborg-SchmidtKKunzelSLaudesMMarschallHULiebWNothlingsUKarlsenTHBainesJFFrankeA.Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet2016;
48:1396–406
165.
WaterhouseMHopeBKrauseLMorrisonMProtaniMMZakrzewskiMNealeRE.Vitamin D and the gut microbiome: a systematic review of in vivo studies. Eur J Nutr2018; In press. https://doi.org/10.1007/s00394-018-1842-7
