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Kafentzi T, Tsounis EP, Tourkochristou E, Avramopoulou E, Aggeletopoulou I, Geramoutsos G, Sotiropoulos C, Pastras P, Thomopoulos K, Theocharis G, Triantos C. Genetic Polymorphisms (ApaI, FokI, BsmI, and TaqI) of the Vitamin D Receptor (VDR) Influence the Natural History and Phenotype of Crohn's Disease. Int J Mol Sci 2025; 26:1848. [PMID: 40076474 PMCID: PMC11899612 DOI: 10.3390/ijms26051848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 02/14/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Vitamin D receptor (VDR) single-nucleotide polymorphisms (SNPs) modulate vitamin D/VDR signaling, a key pathway in inflammatory bowel disease (IBD) pathogenesis. This study investigates how ApaI, BsmI, TaqI, and FokI SNPs affect IBD phenotype and progression. A total of 76 Crohn's disease (CD) and 68 ulcerative colitis (UC) patients were genotyped. On initial bivariate analysis, the AA genotype of ApaI was accompanied by higher rates of penetrating (B3) CD (36.7% vs. 8.7%; p = 0.012). The FokI SNP was associated with disease location, with the ff genotype predisposing to CD and affecting the upper GI (36.4% vs. 7.7%; p = 0.044) or the colon (90.9% vs. 50.8%; p = 0.038). Moreover, patients harboring the ApaI A allele (AA/Aa) experienced higher rates of steroid-refractory or steroid-dependent CD. In multivariate analyses, the aa genotype showed a protective effect against hospitalization (aOR = 0.17; p = 0.013) in CD, whereas the TT genotype emerged as an independent risk factor (aOR = 4.79; p = 0.044). Moreover, the aa genotype was independently associated with a decreased risk of IBD-related surgery (aOR = 0.055; p = 0.014). VDR SNPs, particularly ApaI, influence disease phenotype, progression, and treatment response in CD. The aa genotype of ApaI appears to confer protection against adverse disease outcomes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, 26504 Patras, Greece; (T.K.); (E.P.T.); (E.T.); (E.A.); (I.A.); (G.G.); (C.S.); (P.P.); (K.T.); (G.T.)
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Rizwan M, Cheng K, Gang Y, Hou Y, Wang C. Immunomodulatory Effects of Vitamin D and Zinc on Viral Infection. Biol Trace Elem Res 2025; 203:1-17. [PMID: 38451442 DOI: 10.1007/s12011-024-04139-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 03/02/2024] [Indexed: 03/08/2024]
Abstract
Several nutrients are crucial in enhancing the immune system and preserving the structural integrity of bodily tissue barriers. Vitamin D (VD) and zinc (Zn) have received considerable interest due to their immunomodulatory properties and ability to enhance the body's immune defenses. Due to their antiviral, anti-inflammatory, antioxidative, and immunomodulatory properties, the two nutritional powerhouses VD and Zn are crucial for innate and adaptive immunity. As observed with COVID-19, deficiencies in these micronutrients impair immune responses, increasing susceptibility to viral infections and severe disease. Ensuring an adequate intake of VD and Zn emerges as a promising strategy for fortifying the immune system. Ongoing clinical trials are actively investigating their potential therapeutic advantages. Beyond the immediate context of the pandemic, these micronutrients offer valuable tools for enhancing immunity and overall well-being, especially in the face of future viral threats. This analysis emphasizes the enduring significance of VD and Zn as both treatment and preventive measures against potential viral challenges beyond the current health crisis. The overview delves into the immunomodulatory potential of VD and Zn in combating viral infections, with particular attention to their effects on animals. It provides a comprehensive summary of current research findings regarding their individual and synergistic impacts on immune function, underlining their potential in treating and preventing viral infections. Overall, this overview underscores the need for further research to understand how VD and Zn can modulate the immune response in combatting viral diseases in animals.
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Affiliation(s)
- Muhammad Rizwan
- College of Fisheries, Huazhong Agriculture University, Wuhan, 430070, China
| | - Ke Cheng
- College of Fisheries, Huazhong Agriculture University, Wuhan, 430070, China
| | - Yang Gang
- College of Fisheries, Huazhong Agriculture University, Wuhan, 430070, China
| | - Yuntao Hou
- College of Fisheries, Huazhong Agriculture University, Wuhan, 430070, China
| | - Chunfang Wang
- College of Fisheries, Huazhong Agriculture University, Wuhan, 430070, China.
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Śledzińska K, Kloska A, Jakóbkiewicz-Banecka J, Landowski P, Oppmann A, Wilczynski S, Zagierska A, Kamińska B, Żmijewski MA, Liberek A. The Role of Vitamin D and Vitamin D Receptor Gene Polymorphisms in the Course of Inflammatory Bowel Disease in Children. Nutrients 2024; 16:2261. [PMID: 39064704 PMCID: PMC11279567 DOI: 10.3390/nu16142261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 07/05/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Background: The etiopathogenesis of inflammatory bowel disease (IBD) is still unclear. Prior studies suggest genetic components that may influence the incidence and severity of the disease. Additionally, it was shown that low levels of serum vitamin D may have an impact on the clinical course of the disease due to its effect on the immunological system. Methods: We aimed to investigate the correlation between the incidence of vitamin D receptor (VDR) gene polymorphisms (rs11568820, rs10735810, rs1544410, rs7975232, and rs731236, commonly described as Cdx2, FokI, Bsm, ApaI, and TaqI, respectively) and vitamin D concentration with the clinical course of IBD (disease activity, extent of the intestinal lesions). Data were obtained from 62 patients with IBD (34 with Crohn's disease, 28 with ulcerative colitis), aged 3-18 years, and compared with controls (N = 47), aged 8-18 years. Results: Although there was no difference in the incidence of individual genotypes between the study groups (IBD, C) in all the polymorphisms examined, we described a significant increase in the chance of developing IBD for heterozygotes of Cdx2 (OR: 2.3, 95% CI 0.88-6.18, p = 0.04) and BsmI (OR: 2.07, 95% CI 0.89-4.82, p = 0.048) polymorphisms. The mean serum 25OHD level in patients with IBD was significantly higher compared with the controls (19.87 ng/mL vs. 16.07 ng/mL; p = 0.03); however, it was still below optimal (>30 ng/mL). Furthermore, a significant correlation was found between vitamin D level and TaqI in patients with IBD (p = 0.025) and patients with CD (p = 0.03), as well as with the BsmI polymorphism in patients with IBD (p = 0.04) and patients with CD (p = 0.04). A significant correlation was described between the degree of disease activity and genotypes for the FokI polymorphism in patients with UC (p = 0.027) and between the category of endoscopic lesions and genotypes for the Cdx2 polymorphism also in patients with UC (p = 0.046). Conclusions: The results suggest a potential correlation of VDR gene polymorphism with the chance of developing IBD, and the clinical course of the disease requires further studies in larger group of patients. Vitamin D supplementation should be recommended in both children with inflammatory bowel disease and in healthy peers.
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Affiliation(s)
- Karolina Śledzińska
- Department of Paediatrics, Haematology and Oncology, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Anna Kloska
- Department of Medical Biology and Genetics, University of Gdańsk, 80-308 Gdansk, Poland; (A.K.); (J.J.-B.)
| | | | - Piotr Landowski
- Department of Paediatrics, Gastroenterology, Nutrition and Allergology, Medical University of Gdansk, 80-210 Gdansk, Poland; (P.L.); (A.Z.); (B.K.)
| | - Aleksandra Oppmann
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland; (A.O.); (S.W.)
| | - Stephen Wilczynski
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland; (A.O.); (S.W.)
| | - Agnieszka Zagierska
- Department of Paediatrics, Gastroenterology, Nutrition and Allergology, Medical University of Gdansk, 80-210 Gdansk, Poland; (P.L.); (A.Z.); (B.K.)
| | - Barbara Kamińska
- Department of Paediatrics, Gastroenterology, Nutrition and Allergology, Medical University of Gdansk, 80-210 Gdansk, Poland; (P.L.); (A.Z.); (B.K.)
| | - Michał A. Żmijewski
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland; (A.O.); (S.W.)
| | - Anna Liberek
- Department of Pediatrics, St. Adalbert Hospital, Copernicus PL Ltd., 80-462 Gdansk, Poland;
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Cusato J, Cafasso C, Antonucci M, Palermiti A, Manca A, Caviglia GP, Vernero M, Armandi A, Saracco GM, D’Avolio A, Ribaldone DG. Correlation between Polymorphisms of Vitamin D Metabolism Genes and Perianal Disease in Crohn's Disease. Biomedicines 2024; 12:320. [PMID: 38397922 PMCID: PMC10886824 DOI: 10.3390/biomedicines12020320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 01/23/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
Although the role of vitamin D (VD) in the pathogenesis and progression of Crohn's disease (CD) is known, the association between single-nucleotide polymorphisms (SNPs) of genes linked to vitamin D pathway and CD risk is still under study. Furthermore, no significant association has been previously found between these SNPs and perianal CD (pCD), a severe phenotypic manifestation of CD that may present as perianal fistula, abscess, and recto-vaginal fistula. Among the mechanisms involved in its pathogenesis, local inflammation and intestinal microbiota alteration are recognized. VD seems to act on these elements. The aim of this study was to evaluate the presence of an association between SNPs of genes coding for enzymes, transporters, and receptors involved in the VD pathway and the occurrence of pCD. Blood samples of 206 patients with CD, including 34 with pCD, were analyzed for VDR, CYP27B1, CYP24A1, and GC genetic variants. VDR Apal Aa genotype and VDR BsmI Bb genotype resulted in an association with pCD (p = 0.01 and p = 0.02, respectively). Our study demonstrates for the first time the impact of the polymorphisms of genes associated with the VD pathway on the onset of pCD. Future multicenter studies are needed to confirm these data.
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Affiliation(s)
- Jessica Cusato
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
| | - Carla Cafasso
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
| | - Miriam Antonucci
- SCDU Infectious Diseases, Amedeo di Savoia Hospital, ASL Città di Torino, 10149 Turin, Italy;
| | - Alice Palermiti
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
| | - Alessandra Manca
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
| | - Gian Paolo Caviglia
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
| | - Marta Vernero
- Gastroenterology-U, “Città della Salute e della Scienza” Hospital, 10126 Turin, Italy;
| | - Angelo Armandi
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
| | - Giorgio Maria Saracco
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
| | - Antonio D’Avolio
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
| | - Davide Giuseppe Ribaldone
- Department of Medical Sciences, Division of Gastroenterology, University of Torino, 10126 Turin, Italy; (J.C.); (C.C.); (A.P.); (A.M.); (G.P.C.); (A.A.); (G.M.S.); (A.D.)
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Cantorna MT, Arora J. Vitamin D, microbiota, and inflammatory bowel disease. FELDMAN AND PIKE'S VITAMIN D 2024:1057-1073. [DOI: 10.1016/b978-0-323-91338-6.00047-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Cantorna MT, Arora J. Two lineages of immune cells that differentially express the vitamin D receptor. J Steroid Biochem Mol Biol 2023; 228:106253. [PMID: 36657728 PMCID: PMC10006341 DOI: 10.1016/j.jsbmb.2023.106253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/29/2022] [Accepted: 01/15/2023] [Indexed: 01/17/2023]
Abstract
Since 1983 it has been known that monocytes and activated T and B cells expressed the vitamin D receptor (VDR) and are therefore vitamin D targets. New data identified two lineages of immune cells that can be differentiated by the expression of the VDR. Monocytes, macrophages, neutrophils, and hematopoietic stem cells were mostly from VDR positive lineages. T cells, ILC1 and ILC3 were also largely VDR positive, which is consistent with the known effects of vitamin D as regulators of type-1 and type-3 immunity. Activation of the VDR negative T cells did not induce the expression of the VDR reporter, suggesting that perhaps only a subset of the T cells in the periphery express the VDR. When activated, the VDR negative T cells responded as if they were VDR knockout T cells in that they made more IFN-γ and proliferated faster than the VDR positive T cells. The ability of vitamin D to regulate immune function will depend on which cells express the VDR and a better understanding of the signals that regulate VDR expression in immune cells.
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Affiliation(s)
- Margherita T Cantorna
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, United States.
| | - Juhi Arora
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, United States
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Saha A, Dreyfuss I, Sarfraz H, Friedman M, Markowitz J. Dietary Considerations for Inflammatory Bowel Disease Are Useful for Treatment of Checkpoint Inhibitor-Induced Colitis. Cancers (Basel) 2022; 15:84. [PMID: 36612082 PMCID: PMC9817715 DOI: 10.3390/cancers15010084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.
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Affiliation(s)
- Aditi Saha
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Isabella Dreyfuss
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Humaira Sarfraz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Mark Friedman
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Joseph Markowitz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
- Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA
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Genetic Aspects of Micronutrients Important for Inflammatory Bowel Disease. Life (Basel) 2022; 12:life12101623. [PMID: 36295058 PMCID: PMC9604584 DOI: 10.3390/life12101623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/07/2022] [Accepted: 10/08/2022] [Indexed: 11/16/2022] Open
Abstract
Inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are complex diseases whose etiology is associated with genetic and environmental risk factors, among which are diet and gut microbiota. To date, IBD is an incurable disease and the main goal of its treatment is to reduce symptoms, prevent complications, and improve nutritional status and the quality of life. Patients with IBD usually suffer from nutritional deficiency with imbalances of specific micronutrient levels that contribute to the further deterioration of the disease. Therefore, along with medications usually used for IBD treatment, therapeutic strategies also include the supplementation of micronutrients such as vitamin D, folic acid, iron, and zinc. Micronutrient supplementation tailored according to individual needs could help patients to maintain overall health, avoid the triggering of symptoms, and support remission. The identification of individuals’ genotypes associated with the absorption, transport and metabolism of micronutrients can modify future clinical practice in IBD and enable individualized treatment. This review discusses the personalized approach with respect to genetics related to micronutrients commonly used in inflammatory bowel disease treatment.
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Triantos C, Aggeletopoulou I, Mantzaris GJ, Mouzaki Α. Molecular basis of vitamin D action in inflammatory bowel disease. Autoimmun Rev 2022; 21:103136. [DOI: 10.1016/j.autrev.2022.103136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 06/29/2022] [Indexed: 12/15/2022]
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Vitamin D Receptor Influences Intestinal Barriers in Health and Disease. Cells 2022; 11:cells11071129. [PMID: 35406694 PMCID: PMC8997406 DOI: 10.3390/cells11071129] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/12/2022] Open
Abstract
Vitamin D receptor (VDR) executes most of the biological functions of vitamin D. Beyond this, VDR is a transcriptional factor regulating the expression levels of many target genes, such as genes for tight junction proteins claudin-2, -5, -12, and -15. In this review, we discuss the progress of research on VDR that influences intestinal barriers in health and disease. We searched PubMed and Google Scholar using key words vitamin D, VDR, tight junctions, cancer, inflammation, and infection. We summarize the literature and progress reports on VDR regulation of tight junction distribution, cellular functions, and mechanisms (directly or indirectly). We review the impacts of VDR on barriers in various diseases, e.g., colon cancer, infection, inflammatory bowel disease, and chronic inflammatory lung diseases. We also discuss the limits of current studies and future directions. Deeper understanding of the mechanisms by which the VDR signaling regulates intestinal barrier functions allow us to develop efficient and effective therapeutic strategies based on levels of tight junction proteins and vitamin D/VDR statuses for human diseases.
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Gleba JJ, Kłopotowska D, Banach J, Turlej E, Mielko KA, Gębura K, Bogunia-Kubik K, Kutner A, Wietrzyk J. Polymorphism of VDR Gene and the Sensitivity of Human Leukemia and Lymphoma Cells to Active Forms of Vitamin D. Cancers (Basel) 2022; 14:387. [PMID: 35053549 PMCID: PMC8774213 DOI: 10.3390/cancers14020387] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/12/2022] [Accepted: 01/12/2022] [Indexed: 12/22/2022] Open
Abstract
The active forms of vitamin D3 (calcitriol and tacalcitol) coupled to the vitamin D receptor (VDR) are known to exhibit anti-cancer properties. However, not all cancer cells are sensitive to the active forms of vitamin D3 and its analogs. The study aimed to determine whether polymorphism of VDR is responsible for the sensitivity of human leukemia and lymphoma cells to calcitriol and tacalcitol. The impact of calcitriol and tacalcitol on the proliferation and morphology of nine different leukemia and lymphoma cell lines was determined. Only MV-4-11, Thp-1, and HL-60 cell lines sensitive to proliferation inhibition by calcitriol and tacalcitol showed morphology changes. Subsequently, the levels of the VDR and 1,25D3-MARRS proteins of calcitriol and tacalcitol binding receptors and the VDR receptor polymorphism in human leukemia and lymphoma cells were ascertained. Contrary to the current understanding, higher levels of VDR are not responsible for the greater sensitivity of cells to calcitriol and tacalcitol. Importantly, we first showed that sensitivity to calcitriol and tacalcitol in leukemias and lymphomas could be determined by the VDR polymorphism. The FokI polymorphism and the presence of the "bat" haplotype were observed only in the sensitive cells.
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Affiliation(s)
- Justyna Joanna Gleba
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
| | - Dagmara Kłopotowska
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
| | - Joanna Banach
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
| | - Eliza Turlej
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
- Department of Experimental Biology, Wroclaw University of Environmental and Life Sciences, Norwida 27 B, 50-375 Wroclaw, Poland;
| | - Karolina Anna Mielko
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
- Department of Biochemistry, Molecular Biology and Biotechnology, Faculty of Chemistry, Wroclaw University of Science and Technology, Norwida 4/6, 50-373 Wroclaw, Poland;
| | - Katarzyna Gębura
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (K.G.); (K.B.-K.)
| | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (K.G.); (K.B.-K.)
| | - Andrzej Kutner
- Department of Bioanalysis and Drug Analysis, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha, 02-097 Warsaw, Poland;
| | - Joanna Wietrzyk
- Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53–114 Wroclaw, Poland; (D.K.); (J.B.); (J.W.)
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12
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Yang Y, Cui X, Li J, Wang H, Li Y, Chen Y, Zhang H. Clinical evaluation of vitamin D status and its relationship with disease activity and changes of intestinal immune function in patients with Crohn's disease in the Chinese population. Scand J Gastroenterol 2021; 56:20-29. [PMID: 33205696 DOI: 10.1080/00365521.2020.1844793] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND High prevalence of vitamin D deficiency has been found among Crohn's disease (CD) patients. Vitamin D probably participates in the pathogenesis of CD, but this idea remains controversial. This study was to investigate the levels of vitamin D in CD patients and analyze the relationship between vitamin D and intestinal inflammation. METHODS Vitamin D levels were measured by chemiluminescence immunoassay in 198 CD patients (96 in active, 102 in remission) and 100 healthy controls. The correlation between vitamin D levels and clinical parameters was analysed. The expression of intestinal tight junction (TJ) proteins in CD patients was measured by immunofluorescence staining. Treg and Th17 percentages in the peripheral blood were determined by flow cytometry. RESULTS CD patients exhibited significantly lower 25(OH)D levels than healthy controls, especially in active CD patients. Serum 25(OH)D levels in CD patients were negatively correlated with the CD activity index (CDAI), the simple endoscopic score for CD (SES-CD), and inflammatory markers, including erythrocyte sedimentation rate (ESR), platelet (PLT) count and faecal calprotectin (FC) levels. Moreover, in patients with vitamin D deficiency, the expression of TJ proteins (Occludin, claudin-1, ZO-1 and JAM-1) in the intestinal mucosa was reduced, and Treg cells in the peripheral blood were decreased, while Th17 cells were increased compared to those with vitamin D sufficiency and controls. CONCLUSIONS Vitamin D deficiency in CD patients is common. Vitamin D is associated with disease activity and intestinal inflammation, which may affect the Treg/Th17 balance and the expression of gut TJ proteins.
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Affiliation(s)
- Yan Yang
- Department of Gastroenterology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China.,Department of Gastroenterology, First Affliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Xiufang Cui
- Department of Gastroenterology, First Affliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Jiajia Li
- Department of Gastroenterology, First Affliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
| | - Haiyang Wang
- Department of Gastroenterology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yi Li
- Department of Gastroenterology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yunzi Chen
- Department of Immunology, Nanjing Medical University, Nanjing, China
| | - Hongjie Zhang
- Department of Gastroenterology, First Affliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, P.R. China
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13
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Levels of Vitamin D Are Low After Crohn's Disease Is Established But Not Before. Clin Gastroenterol Hepatol 2020; 18:1769-1776.e1. [PMID: 31589971 PMCID: PMC7163919 DOI: 10.1016/j.cgh.2019.09.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 09/04/2019] [Accepted: 09/26/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Low serum levels of vitamin D have been associated with Crohn's disease (CD). However, it is unclear whether low vitamin D levels cause CD or CD reduces serum vitamin D. METHODS United States military personnel with CD (n = 240) and randomly selected individuals without CD (controls, n = 240) were matched by age, sex, race, military branch, and geography. We measured 25-hydroxyvitamin D in sera 8-3 years (pre-2) and 3 years to 3 months before diagnosis (pre-1) and 3 months before through 21 months after diagnosis (pre-0). We genotyped VDR and GC vitamin D related polymorphisms. We used conditional logistic regression, including adjustments for smoking, season, enlistment status, and deployment, to estimate relative odds of CD according to vitamin D levels and interactions between genetic factors and levels of vitamin D. RESULTS Levels of vitamin D before diagnosis were not associated with CD in pre-2 (P trend = .65) or pre-1 samples (P trend = .84). However, we found an inverse correlation between CD and highest tertile of vitamin D level in post-diagnosis samples (P trend = .01; odds ratio, 0.51; 95% CI, 0.30-0.86). Interactions were not detected between vitamin D levels and VDR or GC polymorphisms. We observed an association between VDR Taq1 polymorphism and CD (independent of vitamin D) (P = .02). CONCLUSIONS In serum samples from military personnel with CD and matched controls, we found no evidence for an association between CD and vitamin D levels up to 8 years before diagnosis. However, we observed an inverse-association between post-diagnosis vitamin D levels and CD. These findings suggest that low vitamin D does not contribute to development of CD-instead, CD leads to low vitamin D.
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14
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Zhang Y, Cai JZ, Xiao L, Chung HK, Ma XX, Chen LL, Rao JN, Wang JY. RNA-binding protein HuR regulates translation of vitamin D receptor modulating rapid epithelial restitution after wounding. Am J Physiol Cell Physiol 2020; 319:C208-C217. [PMID: 32432928 DOI: 10.1152/ajpcell.00009.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Homeostasis of the intestinal epithelium is tightly regulated by numerous extracellular and intracellular factors including vitamin D and the vitamin D receptor (VDR). VDR is highly expressed in the intestinal epithelium and is implicated in many aspects of gut mucosal pathophysiology, but the exact mechanism that controls VDR expression remains largely unknown. The RNA-binding protein human antigen R (HuR) regulates the stability and translation of target mRNAs and thus modulates various cellular processes and functions. Here we report a novel role of HuR in the posttranscriptional control of VDR expression in the intestinal epithelium. The levels of VDR in the intestinal mucosa decreased significantly in mice with ablated HuR, compared with control mice. HuR silencing in cultured intestinal epithelial cells (IECs) also reduced VDR levels, whereas HuR overexpression increased VDR abundance; neither intervention changed cellular Vdr mRNA content. Mechanistically, HuR bound to Vdr mRNA via its 3'-untranslated region (UTR) and enhanced VDR translation in IECs. Moreover, VDR silencing not only inhibited IEC migration over the wounded area in control cells but also prevented the increased migration in cells overexpressing HuR, although it did not alter IEC proliferation in vitro and growth of intestinal organoids ex vivo. The human intestinal mucosa from patients with inflammatory bowel diseases exhibited decreased levels of both HuR and VDR. These results indicate that HuR enhances VDR translation by directly interacting with its mRNA via 3'-UTR and that induced VDR by HuR is crucial for rapid intestinal epithelial restitution after wounding.
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Affiliation(s)
- Yunzhan Zhang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Jia-Zhong Cai
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Lan Xiao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Hee K Chung
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Xiang-Xue Ma
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Lin-Lin Chen
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Jaladanki N Rao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Jian-Ying Wang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland.,Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.,Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
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15
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The relationship between selected VDR gene polymorphisms and susceptibility to inflammatory bowel disease in Slovak population. Biologia (Bratisl) 2019. [DOI: 10.2478/s11756-019-00212-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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16
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Nobile S, Tenace MA, Pappa HM. The Role of Vitamin D in the Pathogenesis of Inflammatory Bowel Disease. GASTROINTESTINAL DISORDERS 2019; 1:231-240. [DOI: 10.3390/gidisord1010018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Vitamin D has a complex role in the pathogenesis of inflammatory bowel disease (IBD), which is still under investigation. We conducted a literature search using PubMed through December 2018 through the use of relevant search terms. We found an abundance of evidence to support the role of vitamin D in regulating the innate and adaptive arms of the immune system. The pathogenesis of IBD implicates the immune dysregulation of these immune system components. Proof of concept of the vitamin’s role in the pathogenesis of IBD is the mapping of the vitamin D receptor in a region of chromosome 12, where IBD is also mapped, and specific VDR polymorphisms’ link to IBD phenotypes. Further research is needed to better delineate vitamin D’s role in preventing IBD and its potential as a therapeutic target for this disease.
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Affiliation(s)
- Stefano Nobile
- Department of Mother and Child Health, Salesi Children’s Hospital, via F. Corridoni 11, 60123 Ancona, Italy
| | - Michela A. Tenace
- Department of Mother and Child Health, Salesi Children’s Hospital, via F. Corridoni 11, 60123 Ancona, Italy
| | - Helen M. Pappa
- Division of Pediatric Gastroenterology and Hepatology, SSM Health Cardinal Glennon Children’s Hospital, Saint Louis University, St. Louis, MO 63104, USA
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17
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Opstelten JL, Chan SSM, Hart AR, van Schaik FDM, Siersema PD, Lentjes EGWM, Khaw KT, Luben R, Key TJ, Boeing H, Bergmann MM, Overvad K, Palli D, Masala G, Racine A, Carbonnel F, Boutron-Ruault MC, Tjønneland A, Olsen A, Andersen V, Kaaks R, Kühn T, Tumino R, Trichopoulou A, Peeters PHM, Verschuren WMM, Witteman BJM, Oldenburg B. 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 Dis 2018; 24:633-640. [PMID: 29462382 DOI: 10.1093/ibd/izx050] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Indexed: 12/12/2022]
Abstract
Background A low vitamin D status has been put forward as a potential risk factor for the development of inflammatory bowel disease (IBD). This study investigated the association between prediagnostic circulating vitamin D concentrations and dietary intakes of vitamin D, and the risk of Crohn's disease (CD) and ulcerative colitis (UC). Methods Among 359,728 participants of the European Prospective Investigation into Cancer and Nutrition cohort, individuals who developed CD or UC after enrollment were identified. Each case was matched with2 controls by center, gender, age, date of recruitment, and follow-up time. At cohort entry, blood samples were collected and dietary vitamin D intakes were obtained from validated food frequency questionnaires. Serum 25-hydroxyvitamin D levels were measured using liquid chromatography-tandem mass spectrometry. Conditional logistic regression was performed to determine the odds of CD and UC. Results Seventy-two participants developed CD and 169 participants developed UC after a median follow-up of 4.7 and 4.1 years, respectively. Compared with the lowest quartile, no associations with the 3 higher quartiles of vitamin D concentrations were observed for CD (p trend = 0.34) or UC (p trend = 0.66). Similarly, no associations were detected when serum vitamin D levels were analyzed as a continuous variable. Dietary vitamin D intakes were not associated with CD (p trend = 0.39) or UC (p trend = 0.83). Conclusions Vitamin D status was not associated with the development of CD or UC. This does not suggest a major role for vitamin D deficiency in the etiology of IBD, although larger studies are needed to confirm these findings.
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Affiliation(s)
- Jorrit L Opstelten
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Simon S M Chan
- Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
- Department of Gastroenterology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, United Kingdom
| | - Andrew R Hart
- Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
- Department of Gastroenterology, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, United Kingdom
| | - Fiona D M van Schaik
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Peter D Siersema
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Eef G W M Lentjes
- Department of Clinical Chemistry and Hematology, University Medical Center, Utrecht, the Netherlands
| | - Kay-Tee Khaw
- Strangeways Research Laboratory, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
| | - Robert Luben
- Strangeways Research Laboratory, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom
| | - Timothy J Key
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
| | - Heiner Boeing
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
| | - Manuela M Bergmann
- Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany
| | - Kim Overvad
- Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
| | - Domenico Palli
- Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy
| | - Giovanna Masala
- Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy
| | - Antoine Racine
- Center for Research in Epidemiology and Population Health, French Institute of Health and Medical Research (Inserm), Institut Gustave Roussy, Villejuif, France
- Department of Gastroenterology, University Hospital of Bicêtre, Assistance Publique - Hôpitaux de Paris, Université Paris-Sud, Le Kremlin Bicêtre, France
| | - Franck Carbonnel
- Center for Research in Epidemiology and Population Health, French Institute of Health and Medical Research (Inserm), Institut Gustave Roussy, Villejuif, France
- Department of Gastroenterology, University Hospital of Bicêtre, Assistance Publique - Hôpitaux de Paris, Université Paris-Sud, Le Kremlin Bicêtre, France
| | - Marie-Christine Boutron-Ruault
- Center for Research in Epidemiology and Population Health, French Institute of Health and Medical Research (Inserm), Institut Gustave Roussy, Villejuif, France
| | - Anne Tjønneland
- Unit of Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Anja Olsen
- Unit of Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Vibeke Andersen
- Institute of Regional Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark
| | - Rudolf Kaaks
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rosario Tumino
- Cancer Registry and Histopathology Unit, "Civic-M.P. Arezzo" Hospital, Ragusa, Italy
| | | | - Petra H M Peeters
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
- MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom
| | - W M Monique Verschuren
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
- Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Ben J M Witteman
- Department of Gastroenterology and Hepatology, Gelderse Vallei Hospital, Ede, the Netherlands
- Division of Human Nutrition, Wageningen University, Wageningen, the Netherlands
| | - Bas Oldenburg
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
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18
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Hu MD, Edelblum KL. Sentinels at the frontline: the role of intraepithelial lymphocytes in inflammatory bowel disease. ACTA ACUST UNITED AC 2017; 3:321-334. [PMID: 29242771 DOI: 10.1007/s40495-017-0105-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Purpose of review Intestinal mucosal immunity is tightly regulated to ensure effective host defense against invasive microorganisms while limiting the potential for aberrant damage. In inflammatory bowel disease (IBD), an imbalance between effector and regulatory T cell populations results in an uncontrolled inflammatory response to commensal bacteria. Intraepithelial lymphocytes (IEL) are perfectly positioned within the intestinal epithelium to provide the first line of mucosal defense against luminal microbes or rapidly respond to epithelial injury. This review will highlight how IELs promote protective intestinal immunity and discuss the evidence indicating that altered IEL responses contribute to the pathogenesis of IBD. Recent findings Although the role of IELs in mucosal homeostasis has been largely underappreciated, many of the same factors that contribute to the dysregulation of host defense in IBD also adversely affect IELs. For example, IL-23 and the endoplasmic reticulum stress response can enhance IEL lytic activity toward enterocytes. Microbial dysbiosis or defective microbial recognition results in the loss of regulatory IELs, further amplifying these pro-inflammatory effects. Migration of T cells into or within the intraepithelial compartment has a profound effect on their differentiation or effector function demonstrating that IELs are exquisitely sensitive to changes in the local intestinal microenvironment. Summary Enhanced mechanistic insight into the regulation of IEL survival, differentiation and effector function may provide useful tools to modulate IEL surveillance or enhance IEL regulatory function. Elucidation of these processes may result in the development of novel therapeutics to reduce intestinal inflammation and reinforce the mucosal barrier in IBD.
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Affiliation(s)
- Madeleine D Hu
- Center for Immunity and Inflammation, Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ 07103
| | - Karen L Edelblum
- Center for Immunity and Inflammation, Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ 07103
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19
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Limketkai BN, Bechtold ML, Nguyen DL. Vitamin D and the Pathogenesis of Inflammatory Bowel Disease. Curr Gastroenterol Rep 2016; 18:52. [PMID: 27538982 DOI: 10.1007/s11894-016-0526-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Vitamin D has traditionally been known for its role in bone metabolism, but emerging evidence has suggested a broader role for vitamin D in immune regulation. Vitamin D deficiency has been associated with the pathogenesis of diverse autoimmune disorders and has similarly been implicated as a contributor to inflammatory bowel disease. In this review, we discuss animal, in vitro, genetic, and epidemiologic studies that have linked vitamin D deficiency with inflammatory bowel disease pathogenesis or severity. Nonetheless, we present the caveat in interpreting these studies in the context of reverse causation: Does vitamin D deficiency lead to gastrointestinal disease, or does gastrointestinal disease (with related changes in dietary choices, intestinal absorption, nutritional status, lifestyle) lead to vitamin D deficiency?
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Affiliation(s)
- Berkeley N Limketkai
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, Alway M211, Stanford, CA, 94305, USA.
| | - Matthew L Bechtold
- Division of Gastroenterology and Hepatology, University of Missouri School of Medicine, Columbia, MO, USA
| | - Douglas L Nguyen
- Division of Gastroenterology, University of California, Irvine, CA, USA
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20
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Studzinski GP, Harrison JS, Wang X, Sarkar S, Kalia V, Danilenko M. Vitamin D Control of Hematopoietic Cell Differentiation and Leukemia. J Cell Biochem 2016; 116:1500-12. [PMID: 25694395 DOI: 10.1002/jcb.25104] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 01/23/2015] [Indexed: 12/20/2022]
Abstract
It is now well known that in the mammalian body vitamin D is converted by successive hydroxylations to 1,25-dihydroxyvitamin D (1,25D), a steroid-like hormone with pleiotropic properties. These include important contributions to the control of cell proliferation, survival and differentiation, as well as the regulation of immune responses in disease. Here, we present recent advances in current understanding of the role of 1,25D in myelopoiesis and lymphopoiesis, and the potential of 1,25D and analogs (vitamin D derivatives; VDDs) for the control of hematopoietic malignancies. The reasons for the unimpressive results of most clinical studies of the therapeutic effects of VDDs in leukemia and related diseases may include the lack of a precise rationale for the conduct of these studies. Further, clinical trials to date have generally used extremely heterogeneous patient populations and, in many cases, small numbers of patients, generally without controls. Although low calcemic VDDs have been used and combined with agents that can increase the leukemia cell killing or differentiation effects in acute leukemias, the sequencing of agents used for combination therapy should to be more clearly delineated. Most importantly, it is recommended that in future clinical trials the rationale for the basis of the enhancing action of drug combinations should be clearly articulated and the effects on anticancer immunity should also be evaluated.
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Affiliation(s)
- George P Studzinski
- Department of Pathology & Laboratory Medicine, Rutgers, NJ Medical School, 185 South Orange Ave, Newark, New Jersey 07103
| | - Jonathan S Harrison
- Department of Medicine, University of Missouri Medical School, One Hospital Drive, Columbia, Missouri 65212
| | - Xuening Wang
- Department of Pathology & Laboratory Medicine, Rutgers, NJ Medical School, 185 South Orange Ave, Newark, New Jersey 07103
| | - Surojit Sarkar
- The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802
| | - Vandana Kalia
- The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802
| | - Michael Danilenko
- Department of Clinical Biochemistry & Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, 84105, Beer-Sheva, Israel
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21
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Intestinal Permeability in Inflammatory Bowel Disease: Pathogenesis, Clinical Evaluation, and Therapy of Leaky Gut. Mediators Inflamm 2015; 2015:628157. [PMID: 26582965 PMCID: PMC4637104 DOI: 10.1155/2015/628157] [Citation(s) in RCA: 463] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 09/21/2015] [Indexed: 12/13/2022] Open
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is multifactorial with data suggesting the role of a disturbed interaction between the gut and the intestinal microbiota. A defective mucosal barrier may result in increased intestinal permeability which promotes the exposition to luminal content and triggers an immunological response that promotes intestinal inflammation. IBD patients display several defects in the many specialized components of mucosal barrier, from the mucus layer composition to the adhesion molecules that regulate paracellular permeability. These alterations may represent a primary dysfunction in Crohn's disease, but they may also perpetuate chronic mucosal inflammation in ulcerative colitis. In clinical practice, several studies have documented that changes in intestinal permeability can predict IBD course. Functional tests, such as the sugar absorption tests or the novel imaging technique using confocal laser endomicroscopy, allow an in vivo assessment of gut barrier integrity. Antitumor necrosis factor-α (TNF-α) therapy reduces mucosal inflammation and restores intestinal permeability in IBD patients. Butyrate, zinc, and some probiotics also ameliorate mucosal barrier dysfunction but their use is still limited and further studies are needed before considering permeability manipulation as a therapeutic target in IBD.
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22
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Wu S, Zhang YG, Lu R, Xia Y, Zhou D, Petrof E, Claud EC, Chen D, Chang EB, Carmeliet G, Sun J. Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis. Gut 2015; 64:1082-94. [PMID: 25080448 PMCID: PMC4312277 DOI: 10.1136/gutjnl-2014-307436] [Citation(s) in RCA: 244] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 07/15/2014] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Vitamin D and the vitamin D receptor (VDR) appear to be important immunological regulators of inflammatory bowel diseases (IBD). Defective autophagy has also been implicated in IBD, where interestingly, polymorphisms of genes such as ATG16L1 have been associated with increased risk. Although vitamin D, the microbiome and autophagy are all involved in pathogenesis of IBD, it remains unclear whether these processes are related or function independently. DESIGN We investigated the effects and mechanisms of intestinal epithelial VDR in healthy and inflamed states using cell culture models, a conditional VDR knockout mouse model (VDR(ΔIEC)), colitis models and human samples. RESULTS Absence of intestinal epithelial VDR affects microbial assemblage and increases susceptibility to dextran sulfate sodium-induced colitis. Intestinal epithelial VDR downregulates expressions of ATG16L1 and lysozyme, and impairs antimicrobial function of Paneth cells. Gain and loss-of-function assays showed that VDR levels regulate ATG16L1 and lysozyme at the transcriptional and translational levels. Moreover, low levels of intestinal epithelial VDR correlated with reduced ATG16L1 and representation by intestinal Bacteroides in patients with IBD. Administration of the butyrate (a fermentation product of gut microbes) increases intestinal VDR expression and suppresses inflammation in a colitis model. CONCLUSIONS Our study demonstrates fundamental relationship between VDR, autophagy and gut microbial assemblage that is essential for maintaining intestinal homeostasis, but also in contributing to the pathophysiology of IBD. These insights can be leveraged to define therapeutic targets for restoring VDR expression and function.
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Affiliation(s)
- Shaoping Wu
- Department of Biochemistry, Rush University, 1735 W. Harrison St., Chicago, IL 60612, USA
| | - Yong-guo Zhang
- Department of Biochemistry, Rush University, 1735 W. Harrison St., Chicago, IL 60612, USA
| | - Rong Lu
- Department of Biochemistry, Rush University, 1735 W. Harrison St., Chicago, IL 60612, USA
| | - Yinglin Xia
- Department of Biostatistics and Computational Biology, University of Rochester, 601 Elmwood Ave. Rochester, NY 14642, USA
| | - David Zhou
- Department of Pathology, University of Rochester, 601 Elmwood Ave. Rochester, NY 14642, USA
| | - Elaine Petrof
- Department of Medicine, GI Diseases Research Unit and Division of Infectious Diseases, Queen's University, 76 Stuart Street, Kingston, Ontario K7L 2V7, Canada
| | - Erika C Claud
- Departments of Pediatrics, The University of Chicago Medical Center, 5841 S. Maryland Ave, Chicago, Illinois 60637, U.S.A., Departments of Medicine, The University of Chicago Medical Center, 5841 S. Maryland Ave, Chicago, Illinois 60637, U.S.A
| | - Di Chen
- Department of Biochemistry, Rush University, 1735 W. Harrison St., Chicago, IL 60612, USA
| | - Eugene B Chang
- Departments of Medicine, The University of Chicago Medical Center, 5841 S. Maryland Ave, Chicago, Illinois 60637, U.S.A
| | - Geert Carmeliet
- Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, B-3000 Belgium
| | - Jun Sun
- Department of Biochemistry, Rush University, 1735 W. Harrison St., Chicago, IL 60612, USA
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23
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Influence of nutrient-derived metabolites on lymphocyte immunity. Nat Med 2015; 21:709-18. [PMID: 26121194 DOI: 10.1038/nm.3894] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 06/01/2015] [Indexed: 12/13/2022]
Abstract
Organisms need to protect themselves against potential dangers from their surroundings, yet they require constant and intimate interactions with the same environment for their survival. The immune system is instrumental for protection against invading organisms and their toxins. The immune system consists of many cell types and is highly integrated within other tissues. Immune activity is particularly enriched at surfaces that separate the host from its environment, such as the skin and the gastrointestinal tract. This enables protection at sites directly at risk but also enables environmental factors to influence the maturation and function of immune structures and cells. Recent work has indicated that the diet in particular is able to influence the immune system and thus affect the development of inflammatory disease. This review aims to highlight recent work on how external factors, with a focus on those derived from the diet such as vitamin A, can have a direct or indirect deterministic influence on the activity and function of immunity.
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24
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Bancil AS, Poullis A. The Role of Vitamin D in Inflammatory Bowel Disease. Healthcare (Basel) 2015; 3:338-50. [PMID: 27417766 PMCID: PMC4939537 DOI: 10.3390/healthcare3020338] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Accepted: 05/18/2015] [Indexed: 12/13/2022] Open
Abstract
Vitamin D is known to be vital in maintaining bone health, mineralisation and for fracture prevention. It has also been implicated in a number of autoimmune diseases and has therefore been studied for its potential role in Inflammatory Bowel Disease (IBD). This review looks at the current literature on the role of vitamin D and its potential role as an immunomodulator, disease modifier and bone health in IBD patients. There is substantial supporting evidence of an important role from epidemiological, genetic and immunological studies, but there is also conflicting evidence and nothing proving to be definitive from clinical studies. There are also a number of confounders with IBD patients, as their lifestyles and medications may affect vitamin D levels. Murine studies have added vast amounts to our knowledge of vitamin D and its antimicrobial role, as well as its effect on immune cell proliferation other inflammatory molecules, such as Tumour Necrosis Factor-α (TNFα). It is clear that larger trials investigating the effects of oral supplementation of vitamin D in IBD patients are necessary.
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Affiliation(s)
- Aaron S Bancil
- Epsom Hospital, Dorking Road, Epsom, Surrey, KT18 7EG, UK.
| | - Andrew Poullis
- St George's Hospital, Blackshaw Road, London, SW17 0QT, UK.
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25
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Masri OA, Chalhoub JM, Sharara AI. Role of vitamins in gastrointestinal diseases. World J Gastroenterol 2015; 21:5191-5209. [PMID: 25954093 PMCID: PMC4419060 DOI: 10.3748/wjg.v21.i17.5191] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
A tremendous amount of data from research was published over the past decades concerning the roles of different vitamins in various gastrointestinal diseases. For instance, most vitamins showed an inverse relationship with the risk of colorectal carcinoma as well as other malignancies like gastric and esophageal cancer in observational trials, however interventional trials failed to prove a clear beneficial preventive role. On the other hand, more solid evidence was obtained from high quality studies for a role of certain vitamins in specific entities. Examples for this include the therapeutic role of vitamin E in patients with non-alcoholic steatohepatitis, the additive role of vitamins B12 and D to the standard therapy of chronic hepatitis C virus, the role of vitamin C in reducing the risk of gallstones, the positive outcome with vitamin B12 in patients with aphthous stomatitis, and the beneficial effect of vitamin D and B1 in patients with inflammatory bowel disease. Other potential uses are yet to be elaborated, like those on celiac disease, pancreatic cancer, pancreatitis, cholestasis and other potential fields. Data from several ongoing interventional trials are expected to add to the current knowledge over the coming few years. Given that vitamin supplementation is psychologically accepted by patients as a natural compound with relative safety and low cost, their use should be encouraged in the fields where positive data are available.
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Vitamin D and inflammatory bowel disease. BIOMED RESEARCH INTERNATIONAL 2015; 2015:470805. [PMID: 26000293 PMCID: PMC4427008 DOI: 10.1155/2015/470805] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 02/02/2015] [Accepted: 02/13/2015] [Indexed: 12/11/2022]
Abstract
Vitamin D deficiency has been recognized as an environmental risk factor for Crohn's disease since the early 80s. Initially, this finding was correlated with metabolic bone disease. Low serum 25-hydroxyvitamin D levels have been repeatedly reported in inflammatory bowel diseases together with a relationship between vitamin D status and disease activity. Subsequently, low serum vitamin D levels have been reported in various immune-related diseases pointing to an immunoregulatory role. Indeed, vitamin D and its receptor (VDR) are known to interact with different players of the immune homeostasis by controlling cell proliferation, antigen receptor signalling, and intestinal barrier function. Moreover, 1,25-dihydroxyvitamin D is implicated in NOD2-mediated expression of defensin-β2, the latter known to play a crucial role in the pathogenesis of Crohn's disease (IBD1 gene), and several genetic variants of the vitamin D receptor have been identified as Crohn's disease candidate susceptibility genes. From animal models we have learned that deletion of the VDR gene was associated with a more severe disease. There is a growing body of evidence concerning the therapeutic role of vitamin D/synthetic vitamin D receptor agonists in clinical and experimental models of inflammatory bowel disease far beyond the role of calcium homeostasis and bone metabolism.
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Xia SL, Yu LQ, Chen H, Hu DY, Shao XX, Guo MD, Jiang LJ, Lin XX, Lin XQ, Jiang Y. Association of vitamin D receptor gene polymorphisms with the susceptibility to ulcerative colitis in patients from Southeast China. J Recept Signal Transduct Res 2014; 35:530-5. [PMID: 25347331 DOI: 10.3109/10799893.2014.975248] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The association studies from different ethnic groups showed that vitamin D receptor (VDR) gene polymorphisms might be connected with the susceptibility to ulcerative colitis (UC); however, the conclusions were less consistent. Our study aimed to analyze the associations of UC with common mutations of VDR in Chinese patients. A total of 382 UC patients and 489 healthy controls were recruited. The genotypes of VDR FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) were examined by SNaPshot assays. Haplotype analysis was performed in all study subjects. After Bonferroni correction, the mutant alleles and genotypes of VDR FokI, BsmI, ApaI and TaqI did not statistically differ between UC patients and the controls (all p > 0.0125). However, the mutant allele C and genotype TC + CC of FokI gene were significantly increased in patients with mild and moderate UC compared to those with severe UC (C allele: 54.1% versus 39.3%, OR = 1.83, 95% CI: 1.21-2.75, p = 0.004; TC + CC genotype: 81.6% versus 57.1%, OR = 3.32, 95% CI: 1.83-6.06, p < 0.001, respectively). Haplotype analysis showed that the VDR BsmI, ApaI and TaqI polymorphic loci were in a strong linkage disequilibrium. Furthermore, the frequency of AAC haplotype was statistically lower in UC patients than that in the controls (3.8 versus 5.9%, OR = 0.63, 95% CI: 0.39-1.01, p = 0.039). In conclusion, the mutation of FokI gene influenced severity of the disease in UC patients. Moreover, the AAC haplotype formed by the VDR BsmI, ApaI and TaqI gene might engender a reduced risk of UC attack.
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Affiliation(s)
- Sheng-Long Xia
- a Department of Gastroenterology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Li-Qin Yu
- a Department of Gastroenterology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Hao Chen
- a Department of Gastroenterology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Ding-Yuan Hu
- a Department of Gastroenterology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Xiao-Xiao Shao
- a Department of Gastroenterology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Mao-Dong Guo
- a Department of Gastroenterology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Li-Jia Jiang
- b Department of Gastroenterology , The Center Hospital of Wenzhou City , Wenzhou , China , and
| | - Xin-Xin Lin
- a Department of Gastroenterology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
| | - Xiu-Qing Lin
- c Department of Gastroenterology , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , Zhejiang Province , China
| | - Yi Jiang
- a Department of Gastroenterology , The Second Affiliated Hospital of Wenzhou Medical University , Wenzhou , China
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Abstract
Technological advances in the large scale analysis of human genetics have generated profound insights into possible genetic contributions to chronic diseases including the inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis. To date, 163 distinct genetic risk loci have been associated with either Crohn's disease or ulcerative colitis, with a substantial degree of genetic overlap between these 2 conditions. Although many risk variants show a reproducible correlation with disease, individual gene associations only affect a subset of patients, and the functional contribution(s) of these risk variants to the onset of IBD is largely undetermined. Although studies in twins have demonstrated that the development of IBD is not mediated solely by genetic risk, it is nevertheless important to elucidate the functional consequences of risk variants for gene function in relevant cell types known to regulate key physiological processes that are compromised in IBD. This article will discuss IBD candidate genes that are known to be, or are suspected of being, involved in regulating the intestinal epithelial barrier and several of the physiological processes presided over by this dynamic and versatile layer of cells. This will include assembly and regulation of tight junctions, cell adhesion and polarity, mucus and glycoprotein regulation, bacterial sensing, membrane transport, epithelial differentiation, and restitution.
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Limketkai BN, Bayless TM, Brant SR, Hutfless SM. Lower regional and temporal ultraviolet exposure is associated with increased rates and severity of inflammatory bowel disease hospitalisation. Aliment Pharmacol Ther 2014; 40:508-17. [PMID: 24943863 DOI: 10.1111/apt.12845] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Revised: 04/30/2014] [Accepted: 05/29/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND In the northern hemisphere, the incidence of inflammatory bowel diseases (IBD) has a north-south gradient, suggesting a link between ultraviolet (UV) exposure or vitamin D status and the pathogenesis of IBD. AIM To test the association of UV exposure with the rates and severity of IBD hospitalisation. METHODS We conducted a retrospective nationwide analysis of 649 932 Crohn's disease (CD), 384 267 ulcerative colitis (UC), and 288 894 297 non-IBD hospitalisations in the US between 1998 and 2010. Mean UV exposure was assigned to each hospitalisation using surface measures from the National Oceanic and Atmospheric Administration. Relative rates across UV exposures were estimated for IBD hospitalisations, prolonged hospitalisations, bowel surgeries and deaths. RESULTS Among IBD patients, lower UV exposures had increased hospitalisation rates for CD (217.8 vs. 182.5 per 100 000 overall hospitalisations with low and very high UV, respectively; P trend <0.001) and UC (123.2 vs. 113.8 per 100 000; P trend = 0.033). Low UV groups had greater relative rates of prolonged hospitalisations [CD: 1.13, 95% confidence interval (CI) 1.07-1.19; UC: 1.21, 95% CI 1.13-1.30], bowel surgeries (CD: 1.24, 95% CI 1.16-1.32; UC: 1.21, 95% CI 1.09-1.33), and CD deaths (CD: 1.76, 95% CI 1.14-2.71; UC: 1.24, 95% CI 0.92-1.67). Among non-IBD patients, low UV was associated with prolonged hospitalisations (1.09; 95% CI 1.07-1.11) and deaths (1.13; 95% CI 1.09-1.17), but not bowel surgeries (1.01; 95% CI 0.99-1.03). CONCLUSIONS Lower ultraviolet exposure is associated with greater rates of hospitalisation, prolonged hospitalisation and the need for bowel surgery in IBD. This trend for bowel surgery was not seen with non-IBD encounters.
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Affiliation(s)
- B N Limketkai
- Division of Gastroenterology, Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
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Adorini L, Amuchastegui S, Corsiero E, Laverny G, Le Meur T, Penna G. Vitamin D receptor agonists as anti-inflammatory agents. Expert Rev Clin Immunol 2014; 3:477-89. [DOI: 10.1586/1744666x.3.4.477] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Mouli VP, Ananthakrishnan AN. Review article: vitamin D and inflammatory bowel diseases. Aliment Pharmacol Ther 2014; 39:125-36. [PMID: 24236989 PMCID: PMC3872479 DOI: 10.1111/apt.12553] [Citation(s) in RCA: 170] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/15/2013] [Accepted: 10/28/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Vitamin D is traditionally associated with bone metabolism. The immunological effects of vitamin D have increasingly come into focus. AIM To review the evidence supporting a role of vitamin D in inflammatory bowel diseases. METHODS A comprehensive search was performed on PubMed using the terms 'crohn's disease' 'ulcerative colitis' and 'vitamin D'. RESULTS Vitamin D deficiency is common in patients with inflammatory bowel diseases (IBD) (16-95%) including those with recently diagnosed disease. Evidence supports immunological role of vitamin D in IBD. In animal models, deficiency of vitamin D increases susceptibility to dextran sodium sulphate colitis, while 1,25(OH)2 D3 ameliorates such colitis. One prospective cohort study found low predicted vitamin D levels to be associated with an increased risk of Crohn's disease (CD). Limited data also suggest an association between low vitamin D levels and increased disease activity, particularly in CD. In a large cohort, vitamin D deficiency (<20 ng/mL) was associated with increased risk of surgery (OR 1.8, 95% CI 1.2-2.5) in CD and hospitalisations in both CD (OR 2.1, 95% CI 1.6-2.7) and UC (OR 2.3, 95% CI 1.7-3.1). A single randomised controlled trial demonstrated that vitamin D supplementation may be associated with reduced frequency of relapses in patients with CD compared with placebo (13% vs. 29%, P = 0.06). CONCLUSIONS There is growing epidemiological evidence to suggest a role for vitamin D deficiency in the development of IBD and also its influence on disease severity. The possible therapeutic role of vitamin D in patients with IBD merits continued investigation.
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Affiliation(s)
- V P Mouli
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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Li P, Lv H, Yang H, Qian JM. IRF5, but not TLR4, DEFB1, or VDR, is associated with the risk of ulcerative colitis in a Han Chinese population. Scand J Gastroenterol 2013; 48:1145-51. [PMID: 23971939 DOI: 10.3109/00365521.2013.828775] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE. IRF5, TLR4, DEFB1, and VDR genetic variations have been associated with ulcerative colitis (UC) in several European patient cohorts. As distinct genetic backgrounds may play a role in different ethnicities, we evaluated the effects of single-nucleotide polymorphisms (SNPs) in these genes and their interactions in UC patients of Han Chinese descent. MATERIAL AND METHODS. DNA samples from 300 UC patients and 302 healthy control subjects from Peking Union Medical College Hospital were genotyped for 14 tag SNPs, which were selected based on haplotype analysis of IRF5, TLR4, DEFB1, and VDR. Multidimensionality reductions were used to explore gene-gene interactions. RESULTS. The only observed association with UC was for IRF5. On an allelic level, SNP rs3807306 was associated with UC risk (p = 6.7 × 10(-3)). On a genotypic level, the CC genotype of SNP rs3807306 (p = 0.03) was associated with protection from UC, and the AA genotype of SNP rs4728142 (p = 7.6 × 10(-3)) was associated with a risk of UC. In the haplotype analysis, GGATT was highly correlated with UC risk (p-Value = 2.0 × 10(-4)). No significant multilocus interactions were detected among these four genes. CONCLUSIONS. Our study confirmed the association of IRF5 with UC in Han Chinese patients. Han Chinese UC patients share part of their genetic susceptibility with Caucasian patients.
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Affiliation(s)
- Pan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences , Beijing , China
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Pastorelli L, De Salvo C, Mercado JR, Vecchi M, Pizarro TT. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front Immunol 2013; 4:280. [PMID: 24062746 PMCID: PMC3775315 DOI: 10.3389/fimmu.2013.00280] [Citation(s) in RCA: 327] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 08/29/2013] [Indexed: 12/12/2022] Open
Abstract
The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier.
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Affiliation(s)
- Luca Pastorelli
- Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH , USA ; Department of Biomedical Sciences for Health, University of Milan , Milan , Italy ; Gastroenterology and Digestive Endoscopy Unit, IRCCS Policlinico San Donato , San Donato Milanese , Italy
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Abstract
Inflammatory bowel disease is associated with industrialization, and its incidence has increased markedly over time. The prospect of reversing these trends motivates the search for the agent(s) involved. Modernity entails several physical and behavioral modifications that compromise both the photosynthesis of cholecalciferol in the skin and of its bioavailability. Although deficiency in this "vitamin" has therefore emerged as a leading candidate, and despite the publication of a randomized control trial that showed a trend toward statistically significant benefit in Crohn's disease, its causal agency has yet to be demonstrated by an adequately powered study. We discuss the strengths and weaknesses of the case being made by epidemiologists, geneticists, clinicians, and basic researchers, and consolidate their findings into a model that provides mechanistic plausibility to the claim. Specifically, converging data sets suggest that local activation of vitamin D coordinates the activity of the innate and adaptive arms of immunity, and of the intestinal epithelium, in a manner that promotes barrier integrity, facilitates the clearance of translocated flora, and diverts CD4 T cell development away from inflammatory phenotypes. Because smoking is an important risk-altering exposure, we also discuss its newly established melanizing effect and other emerging evidence linking tobacco use to immune function through vitamin D pathways.
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Larmonier CB, McFadden RMT, Hill FM, Schreiner R, Ramalingam R, Besselsen DG, Ghishan FK, Kiela PR. High vitamin D3 diet administered during active colitis negatively affects bone metabolism in an adoptive T cell transfer model. Am J Physiol Gastrointest Liver Physiol 2013; 305:G35-46. [PMID: 23639807 PMCID: PMC3725694 DOI: 10.1152/ajpgi.00065.2013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Decreased bone mineral density (BMD) represents an extraintestinal complication of inflammatory bowel disease (IBD). Vitamin D₃ has been considered a viable adjunctive therapy in IBD. However, vitamin D₃ plays a pleiotropic role in bone modeling and regulates the bone formation-resorption balance, depending on the physiological environment, and supplementation during active IBD may have unintended consequences. We evaluated the effects of vitamin D₃ supplementation during the active phase of disease on colonic inflammation, BMD, and bone metabolism in an adoptive IL-10-/- CD4⁺ T cell transfer model of chronic colitis. High-dose vitamin D₃ supplementation for 12 days during established disease had negligible effects on mucosal inflammation. Plasma vitamin D₃ metabolites correlated with diet, but not disease, status. Colitis significantly reduced BMD. High-dose vitamin D₃ supplementation did not affect cortical bone but led to a further deterioration of trabecular bone morphology. In mice fed a high vitamin D₃ diet, colitis more severely impacted bone formation markers (osteocalcin and bone alkaline phosphatase) and increased bone resorption markers, ratio of receptor activator of NF-κB ligand to osteoprotegrin transcript, plasma osteoprotegrin level, and the osteoclast activation marker tartrate-resistant acid phosphatase (ACp5). Bone vitamin D receptor expression was increased in mice with chronic colitis, especially in the high vitamin D₃ group. Our data suggest that vitamin D₃, at a dose that does not improve inflammation, has no beneficial effects on bone metabolism and density during active colitis or may adversely affect BMD and bone turnover. These observations should be taken into consideration in the planning of further clinical studies with high-dose vitamin D₃ supplementation in patients with active IBD.
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Affiliation(s)
- C. B. Larmonier
- 1Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona;
| | - R.-M. T. McFadden
- 1Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona; ,4Oral Biology Program, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina; and
| | - F. M. Hill
- 1Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona;
| | - R. Schreiner
- 5Laboratory of Dr. Limbach and Associates, Heidelberg, Germany
| | - R. Ramalingam
- 1Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona;
| | - D. G. Besselsen
- 3Department of Animal Care, University of Arizona Health Sciences Center, Tucson, Arizona;
| | - F. K. Ghishan
- 1Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona;
| | - P. R. Kiela
- 1Department of Pediatrics, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona; ,2Department of Immunobiology, University of Arizona Health Sciences Center, Tucson, Arizona;
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Blanck S, Aberra F. Vitamin d deficiency is associated with ulcerative colitis disease activity. Dig Dis Sci 2013; 58:1698-702. [PMID: 23334382 DOI: 10.1007/s10620-012-2531-7] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 12/11/2012] [Indexed: 02/06/2023]
Abstract
PURPOSE Previous studies on experimental mouse models have suggested a role of vitamin D in immune system regulation and IBD disease severity. In this study, we examine the relationship between vitamin D levels and clinical disease activity in human subjects with ulcerative colitis (UC). We hypothesized that patients with vitamin D deficiency will display increased UC disease activity as compared to patients with normal vitamin D levels. METHODS A cross-sectional study was performed by querying the outpatient electronic medical record of our health system for patients seen in the gastroenterology clinic from January 2007 to October 2009 who carried both a diagnosis of UC and a documented 25-OH vitamin D level within 30 days of their clinic visit. Demographic and clinical variables were collected. Clinical disease activity was calculated using the six-point partial Mayo index. Active disease was defined as a six-point index score of ≥ 1. Vitamin D deficiency was defined as a 25-OH D level below 30 ng/ml. Data were analyzed using the chi-square distribution test. RESULTS Thirty-four patients met inclusion criteria (53 % female, mean age 45.7 ± 24.7 years). Fifteen patients had normal vitamin D levels and 19 patients were vitamin D deficient. Twelve patients had vitamin D levels <20 ng/ml. Vitamin D deficient patients were statistically more likely to have increased disease activity than patients with normal vitamin D levels (p = 0.04), with 68 % of deficient patients displaying active disease compared with 33 % in the sufficient group. There was also a statistically significant association between vitamin D status and need for treatment with steroids, with a higher percentage of vitamin D deficient patients (47 %) requiring such treatment compared with 7 % in the sufficient group (p = 0.02). There was no association between season of visit and disease activity. CONCLUSION Vitamin D deficiency is common among patients with active UC, particularly those requiring corticosteroids. Further investigation is needed to determine the clinical utility of vitamin D monitoring in patients with UC and whether there is a role for vitamin D as a treatment for UC.
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Affiliation(s)
- Stacey Blanck
- Department of Medicine, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA.
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Xue LN, Xu KQ, Zhang W, Wang Q, Wu J, Wang XY. Associations between vitamin D receptor polymorphisms and susceptibility to ulcerative colitis and Crohn's disease: a meta-analysis. Inflamm Bowel Dis 2013; 19:54-60. [PMID: 22467262 DOI: 10.1002/ibd.22966] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Several polymorphisms have been identified in the vitamin D receptor (VDR) gene, while their roles in the incidence of ulcerative colitis (UC) and Crohn's disease (CD) are conflicting. This meta-analysis was designed to clarify the impact of these polymorphisms on UC and CD risk. METHODS The PubMed, Embase, and Cochrane electronic databases were searched from February 1995 to August 2011 for studies on the four VDR polymorphisms: TaqI, BsmI, FokI, and ApaI. Data were extracted and pooled odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS Nine studies were included. In Asians, the ff genotype of FokI was associated with increased UC risk (OR = 1.65; 95% CI, 1.11- 2.45). The "a" allele carrier status of ApaI appeared to be a protective factor for CD (OR = 0.81; 95% CI, 0.67-0.97). The tt genotype increased the risk of CD in Europeans (OR = 1.23; 95% CI, 1.02-1.49). Moreover, the tt genotype of TaqI in males had a moderate elevated risk of UC (OR = 1.56; 95% CI, 1.02-2.39) and CD (OR = 1.84; 95% CI, 1.19-2.83). CONCLUSIONS The meta-analysis reveals a significant increase in CD risk for Europeans carrying TaqI tt genotype and a significant decrease in CD risk for all carriers of the Apal "a" allele. For Asians, the VDR FokI polymorphism appears to confer susceptibility to UC. For males, the TaqI tt genotype is associated with susceptibilities to both UC and CD. Our study explored the genetic risk prediction in UC and CD, and may provide valuable insights into IBD therapy.
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Affiliation(s)
- Le-Ning Xue
- Department of Gastroenterology, Changzhou No 2 Hospital, Affiliated with Nanjing Medical University, Changzhou City, Jiangsu Province, China
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Madia F, Grossi V, Peserico A, Simone C. Updates from the Intestinal Front Line: Autophagic Weapons against Inflammation and Cancer. Cells 2012; 1:535-57. [PMID: 24710489 PMCID: PMC3901109 DOI: 10.3390/cells1030535] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Revised: 07/04/2012] [Accepted: 08/01/2012] [Indexed: 12/11/2022] Open
Abstract
The intestine lies at the interface between the organism and its environment and responds to infection/inflammation in a multi-leveled manner, potentially leading to chronic inflammatory pathologies and cancer formation. Indeed, the immune response at the intestinal epithelium has been found to be involved in the origin and development of colorectal cancer, which is the third most commonly diagnosed neoplastic disease. Among the mechanisms induced upon inflammation, autophagy appears as a defensive strategy for the clearance of invading microbes and intracellular waste components. Autophagy has also been found to play an important role in colorectal cancer, where it seems to have a pro-survival or pro-death function depending on the stage of the neoplastic process. In this paper we discuss the dual role of autophagy in colorectal cancer and review evidence showing that modulation of autophagy affects the immune response and cancer biology. The study of key players involved in autophagy might contribute to the design of new approaches for colorectal cancer, consisting in combined therapies capable of modifying cancer-specific metabolism rather than simply evoking a generic apoptotic and/or autophagic response, thus enhancing the efficacy of currently used drugs and treatments.
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Affiliation(s)
- Federica Madia
- Laboratory of Signal-dependent Transcription, Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH) 66030, Italy.
| | - Valentina Grossi
- Laboratory of Signal-dependent Transcription, Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH) 66030, Italy.
| | - Alessia Peserico
- Laboratory of Signal-dependent Transcription, Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH) 66030, Italy.
| | - Cristiano Simone
- Laboratory of Signal-dependent Transcription, Department of Translational Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro (CH) 66030, Italy.
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De Silva P, Ananthakrishnan AN. Vitamin D and IBD: more pieces to the puzzle, still no complete picture. Inflamm Bowel Dis 2012; 18:1391-3. [PMID: 22180018 DOI: 10.1002/ibd.22854] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 11/17/2011] [Indexed: 12/31/2022]
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Kabi A, Nickerson KP, Homer CR, McDonald C. Digesting the genetics of inflammatory bowel disease: insights from studies of autophagy risk genes. Inflamm Bowel Dis 2012; 18:782-92. [PMID: 21936032 PMCID: PMC3245781 DOI: 10.1002/ibd.21868] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 07/26/2011] [Indexed: 12/16/2022]
Abstract
The success of genetic analyses identifying multiple loci associated with inflammatory bowel disease (IBD) susceptibility has resulted in the identification of several risk genes linked to a common cellular process called autophagy. Autophagy is a process involving the encapsulation of cytosolic cellular components in double-membrane vesicles, their subsequent lysosomal degradation, and recycling of the degraded components for use by the cell. It plays an important part in the innate immune response to a variety of intracellular pathogens, and it is this component of autophagy that appears to be defective in IBD. This has lead to the hypothesis that Crohn's disease may result from an impaired antibacterial response, which leads to ineffective control of bacterial infection, dysbiosis of the intestinal microbiota, and chronic inflammation. Several recurrent themes have surfaced from studies examining the function of autophagy-related genes in the context of IBD, with cellular context, disease status, risk variant effect, and risk gene interplay all affecting the interpretation of these studies. The identification of autophagy as a major risk pathway in IBD is a significant step forward and may lead to pathway-focused therapy in the future; however, there is more to understand in order to unravel the complexity of this disease.
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Affiliation(s)
- Amrita Kabi
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Kourtney P. Nickerson
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Craig R. Homer
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Christine McDonald
- Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio,Correspondence to: Christine McDonald, Ph.D., Department of Pathobiology, NC22, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, (216) 445-7058 phone, (216) 636-0104 fax,
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Ananthakrishnan AN, Khalili H, Higuchi LM, Bao Y, Korzenik JR, Giovannucci EL, Richter JM, Fuchs CS, Chan AT. Higher predicted vitamin D status is associated with reduced risk of Crohn's disease. Gastroenterology 2012; 142:482-9. [PMID: 22155183 PMCID: PMC3367959 DOI: 10.1053/j.gastro.2011.11.040] [Citation(s) in RCA: 313] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2011] [Revised: 10/24/2011] [Accepted: 11/29/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Vitamin D influences innate immunity, which is believed to be involved in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). However, data examining vitamin D status in relation to risk of CD and UC are lacking. METHODS We conducted a prospective cohort study of 72,719 women (age, 40-73 y) enrolled in the Nurses' Health Study. In 1986, women completed an assessment of diet and lifestyle, from which a 25-hydroxy vitamin D [25(OH)D] prediction score was developed and validated against directly measured levels of plasma 25(OH)D. Through 2008, we confirmed reported diagnoses of incident CD or UC through medical record review. We used Cox proportional hazards modeling to examine the hazard ratio (HR) for incident CD or UC after adjusting for potential confounders. RESULTS During 1,492,811 person-years of follow-up evaluation, we documented 122 incident cases of CD and 123 cases of UC. The median predicted 25(OH)D level was 22.3 ng/mL in the lowest and 32.2 ng/mL in the highest quartiles. Compared with the lowest quartile, the multivariate-adjusted HR associated with the highest quartile of vitamin D was 0.54 (95% confidence interval [CI], 0.30-.99) for CD (P(trend) = .02) and 0.65 (95% CI, 0.34-1.25) for UC (P(trend) = .17). Compared with women with a predicted 25(OH)D level less than 20 ng/mL, the multivariate-adjusted HR was 0.38 (95% CI, 0.15-0.97) for CD and 0.57 (95% CI, 0.19-1.70) for UC for women with a predicted 25(OH)D level greater than 30 ng/mL. There was a significant inverse association between dietary and supplemental vitamin D and UC, and a nonsignificant reduction in CD risk. CONCLUSIONS Higher predicted plasma levels of 25(OH)D significantly reduce the risk for incident CD and nonsignificantly reduce the risk for UC in women.
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Affiliation(s)
- Ashwin N. Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Leslie M. Higuchi
- Division of Gastroenterology and Nutrition, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
| | - Ying Bao
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Joshua R. Korzenik
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Edward L. Giovannucci
- Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachusetts
| | - James M. Richter
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Charles S. Fuchs
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Andrew T. Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts,Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Ooi JH, Chen J, Cantorna MT. Vitamin D regulation of immune function in the gut: why do T cells have vitamin D receptors? Mol Aspects Med 2011; 33:77-82. [PMID: 22079836 DOI: 10.1016/j.mam.2011.10.014] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2011] [Revised: 10/04/2011] [Accepted: 10/29/2011] [Indexed: 12/15/2022]
Abstract
Low vitamin D status is associated with an increased risk of immune-mediated diseases like inflammatory bowel disease (IBD) in humans. Experimentally vitamin D status is a factor that shapes the immune response. Animals that are either vitamin D deficient or vitamin D receptor (VDR) deficient are prone to develop IBD. Conventional T cells develop normally in VDR knockout (KO) mice but over-produce IFN-γ and IL-17. Naturally occurring FoxP3+ regulatory T cells are present in normal numbers in VDR KO mice and function as well as wildtype T regs. Vitamin D and the VDR are required for the development and function of two regulatory populations of T cells that require non-classical MHC class 1 for development. The two vitamin D dependent cell types are the iNKT cells and CD4/CD8αα intraepithelial lymphocytes (IEL). Protective immune responses that depend on iNKT cells or CD8αα IEL are therefore impaired in the vitamin D or VDR deficient host and the mice are more susceptible to immune-mediated diseases in the gut.
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Affiliation(s)
- Jot Hui Ooi
- Center for Molecular Immunology and Infectious Disease, Department of Veterinary and Biomedical Science, The Pennsylvania State University, University Park, PA 16802, United States
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Common variation in the vitamin D receptor gene and risk of inflammatory bowel disease in an Irish case-control study. Eur J Gastroenterol Hepatol 2011; 23:807-12. [PMID: 21818054 DOI: 10.1097/meg.0b013e328349283e] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Vitamin D may protect against the development of inflammatory bowel disease (IBD). Several preliminary studies in separate geographical locations suggest that these effects may be partly mediated by genetic variants of the vitamin D receptor (VDR). The data, however, are yet to be confirmed in large European cohorts. This study aimed to determine if common VDR polymorphisms affected IBD risk in an Irish population. MATERIALS AND METHODS The study was based on a cohort of 1359 Irish participants. Frequencies of the common VDR gene polymorphisms rs2228570 (FokI), rs1544410 (BsmI), rs7975232 (ApaI), and rs731236 (TaqI) were determined using allele-specific PCR in a case-control analysis of 660 patients with IBD and 699 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between these variants and risk of IBD. RESULTS There was no statistically significant effect observed on IBD risk for any of the four VDR polymorphisms tested. Furthermore, no significant differences were observed in susceptibility when the population was stratified by sex or IBD subtype (Crohn's disease or ulcerative colitis). Notably, however, there was an increased risk observed for both IBD and ulcerative colitis associated with heterozygote carriage of the FokI allele that approached significance (OR=1.21, 95% CI=0.95-1.53, P=0.12 and OR=1.36, 95% CI=0.98-1.89, P=0.06, respectively), this merits further investigation. CONCLUSION This study indicates that there is no major effect for common variation in the VDR gene alone on predisposition to IBD in the Irish population.
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Pei FH, Wang YJ, Gao SL, Liu BR, DU YJ, Liu W, Yu HY, Zhao LX, Chi BR. Vitamin D receptor gene polymorphism and ulcerative colitis susceptibility in Han Chinese. J Dig Dis 2011; 12:90-8. [PMID: 21401893 DOI: 10.1111/j.1751-2980.2011.00483.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Specific polymorphisms in the vitamin D receptor (VDR) gene have been associated with genetic susceptibility to inflammatory bowel disease (IBD) in different ethnic populations. METHODS A total of 218 ulcerative colitis (UC) patients and 251 healthy controls were genotyped for VDR gene polymorphisms using PCR-restriction fragment length polymorphism (PCR-RFLP) assay. VDR gene polymorphisms (Apa I, Taq I, Bsm I and Fok I) were analyzed for both genotypic and phenotypic susceptibilities. RESULTS Among the four examined VDR gene polymorphisms, the Bsm I polymorphism showed a slightly higher distribution in our study population than that in the previous studies. We also found that the increased frequency of the Bb genotype of the Bsm I VDR gene polymorphism was associated with UC in Han Chinese, as compared with healthy controls (28.4% vs. 18.7%, χ(2) = 6.044, P = 0.014, OR = 1.739, 95% CI = 1.122-2.697). Moreover, Bsm I polymorphic allele (B) frequency was significantly increased in the UC cases, as compared to the healthy controls (14.7% vs. 7.8% χ(2) = 6.222, P = 0.013; OR = 1.670, 95% CI = 1.113-2.506). In contrast, the other three VDR gene polymorphisms (Apa I, Taq I and Fok I) were not associated with UC susceptibility in the Han Chinese cohort. In addition, none of these four VDR polymorphisms had statistical association with clinicopathological parameters of these UC patients. CONCLUSION This study demonstrated a probable association of the Bsm I polymorphism of the VDR gene with ulcerative colitis susceptibility in Han Chinese.
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Affiliation(s)
- Feng Hua Pei
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, Jilin Province, China
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Hardenberg G, Steiner TS, Levings MK. Environmental influences on T regulatory cells in inflammatory bowel disease. Semin Immunol 2011; 23:130-8. [PMID: 21295492 DOI: 10.1016/j.smim.2011.01.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2010] [Accepted: 01/10/2011] [Indexed: 12/24/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic, idiopathic inflammation of the intestine. The disease is thought to result from a combination of genetic and environmental factors which ultimately leads to a mucosal immune system that overreacts to normal constituents of the mucosal microbiota. The inflammation in IBD is primarily mediated by inappropriate production of proinflammatory cytokines by CD4(+) T effector cells, effects that are suppressed by CD4(+) T regulatory cells. Defects in both the function of T regulatory cells, and the ability of T effector cells to be suppressed, have been implicated in IBD. In this review we will discuss environmental factors, including cytokines, vitamins A and D, and commensal bacteria, which influence the phenotype and function of regulatory T cells and thereby alter the course of IBD. We will also discuss how these environmental signals can be manipulated therapeutically in order to improve the function of regulatory T cells and ultimately restore mucosal homeostasis in patients with IBD.
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Affiliation(s)
- Gijs Hardenberg
- Department of Surgery, University of British Columbia and Immunity in Health & Disease, Child and Family Research Institute, British Columbia Children's Hospital, Vancouver, BC, Canada
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Bruce D, Cantorna MT. Intrinsic requirement for the vitamin D receptor in the development of CD8αα-expressing T cells. THE JOURNAL OF IMMUNOLOGY 2011; 186:2819-25. [PMID: 21270396 DOI: 10.4049/jimmunol.1003444] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Vitamin D and vitamin D receptor (VDR) deficiency results in severe symptoms of experimental inflammatory bowel disease in several different models. The intraepithelial lymphocytes of the small intestine contain large numbers of CD8αα(+) T cells that have been shown to suppress the immune response to Ags found there. In this study, we determined the role of the VDR in the development of CD8αα(+) T cells. There are fewer total numbers of TCRαβ(+) T cells in the gut of VDR knockout (KO) mice, and that reduction was largely in the CD8αα(+) TCRαβ(+) cells. Conversely TCRγδ(+) T cells were normal in the VDR KO mice. The thymic precursors of CD8αα(+) TCRαβ(+) cells (triple-positive for CD4, CD8αα, and CD8αβ) were reduced and less mature in VDR KO mice. In addition, VDR KO mice had a higher frequency of the CD8αα(+) TCRαβ(+) precursors (double-negative [DN] TCRαβ(+) T cells) in the gut. The proliferation rates of the DN TCRαβ(+) gut T cells were less in the VDR KO compared with those in wild type. Low proliferation of DN TCRαβ(+) T cells was a result of the very low expression of the IL-15R in this population of cells in the absence of the VDR. Bone marrow transplantation showed that the defect in VDR KO CD8αα(+) TCRαβ(+) cells was cell intrinsic. Decreased maturation and proliferation of CD8αα(+) TCRαβ(+) cells in VDR KO mice results in fewer functional CD8αα(+) TCRαβ(+) T cells, which likely explains the increased inflammation in the gastrointestinal tract of VDR KO and vitamin D-deficient mice.
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Affiliation(s)
- Danny Bruce
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802, USA
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Yamamoto-Furusho JK. Genetic Susceptibility in Inflammatory Bowel Disease. Clin Rev Bone Miner Metab 2010. [DOI: 10.1007/s12018-009-9068-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Abstract
Vitamin D and the vitamin D receptor (VDR) have been shown to be important regulators of the immune system. In particular, vitamin D and VDR deficiency exacerbates experimental autoimmune diseases such as inflammatory bowel disease (IBD). IBD develops due to an immune-mediated attack by pathogenic T-cells that overproduce IL-17 and IFN-gamma and a few regulatory cells. VDR knockout mice have twice as many T-cells making IL-17 and IFN-gamma than wild-type mice. In addition, vitamin D and the VDR are required for normal numbers of regulatory T-cells (iNKT and CD8alphaalpha) that have been shown to suppress experimental IBD. In the absence of vitamin D and the VDR, autoimmunity occurs in the gastrointestinal tract due to increased numbers of IL-17 and IFN-gamma secreting T-cells and a concomitant reduction in regulatory T-cells.
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Chan AT, Giovannucci EL. Primary prevention of colorectal cancer. Gastroenterology 2010; 138:2029-2043.e10. [PMID: 20420944 PMCID: PMC2947820 DOI: 10.1053/j.gastro.2010.01.057] [Citation(s) in RCA: 418] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2009] [Revised: 01/10/2010] [Accepted: 01/14/2010] [Indexed: 02/07/2023]
Abstract
Colorectal cancer has been strongly associated with a Western lifestyle. In the past several decades, much has been learned about the dietary, lifestyle, and medication risk factors for this malignancy. Although there is controversy about the role of specific nutritional factors, consideration of dietary pattern as a whole appears useful for formulating recommendations. For example, several studies have shown that high intake of red and processed meats, highly refined grains and starches, and sugars is related to increased risk of colorectal cancer. Replacing these factors with poultry, fish, and plant sources as the primary source of protein; unsaturated fats as the primary source of fat; and unrefined grains, legumes and fruits as the primary source of carbohydrates is likely to lower risk of colorectal cancer. Although a role for supplements, including vitamin D, folate, and vitamin B6, remains uncertain, calcium supplementation is likely to be at least modestly beneficial. With respect to lifestyle, compelling evidence indicates that avoidance of smoking and heavy alcohol use, prevention of weight gain, and maintenance of a reasonable level of physical activity are associated with markedly lower risks of colorectal cancer. Medications such as aspirin and nonsteroidal anti-inflammatory drugs and postmenopausal hormones for women are associated with substantial reductions in colorectal cancer risk, though their utility is affected by associated risks. Taken together, modifications in diet and lifestyle should substantially reduce the risk of colorectal cancer and could complement screening in reducing colorectal cancer incidence.
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Greenwood A, Elstein D, Zimran A, Altarescu G. Effect of vitamin D receptor (VDR) genotypes on the risk for osteoporosis in type 1 Gaucher disease. Clin Rheumatol 2010; 29:1037-41. [DOI: 10.1007/s10067-010-1464-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2010] [Revised: 03/09/2010] [Accepted: 04/07/2010] [Indexed: 11/30/2022]
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