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Gut instincts: vitamin D/vitamin D receptor and microbiome in neurodevelopment disorders.
Ogbu, D, Xia, E, Sun, J
Open biology. 2020;(7):200063
Abstract
The gut microbiome regulates a relationship with the brain known as the gut-microbiota-brain (GMB) axis. This interaction is influenced by immune cells, microbial metabolites and neurotransmitters. Recent findings show gut dysbiosis is prevalent in autism spectrum disorder (ASD) as well as attention deficit hyperactivity disorder (ADHD). There are previously established negative correlations among vitamin D, vitamin D receptor (VDR) levels and severity of ASD as well as ADHD. Both vitamin D and VDR are known to regulate homeostasis in the brain and the intestinal microbiome. This review summarizes the growing relationship between vitamin D/VDR signalling and the GMB axis in ASD and ADHD. We focus on current publications and summarize the progress of GMB in neurodevelopmental disorders, describe effects and mechanisms of vitamin D/VDR in regulating the microbiome and synoptically highlight the potential applications of targeting vitamin D/VDR signalling in neurodevelopment disorders.
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Mechanisms of action of vitamin D in colon cancer.
Ferrer-Mayorga, G, Larriba, MJ, Crespo, P, Muñoz, A
The Journal of steroid biochemistry and molecular biology. 2019;:1-6
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Abstract
Colorectal cancer (CRC) is the neoplasia that is most frequently associated with vitamin D deficiency in epidemiological and observational studies in terms of incidence and mortality. Many mechanistic studies show that the active vitamin D metabolite (1α,25-dihydroxyvitamin D3 or calcitriol) inhibits proliferation and promotes epithelial differentiation of human colon carcinoma cell lines that express vitamin D receptor (VDR) via the regulation of a high number of genes. A key action underlining this effect is the multilevel inhibition of the Wnt/β-catenin signaling pathway, whose abnormal activation in colon epithelial cells initiates and promotes CRC. Recently, our group has shown that calcitriol modulates gene expression and inhibits protumoral properties of patient-derived colon cancer-associated fibroblasts (CAFs). Accordingly, high VDR expression in tumor stromal fibroblasts is associated with longer survival of CRC patients. Moreover, many types of immune cells express VDR and are regulated by calcitriol, which probably contributes to its action against CRC. Given the role attributed to the intestinal microbiota in CRC and the finding that it is altered by vitamin D deficiency, an indirect antitumoral effect of calcitriol is also plausible at this level. In summary, calcitriol has an array of potential protective effects against CRC by acting on carcinoma cells, CAFs, immune cells and probably also the gut microbiota.
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Associations between vitamin D receptor genetic variants and tuberculosis: a meta-analysis.
Xu, X, Shen, M
Innate immunity. 2019;(5):305-313
Abstract
We performed a meta-analysis to evaluate potential associations between vitamin D receptor ( VDR) genetic variants and tuberculosis (TB). Systematic literature research was conducted in PubMed, Web of Science, and Embase. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) to estimate strength of associations in all possible genetic models, and P values ≤ 0.05 were considered to be statistically significant. In total, 42 studies were enrolled for analyses. Pooled overall analyses suggested that VDR rs1544410 (dominant model: P = 0.02; allele model: P = 0.03) and rs731236 (dominant model: P = 0.04; recessive model: P = 0.02; allele model: P = 0.01) variants were significantly associated with TB. Further subgroup analyses by ethnicity revealed that rs1544410 (dominant and allele models) and rs731236 (dominant, recessive, and allele models) variants were both significantly associated with TB in South Asians. When we stratified data by type of disease, positive results were detected for rs7975232 variant in EPTB (dominant, recessive, over-dominant, and allele models) subgroup, and for rs2228570 variant in PTB (dominant, recessive, and allele models) and EPTB (dominant, recessive, over-dominant, and allele models) subgroups. Our meta-analysis supported that rs7975232, rs1544410, rs2228570, and rs731236 variants might serve as genetic biomarkers of certain types of TB.
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Extra-Skeletal Effects of Vitamin D.
Marino, R, Misra, M
Nutrients. 2019;(7)
Abstract
The vitamin D receptor is expressed in multiple cells of the body (other than osteoblasts), including beta cells and cells involved in immune modulation (such as mononuclear cells, and activated T and B lymphocytes), and most organs in the body including the brain, heart, skin, gonads, prostate, breast, and gut. Consequently, the extra-skeletal impact of vitamin D deficiency has been an active area of research. While epidemiological and case-control studies have often suggested a link between vitamin D deficiency and conditions such as type 1 and type 2 diabetes, connective tissue disorders, inflammatory bowel disorders, chronic hepatitis, food allergies, asthma and respiratory infections, and cancer, interventional studies for the most part have failed to confirm a causative link. This review examines available evidence to date for the extra-skeletal effects of vitamin D deficiency, with a focus on randomized controlled trials and meta-analyses.
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Effects of human interleukins in the transgenic gene reporter cell lines IZ-VDRE and IZ-CYP24 designed to assess the transcriptional activity of vitamin D receptor.
Bartonkova, I, Kallay, E, Dvorak, Z
PloS one. 2018;(2):e0193655
Abstract
The role of vitamin D receptor (VDR) in immune responses has been broadly studied and it has been shown that activated VDR alters the levels of some interleukins (ILs). In this study, we studied the opposite, i.e. whether 13 selected pro-inflammatory and anti-inflammatory ILs influence the transcriptional activity of human VDR. The experimental models of choice were two human stably transfected gene reporter cell lines IZ-VDRE and IZ-CYP24, which were designed to evaluate the transcriptional activity of VDR. The gene reporter assays revealed inhibition of calcitriol-induced luciferase activity by IL-4 and IL-13, when 1 ng/mL of these two compounds decreased the effect of calcitriol down to 60% of the control value. Consistently, calcitriol-induced expression of CYP24A1 mRNA was also significantly decreased by IL-4 and IL-13. The expression of VDR and CYP27B1 mRNAs was not influenced by any of the 13 tested ILs. These data suggest possible cross-talk between the VDR signalling pathway and IL-4- and IL-13-mediated cell signalling.
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Dietary vitamin D, vitamin D receptor, and microbiome.
Sun, J
Current opinion in clinical nutrition and metabolic care. 2018;(6):471-474
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Abstract
PURPOSE OF REVIEW The current review is to summarize the recent progress of vitamin D/vitamin D receptor (VDR) and microbiome in intestinal homeostasis, airway function, and other organs. RECENT FINDINGS Microbiome is considered as a newly discovered human organ. It is critical in the synthesis of vitamins and harvest of otherwise inaccessible nutrients, metabolism of xenobiotics, body fat storage, renewal of gut epithelial cells, and mature of immune system. Vitamin D and VDR are known to regulate microbiome in health and disease. We will focus on the recent findings published in 12-18 months and discuss the vitamin D supplement and its effects on microbiome, intestinal homeostasis, airway function, and metabolism. We will emphasize the tissue specificity and genetic factor of VDR and microbiome. SUMMARY The findings in dietary vitamin D, VDR, and microbiome with personalized genetic information will be implicated for optimal prevention and treatment of chronic diseases.
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Vitamin D and Autoimmune Diseases: Is Vitamin D Receptor (VDR) Polymorphism the Culprit?
Bizzaro, G, Antico, A, Fortunato, A, Bizzaro, N
The Israel Medical Association journal : IMAJ. 2017;(7):438-443
Abstract
Vitamin D deficiency is becoming an increasing problem worldwide. It should not be underestimated, not only due to the well-known consequences vitamin D deficiency has on bone health, but primarily because recent studies have shown how the biologically active form of vitamin D - 1,25(OH)2D - is involved in many biological processes, including immune system modulation. Moreover, the presence of a vitamin D receptor was discovered in almost all immune cells and some of its polymorphisms were found to be associated with increased incidence of autoimmune diseases. This finding led to a proposed link between vitamin D deficiency and autoimmune diseases. Patients affected by various autoimmune diseases showed low levels of vitamin D. However, it is not always clear whether vitamin D deficiency is the cause or rather a consequence of the disease. Limitations of the studies, such as the small number of patients, heterogeneity of selected groups, environmental conditions, methods used to measure vitamin D serum concentration and other confounding factors do not lead to unequivocal results to demonstrate a direct link between low vitamin D levels and autoimmune disease. Therefore, randomized trials are needed to clarify conflicting results.
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Vitamin D receptor activation reduces inflammatory cytokines and plasma MicroRNAs in moderate chronic kidney disease - a randomized trial.
Mansouri, L, Lundwall, K, Moshfegh, A, Jacobson, SH, Lundahl, J, Spaak, J
BMC nephrology. 2017;(1):161
Abstract
BACKGROUND Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD), partly due to endothelial dysfunction and chronic inflammation. Vitamin D treatment in end stage renal disease is suggested to modulate the immune system and lead to improved outcomes. We and others have demonstrated that treatment with vitamin D or activated vitamin D analogues protects the endothelial function in less severe renal disease as well. Since the endothelial protection might be mediated by vitamin D effects on inflammation, we assessed levels of pro-inflammatory cytokines and micro RNAs (miRs) in patients with moderate CKD, treated with an active vitamin D analogue (paricalcitol). METHODS Thirty-six patients with moderate CKD were randomized to 12 weeks treatment with placebo, 1 μg, or 2 μg paricalcitol daily. Cytokines were measured by Milliplex 26-plex. Total RNA was isolated from plasma and miRs were determined by quantitative reverse transcription PCR analysis. RESULTS Selected pro-inflammatory cytokines decreased significantly following treatment, while no change was observed in the placebo group. The micro RNAs; miR 432-5p, miR 495-3p, and miR 576-5p were significantly downregulated in the active treated groups, compared to the placebo group. CONCLUSION Paricalcitol treatment for 12 weeks in patients with moderate CKD reduces cytokines and micro RNAs involved in atherosclerosis and inflammation. The potentially protective role of vitamin D receptor activation in the inflammatory processes regarding the long-term outcomes in CKD patients warrants further studies. TRIAL REGISTRATION SOLID study; NCT01204528 , April 27, 2010.
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Vitamin D/VDR, Probiotics, and Gastrointestinal Diseases.
Shang, M, Sun, J
Current medicinal chemistry. 2017;(9):876-887
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Vitamin D is an important factor in regulating inflammation, immune responses, and carcinoma inhibition via action of its receptor, vitamin D receptor (VDR). Recent studies have demonstrated the role of vitamin D/VDR in regulating host-bacterial interactions. Probiotics are beneficial bacteria with the power of supporting or favoring life on the host. In the current review, we will discuss the recent progress on the roles of vitamin D/VDR in gut microbiome and inflammation. We will summarize evidence of probiotics in modulating vitamin D/VDR and balancing gut microbiota in health and gastrointestinal diseases. Moreover, we will review the clinical application of probiotics in prevention and therapy of IBD or colon cancer. Despite of the gains, there remain several barriers to advocate broad use of probiotics in clinical therapy. We will also discuss the limits and future direction in scientific understanding of probiotics, vitamin D/VDR, and host responses.
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Role of Placental VDR Expression and Function in Common Late Pregnancy Disorders.
Knabl, J, Vattai, A, Ye, Y, Jueckstock, J, Hutter, S, Kainer, F, Mahner, S, Jeschke, U
International journal of molecular sciences. 2017;(11)
Abstract
Vitamin D, besides its classical role in bone metabolism, plays a distinct role in multiple pathways of the feto-maternal unit. Calcitriol is the major active ligand of the nuclear vitamin D receptor (VDR). The vitamin D receptor (VDR) is expressed in different uteroplacental parts and exerts a variety of functions in physiologic pregnancy. It regulates decidualisation and implantation, influences hormone secretion and placental immune modulations. This review highlights the role of the vitamin D receptor in physiologic and disturbed pregnancy, as preeclampsia, fetal growth restriction, gestational diabetes and preterm birth. We discuss the existing literature regarding common VDR polymorphisms in these pregnancy disorders.