Effects of Vitamin D Supplementation on Inflammation, Colonic Cell Kinetics, and Microbiota in Colitis: A Review
Abstract
:1. Introduction
2. Results
2.1. Dose-Dependent Effects of Vitamin D Supplementation on Ulcerative Colitis and Crohn’s Disease
2.2. Vitamin D and Inflammation
2.2.1. Cyclooxygenase-2
2.2.2. CYP24A1 and CYP27B1
2.2.3. Tumor Necrosis Factor Alpha
2.2.4. Nuclear Factor Kappa B
2.2.5. Mitogen Activated Protein Kinase
2.2.6. Retinoid X Receptor Alpha
2.3. Vitamin D and Cell Kinetics
2.3.1. Cell Proliferation
Author (Year) | Study Type, Population | Measurements | Results | Conclusion |
---|---|---|---|---|
Kong et al. (2008) [65] | VDR+/+ (wild-type) and VDR−/− (KO) mice 2.5% DSS treatment; cell study | Colonic samples; histology, immunostaining, electron microscopy, Western blotting, RT-PCR | VDR KO mice had more severe colitis/ulceration, symptoms like diarrhea, gross bleeding, rectal prolapse, ↑ mucosal permeability, impaired epithelial junction compared to wild-type mice; vitamin D treatment ↑ tight junction proteins in 24 h | Vitamin D may protect intestinal epithelial barrier by increasing tight junction proteins |
Xin et al. (2017) [69] | C57BL/6 mice 12.5 mg/kg AOM, 2.5% DSS treatment; Cell culture (SW480 cells) w/ 100 nmol/L 1,25-OHD treatment | Serum vitamin D, calcium, creatinine levels; vitamin D (15, 30, or 60 IU⋅g−1⋅w−1); transient transfection, luciferase assay; RNA isolation, RT-PCR, immunoprecipitation and Western blotting | AOM/DSS treatment ↓ serum vitamin D levels; vitamin D administration significantly ↓ the number and colorectal neoplasms in a dose-dependent manner by up to 59%, ameliorated colon length shortening, ↓ cell proliferation in the colon ↓ β-catenin expression in vivo, ↑β-catenin binding to E-cadherin in vivo | Vitamin D is beneficial against AOM-DSS-induced colitis-associated carcinogenesis E-cadherin upregulation is beneficial on vitamin D’s preventive effect on β-catenin |
Fedirko et al. (2009) [72] | Randomized, double-blind, placebo-controlled, clinical trial in men and women (N = 92) with confirmed colorectal adenoma | Automated immunohistochemistry and image analysis to detect and quantify expression and distribution of p21waf1/cip1, MIB-1, and hTERT in colorectal crypts | p21 expression ↑ 2-fold in Vitamin D and Vitamin D plus calcium but not in placebo group; no change in MIB-1 or hTERT expression; proportion of hTERT extending into upper 40% of the crypts ↓ by 15% | Calcium and Vitamin D promote differentiation of colorectal epithelial cells and may regulate colorectal crypt proliferative zone in patients with sporadic adenoma |
Zhu et al. (2015) [73] | Biopsies from IBD patients; C57BL6/J mice treated with 100 mg/kg TNBS and randomly divided into 2 groups: TNBS and control w/ either paricalcitol 0.5 µg/kg body weight or dissolvent only | Western blotting, hematoxylin/eosin staining, serum vitamin D levels, FTC-dextran intestinal permeability | ↓ serum vitamin D and VDR among IBD patients; paricalcitol ↓ TNBS-induced colitis (i.e., minor weight loss, mild colitis, minimal histological damage), protects intestinal permeability, inhibits intestinal epithelial cell apoptosis by ↓ PUMA expression | Vitamin D and vitamin D analogs show promise when treating IBD by downregulating PUMA expression |
2.3.2. E-Cadherin
2.3.3. Wnt/β-Catenin
2.3.4. Cell Apoptosis
2.4. Vitamin D and Microbiota
Author (Year) | Study Type, Population | Measurements | Results | Conclusion |
---|---|---|---|---|
Sharifi et al. (2016) [17] | Double-blind, randomized, controlled trial with parallel design including UC patients in remission (N = 90) | Serum levels of 25-OHD, PTH, Calcium, ESR, and hs-CRP and cathelicidin expression via qRT-PCR pre and post 90 days of 300,000 IU intramuscular Vitamin D or saline placebo | From pre to post, ↑ 25 -OH D, ↑ hCAP18 (human cationic antimicrobial protein 18) gene expression, ↓ Hs-CRP and ↓ ESR only in Vitamin D group | Supplementation of Vitamin D may benefit UC patients as evidenced by ↓ ESR, ↓ hs-CRP, and ↑ LL37 gene expression |
Wu et al. (2015) [96] | C57BL/6 mice and VDR KO C57BL/6 mice; Salmonella-induced colitis mouse model | Salmonella infection Histology, Western blotting; immunofluorescence; VDR protein expression transcriptional activity; RT-PCR | VDR KO mice significantly lost more body weight, probiotics had no protection from Salmonella-induced colitis, and more Salmonella infection occurred compared to VDR+/+ mice; Lactobacillus rhamnosus strain GG (LGG) and Lactobacillus plantarum (LP) ↑ VDR expression in vitro | Probiotics are suggested to enhance VDR expression and may help protect against colitis |
Ananthakrishnan et al. (2014) [102] | Multi-institutional cohort of IBD patients (n = 3188); 35 patients developed Clostridium difficile infection (CDI) w/ mean age of 60.5 years old | Serum vitamin D level measurement via radioimmunoassay, high-performance liquid chromatography w/ mass spectrometry | IBD patients with CDI who died had a mean serum average of 12.8 + 8.1 ng/mL compared to IBD patients who remained alive at the end of follow up (24.3 + 13.2 ng/mL); 1 ng/mL increase in serum vitamin D = w/ a 4% CDI reduction | Higher serum vitamin D levels were associated with a decreased CDI risk |
Wu et al. (2015) [106] | Conditional VDR KO mouse model (VDRΔIEC) 5% DSS treatment, butyrate treatment (fermentation product of gut microbes) | Vitamin D-responsive element transcriptional activity, Western blotting, intestine histology, immunofluorescence, lysotracker staining, RT-PCR, chromatin immunoprecipitation (CHIP) assay | VDRΔIEC susceptible to DSS-induced colitis, ↓ weight, ↓ cecum length, fecal blood present, ↑ intestinal inflammation, fewer butyrate-producing bacteria and butyrate compared to no DSS treatment; butyrate ↑ VDR expression and inhibited inflammation; ↑ E. coli and Bacteriocides | VDR may help regulate intestinal homeostasis via production of antimicrobial peptides |
Lagishetty et al. (2010) [108] | C57BL/6 mice raised on a normal diet (n = 16) or vitamin D-deficient diet (n = 16) × 6 weeks 2.5% DSS treatment | Tissue collection/analysis, clinical colitis score, histological colitis score, flow cytometry, RT-PCR; Ang4 immunohistochemical analysis | Vitamin D-deficient mice treated with DSS had more severe colitis, ↓ colonic Ang4 expression, ↑ bacterial infiltration compared to mice with normal diet; DSS-treated vitamin D-deficient mice had ↓ serum vitamin D level (2.5 ± 0.1 ng/mL) compared to mice with normal diet (24.4 ± 1.8 ng/mL) | Ang4 promotes bacterial innate immunity against gut microbes and its function under a low serum vitamin D levels is impeded |
Ooi et al. (2013) [76] | Cyp wild-type mice, Cyp KO mice, VDR wild-type mice, VDR KO mice 3.5% DSS treatment x 5 days | Fecal samples from mice Denaturing gradient gel electrophoresis, metagenomic analysis, RT-PCR, cell isolation | Firmicutes and Bacteroidetes are the dominant phyla in all mice; Cyp KO and VDR KO had ↓ Firmicutes and Deferribacteres, ↑ Proteobacteria and Bacteroidetes phyla than wild-type mice; vitamin D treatment ↓ Helicobacteraceae | Vitamin D and VDR may influence microbiome composition and protect against GI insults |
Garg et al. (2018) [98] | Patients with active UC, inactive UC and noninflammatory bowel disease controls; received 40,000 units cholecalciferol weekly for 8 weeks. | Markers of inflammation and fecal microbiota | Patients with active UC ↓ faecal calprotectin levels; this did not change in patients with inactive UC or non-IBD controls. No changes in overall fecal bacterial diversity. were noted although a significant ↑ in Enterobacteriaceae abundance in patients with UC | Vitamin D supplementation reduced intestinal inflammation in patients with active UC, with an increase in Enterobacteriaceae and a trend to reduction in the mucolytic species Ruminococcus gnavus but no change in overall fecal microbial diversity |
Schaffler et al. (2018) [111] | A prospective, longitudinal, controlled interventional analysis in seven patients with Crohn’s disease (CD) in clinical remission and 10 healthy controls (HC); orally administration of vitamin D | Intestinal bacterial composition | ↓ bacterial richness in the CD microbiome. ↑ Alistipes, Barnesiella, unclassified Porphyromonadaceae (both Actinobacteria), Roseburia, Anaerotruncus, Subdoligranulum and an unclassified Ruminococaceae (all Firmicutes) | Vitamin D has a specific influence on the bacterial communities in CD, but not in HC. Administration of vitamin D may have a positive effect in CD by modulating the intestinal bacterial composition and also by increasing the abundance of potential beneficial bacterial strains. Vitamin D did not change the bacterial communities in HC. |
3. Discussion
4. Materials and Methods
Author Contributions
Funding
Conflicts of Interest
Abbreviations
25-OHD | 25-hydroxy vitamin D |
1,25-OHD | 1,25-duhydroxyvitamin D |
AOM | azoxymethane |
BMI | body mass index |
CDC | Centers for Disease Control and Prevention |
CDI | Clostridium difficile infection |
COX-2 | cyclooxygenase-2 |
CRP | C-reactive protein |
DRI | Dietary Reference Intake |
DSS | dextran sulfate sodium |
ERK | extracellular signal related kinase |
ESR | erythrocyte sedimentation rate |
hTERT | Telomerase reverse transcriptase |
IBD | inflammatory bowel disease |
IL-6 | interleukin-6 |
IU | international units |
MLCK | myosin light chain kinase pathway |
LL37 | cathelicidin |
MAPK | mitogen-activated protein kinase |
PUMA | p53-upregulated modulator of apoptosis |
RXRα | Retinoid X Receptor alpha |
TNBS | 2,4,6-trinitrobenzene sulfonic acid |
TNF-α | tumor necrosis factor-alpha |
UC | ulcerative colitis |
USDHHS | United States Department of Health and Human Services |
VDR | vitamin D receptor |
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Author (Year) | Study Type, Population | Measurements | Results | Conclusion |
---|---|---|---|---|
Brozek et al. (2012) [24] | Factor and cluster analysis of 105 patients undergoing primary curative surgery for adenocarcinomas | Expression of VDR, CYP27B1, CYP24A1 and COX-2 in relation to tumor grade, anatomical location, and gender | Compared to adjacent mucosa mRNA expression in cancerous lesions was ↑ in CYP27B1 (4-fold in low/high grade cancers), CYP24A1 (20-35-fold in low/high grade lesions) and COX-2 (2-fold in high grade cancers) but not VDR; in distal colon tumors CYP27B1 expression 2-fold ↑ in men than women | Antagonism between COX-2 and Vitamin D could be important factor in epithelial colorectal cancer cell growth; differences in COX-2 expression could influence variation in incidence at different anatomical subsites; cancer incidence gender-specific differences correlate with age |
Frăţilă & Iliaş (2013) [25] | Retrospective study 2006–2010 80 patients w/ longstanding ulcerative colitis (LUC) dx (42 women, 38 men) 53.5 ± 14.2 years old | Colonoscopy biopsies: 20 high-grade dysplasia (HGD), 20 low grade dysplasia (LGD), 20 regenerative atypia, 20 indefinite for dysplasia; immunohistochemical (IHC) staining applied for Ki-67, clone MIB-1, and anti-COX-2 | COX-2 is positive in 72.5% LUC biopsies; LGD and HGD had Ki-67 staining | IHC staining may be used to manage increased colorectal cancer risk in LUC patients |
Leedham et al. (2009) [26] | Mutation burden analysis of individual crypts across colitis associated neoplasms | PCR and sequencing analysis to establish individual crypt adenomatous polyposis coli (APC), p53, K-RAS, and 17p loss of heterozygosity mutation burden | Monoclonality observed in most lesions typically from p53 lesion and occasionally K-RAS | p53 mutation was the initiator in the majority of lesions; K-RAS activation found to be gatekeeping mutation |
Wang et al. (2014) [27] | Macrophages from COX-2 KO and COXNeo/Neo mice | COX-2 expression and PG expression in the presence and absence of LPS stimulation | 1,25-OHD results in dose-dependent inhibition of COX-2 expression and phosphorylation of Akt and IκBα in murine macrophages with and without LPS stimulation | Vitamin D influences inflammation and supplementation could improve chronic inflammatory diseases via targeting THEM4/Akt/NF-κB signaling |
Hummel et al. (2014) [16] | Adenocarcinoma cell line COGA-1A culture and treatment | COGA-1A cells treated with 10 nM 1,25-OHD, 100 ng/mL IL-6, 50 ng/mL or combination of for 6, 12, and 24 hrs; total RNA isolation; reverse transcription polymerase chain reaction (RT-PCR) | COGA-1A cells + 1,25-OHD = ↑ VDR expression; IL-6 ↑ CYP24A1 expression 3x; COX-2 and 15-PGH expression “unresponsive” with 1,25-OHD in COGA-1A cells, but TNF-α “highly ↑ COX-2 expression” | TNF-α and IL-6 inhibited vit D expression-activating gene CYP27B1 in COGA-1A cells |
Fichera et al. (2007) [28] | Male A/J mice (25 g) AOM/DSS-induced colitis | Vitamin D analog Ro26-2198 (0.01 µg/kg body wt/day x 28 days); severity of colitis assessed via the Disease Activity Index; hematoxylin and eosin colonic sections examined for dysplasia; colonic lysates assessed for c-Myc, COX-2, phosphor-(active) extracellular signal regulated kinase (ERK) via Western blotting | DSS treatment ↑ c-Myc 15-fold, ERK 10-fold, COX-2 2.5-fold Ro26-2198 ↓ proliferative (c-Myc, ERK) and pro-inflammatory (COX-2) signals and dysplasia progression | Vitamin D analog can be considered when treating colitis |
Liu et al. (2016) [29] | 25-OHD 1α-hydroxylase knockout (Cyp27b1−/−) mice fed high calcium, phosphate, and lactose rescue diet | Body weight, colon length, and colonic histologic structure | Cyp27b1-/- had ↓ bodyweight, colon length, colon length to bodyweight ratio, mucosa thickness and ↑ crypt damage | 1,25-OHD may influence colon inflammation and cancer development and progression |
Laverny et al. (2010) [30] | Peripheral blood mononuclear cells (PBMC) obtained from IBD patients (21 ulcerative colitis patients, 22 Crohn’s Disease patients) 26 males, 13 females; C57BL/6 mice w/ 3% DSS treatment; cell study | VDR agonist BXL-62 administration; histology; cytokine quantification; RT-PCR | BXL-62 has 3x less calcemic activity, ↓ proinflammatory cytokines in cells of IBD patients, ↑ CYP24A1 expression, ameliorates experimental colitis compared to 1,25-OHD | BXL-62 is a VDR agonist that does not promote hypercalcemia, ↓ in vitro pro-inflammatory cytokines, and may be used as IBD treatment |
Li et al. (2015) [31] | Gene therapy (regulate CYP27B1 expression via CD11b+/Gr1+ monocytes) in murine DSS-induced IBD model | Survival rate, weight, colonic structure, mucosal regeneration index, cytokine expression | ↑ survival, body weight gain, colon length, mucosal regeneration and ↓ proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-12, IL-23, Th1 and Th17) | This preliminary evidence of a monocyte-based adoptive CYP27B1 gene therapy in a murine IBD model may lead to novel therapy for autoimmune disease like IBD |
Chen et al. (2017) [32] | Genotyping of patients with colonic polyps (n = 144), colon cancer (n = 96), and UC (n = 44) to determine correlations between CYP24A1 SNPs and diseases | Genotyping of four SNPs (rs4809957, rs6068816, rs6091822 and rs8124792) and their association with colonic polyps, colon cancer, and UC | CYP24A1 polymorphisms rs4809957 A/G and rs6068816 C/T were associated with colonic polyps, colon cancer, and UC | rs4809957, rs6068816, rs6091822 and rs8124792 are related to risk of colonic polyps and cancer; the A allele in rs8124792 may indicate colonic polyps and cancer not UC |
Stio et al. (2006) [33] | PBMC of IBD patients; KH 1060 (vitamin D analog) treatment | [3H]thymidine incorporation; ELISA kit; VDR levels w/ Western blotting | KH 1060 ↓ PBMC proliferation, ↓ TNF-α, ↑ VDR expression | KH 1060 can be used on IBD patients to ↓ TNF-α |
Zhao et al. (2012) [34] | C57BL/6 mice (n = 30), equally divided among 3 groups: 2% DSS treatment, control, and vitamin D | Serum vitamin D levels, Rachmilewitz DAI (disease activity), colonic injury/inflammation; myeloperoxidase (MPO) activity, mesenteric lymph nodes cells (MLNs) and LPMC isolation; immunohistochemistry; immunofluorescence; in vivo/in vitro permeability; TEER measurement; qT-PCR; Western blotting | Serum vitamin D levels were ↓ in DSS group compared to control; DSS damaged mucosal barrier and ↑ colonic inflammation, ↑ weight loss; vitamin D inhibited colonic inflammation, maintained intestinal permeability, preserved colonic structural integrity, prevented DSS-induced tight junction disruption | Vitamin D warrants therapeutic potential against IBD |
Strauch et al. (2007) [35] | Female Balb/c mice w/ 3% DSS treatment; ZK191784 (vitamin D analog) 100 μg/kg per day | Histological examination; ELISA of MLNs; RT-PCR; immunohistochemistry | ZK191784 treatment ameliorates acute and chronic DSS-induced colitis, suppresses proinflammatory cytokine secretion by MLNs and primary dendritic cells | Another study by which vitamin D analog is shown to be beneficial against experimental colitis |
Verlinden et al. (2013) [36] | DSS-induced colitis in mice; TX527 (vitamin D analog) | Histological examination, transcript levels of proinflammatory cytokines | TX527 ameliorated DSS-colitis symptoms by ↓ diarrhea and bleeding, ↓ mucosal damage, crypt loss, immune cell infiltration, and ↓ proinflammatory cytokines (IL-1, IL-6, IFN-γ and TNF-α) | TX527 suggests therapeutic potential for IBD management |
D’Ambrosio et al. (1998) [37] | Cotransfected monocytic RAW264.7 cells with p40 promotor/reporter constructs and expression vectors of VDR and RXR-α | Expression of NF-κB pathway and cytokines following 1,25-OHD | 1,25-OH D caused downregulation of NF-κB activation and ↓ in downstream IL-12 | 1,25-OHD may downregulate IL-12 production via downregulation of NF-kB activation and p40-kB sequence binding |
Du et al. (2015) [38] | Cell study (HCT116, Caco-2, SW480) w/ TNF-α ± 1,25-OHD treatment; C57BL/6 mice w/ paricalcitol (vitamin D analog) treatment; Human colonic mucosal biopsies | Histology/immunostaining; Western blotting, RT-PCR, chromatin immunoprecipitation assay, myeloid perioxidase assay | TNF-α ↓ cells’ transepithelial electrical resistance (TER); > 70% VDR ↓ unable to counteract TNF-α activity and maintain TER; 1,25-OHD counteracts NF-κB by suppressing the myosin light chain kinase signaling pathway (MLCK); MLCK pathway activation = ↓ VDR in human biopsies; paricalcitol inhibits MLCK activation, regulates mucosal barrier, and ameliorates colitis in the mouse model | VDR is required to maintain and protect intestinal epithelial barrier |
Meeker et al. (2014) [8] | Smad3−/− mice fed w/ maintenance diet, high vitamin D diet (5 IU/g), or vitamin D-deficient (1 IU/g) diet infected with ~2 × 107 CFU Hb in Brucella broth or Brucella broth alone (control) | Helicobacter bilis infection; Fecal polymerase chain reaction; serum vitamin D and calcium; histopathology; immunochemistry; epithelial and lamina propria leukocyte cell samples; Western blotting | ↑ vitamin D diet after H. bilis infection = ↑ serum vitamin D w/o affecting calcium levels. ↓ dysplasia, ↓ inflammation (MAPK, NF-κB), ↓ IBD scores | Vitamin D intake suggests reduced colitis symptoms and delay progression to early stage carcinogenesis |
Knackstedt et al. (2013) [13] | Female C57BL/6J mice fed normal chow or vitamin D-deficient diet; Acute colitis: 10 mg/kg AOM + 2% DSS treatment Colitis-associated cancer (CAC): 12 mg/kg AOM + 4% DSS treatment | Vitamin D quantification; colitis scoring; immunohistochemistry; protein extraction; immunoblotting; RT-PCR | AOM/DSS-induced acute colitis mice had ↓ body weight, ↑ blood loss, shortened colon, ↓ serum vitamin D compared to control; CAC model had mortality rate between 10–40%, shortened colon, ↓ serum vitamin D, TNF-α upregulated, RXRα and VDR downregulated | Vitamin D-deficient diet leads to increased colitis scores in the mouse model, downregulated RXRα, VDR, and decreased serum vitamin D levels |
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Garcia, P.M.; Moore, J.; Kahan, D.; Hong, M.Y. Effects of Vitamin D Supplementation on Inflammation, Colonic Cell Kinetics, and Microbiota in Colitis: A Review. Molecules 2020, 25, 2300. https://doi.org/10.3390/molecules25102300
Garcia PM, Moore J, Kahan D, Hong MY. Effects of Vitamin D Supplementation on Inflammation, Colonic Cell Kinetics, and Microbiota in Colitis: A Review. Molecules. 2020; 25(10):2300. https://doi.org/10.3390/molecules25102300
Chicago/Turabian StyleGarcia, Patricia Mae, Jeff Moore, David Kahan, and Mee Young Hong. 2020. "Effects of Vitamin D Supplementation on Inflammation, Colonic Cell Kinetics, and Microbiota in Colitis: A Review" Molecules 25, no. 10: 2300. https://doi.org/10.3390/molecules25102300