The 2023's Growing Evidence Confirming the Relationship between Vitamin D and Autoimmune Diseases.

The second Special Issue of Nutrients dedicated to "Vitamin D, Immune Response, and Autoimmune Diseases" will include original data and recent achievements from authors who would like to participate in this research topic [...].

Immunomodulatory Properties of Vitamin D in the Intestinal and Respiratory Systems.

Vitamin D plays a crucial role in modulating the innate immune response by interacting with its intracellular receptor, VDR. In this review, we address vitamin D/VDR signaling and how it contributes to the regulation of intestinal and respiratory microbiota. We additionally review some components of the innate immune system, such as the barrier function of the pulmonary and intestinal epithelial membranes and secretion of mucus, with their respective modulation by vitamin D. We also explore the mechanisms by which this vitamin D/VDR signaling mounts an antimicrobial response through the transduction of microbial signals and the production of antimicrobial peptides that constitute one of the body's first lines of defense against pathogens. Additionally, we highlight the role of vitamin D in clinical diseases, namely inflammatory bowel disease and acute respiratory distress syndrome, where excessive inflammatory responses and dysbiosis are hallmarks. Increasing evidence suggests that vitamin D supplementation may have potentially beneficial effects on those diseases.

How Does Vitamin D Affect Immune Cells Crosstalk in Autoimmune Diseases?

Vitamin D is a secosteroid hormone that is highly involved in bone health. Mounting evidence revealed that, in addition to the regulation of mineral metabolism, vitamin D is implicated in cell proliferation and differentiation, vascular and muscular functions, and metabolic health. Since the discovery of vitamin D receptors in T cells, local production of active vitamin D was demonstrated in most immune cells, addressing the interest in the clinical implications of vitamin D status in immune surveillance against infections and autoimmune/inflammatory diseases. T cells, together with B cells, are seen as the main immune cells involved in autoimmune diseases; however, growing interest is currently focused on immune cells of the innate compartment, such as monocytes, macrophages, dendritic cells, and natural killer cells in the initiation phases of autoimmunity. Here we reviewed recent advances in the onset and regulation of Graves' and Hashimoto's thyroiditis, vitiligo, and multiple sclerosis in relation to the role of innate immune cells and their crosstalk with vitamin D and acquired immune cells.

Vitamin D and malabsorptive gastrointestinal conditions: A bidirectional relationship?

This paper is one of the outcomes of the 5th International Conference "Controversies in Vitamin D" held in Stresa, Italy from 15 to 18 September 2021 as part of a series of annual meetings which was started in 2017. The scope of these meetings is to discuss controversial issues about vitamin D. Publication of the outcomes of the meeting in international journals allows a wide sharing of the most recent data with the medical and academic community. Vitamin D and malabsorptive gastrointestinal conditions was one of the topics discussed at the meeting and focus of this paper. Participants to the meeting were invited to review available literature on selected issues related to vitamin D and gastrointestinal system and to present their topic to all participants with the aim to initiate a discussion on the main outcomes of which are reported in this document. The presentations were focused on the possible bidirectional relationship between vitamin D and gastrointestinal malabsorptive conditions such as celiac disease, inflammatory bowel diseases (IBDs) and bariatric surgery. In fact, on one hand the impact of these conditions on vitamin D status was examined and on the other hand the possible role of hypovitaminosis D on pathophysiology and clinical course of these conditions was also evaluated. All examined malabsorptive conditions severely impair vitamin D status. Since vitamin D has known positive effects on bone this in turn may contribute to negative skeletal outcomes including reduced bone mineral density, and increased risk of fracture which may be mitigated by vitamin D supplementation. Due to the immune and metabolic extra-skeletal effects there is the possibility that low levels of vitamin D may negatively impact on the underlying gastrointestinal conditions worsening its clinical course or counteracting the effect of treatment. Therefore, vitamin D status assessment and supplementation should be routinely considered in all patients affected by these conditions. This concept is strengthened by the existence of a possible bidirectional relationship through which poor vitamin D status may negatively impact on clinical course of underlying disease. Sufficient elements are available to estimate the desired threshold vitamin D level above which a favourable impact on the skeleton in these conditions may be obtained. On the other hand, ad hoc controlled clinical trials are needed to better define this threshold for obtaining a positive effect of vitamin D supplementation on occurrence and clinical course of malabsorptive gastrointestinal diseases.

Rickets, Vitamin D, and Ca/P Metabolism.

Rickets was a major public health problem dating from Roman times, and medical descriptions of rickets date from the 17th century. Sniadecki first advocated treatment by exposure to sunshine in 1822; contemporaneously, several British physicians advocated use of cod liver oil. Both approaches were successful. Work in 1924 showed that exposure to UV light endowed fats and other foods with antirachitic properties. Vitamins D2 and D3, the antirachitic agent in cod liver oil, were, respectively, produced by UV radiation of ergosterol and 7-dehydrocholesterol. Calcitriol (1,25[OH]2D3) was identified as the biologically active form of vitamin D in the early 1970s. The vitamin D 25-hydroxylase, 24-hydroxylase, and 1α-hydroxylase were cloned in the 1990s and their genetic defects were soon delineated. The vitamin D receptor was also cloned and its mutations identified in vitamin D-resistant rickets. Work with parathyroid hormone (PTH) began much later, as the parathyroids were not identified until the late 19th century. In 1925, James B. Collip (of insulin fame) identified PTH by its ability to correct tetany in parathyroidectomized dogs, but only in the 1970s was it clear that only a small fragment of PTH conveyed its activity. Congenital hypoparathyroidism with immune defects was described in 1968, eventually linked to microdeletions in chromosome 22q11.2. X-linked hypophosphatemic rickets was reported in 1957, and genetic linkage analysis identified the causative PHEX gene in 1997. Autosomal dominant hypophosphatemic rickets similarly led to the discovery of FGF23, a phosphate-wasting humoral factor made in bone, in 2000, revolutionizing our understanding of phosphorus metabolism.

Vitamin D and the Central Nervous System: Causative and Preventative Mechanisms in Brain Disorders.

Twenty of the last one hundred years of vitamin D research have involved investigations of the brain as a target organ for this hormone. Our group was one of the first to investigate brain outcomes resulting from primarily restricting dietary vitamin D during brain development. With the advent of new molecular and neurochemical techniques in neuroscience, there has been increasing interest in the potential neuroprotective actions of vitamin D in response to a variety of adverse exposures and how this hormone could affect brain development and function. Rather than provide an exhaustive summary of this data and a listing of neurological or psychiatric conditions that vitamin D deficiency has been associated with, here, we provide an update on the actions of this vitamin in the brain and cellular processes vitamin D may be targeting in psychiatry and neurology.

Physiological regulation of phosphate homeostasis.

Phosphate homeostasis is dependent on the interaction and coordination of four main organ systems: thyroid/parathyroids, gastrointestinal tract, bone and kidneys, and three key hormonal regulators, 1,25-hydroxyvitamin D3, parathyroid hormone and FGF23 with its co- factor klotho. Phosphorus is a critical nutritional element for normal cellular function, but in excess can be toxic to tissues, particularly the vasculature. As phosphate, it also has an important interaction and inter-dependence with calcium and calcium homeostasis sharing some of the same controlling hormones, although this is not covered in our article. We have chosen to provide a current overview of phosphate homeostasis only, focusing on the role of two major organ systems, the gastrointestinal tract and kidneys, and their contribution to the control of phosphate balance. We describe in some detail the mechanisms of intestinal and renal phosphate transport, and compare and contrast their regulation. We also consider a significant example of phosphate imbalance, with phosphate retention, which is chronic kidney disease; why consequent hyperphosphatemia is important, and some of the newer means of managing it.

Molecular basis of vitamin D action in inflammatory bowel disease.

There is growing evidence of vitamin D involvement in immune regulation and gut barrier function, suggesting that vitamin D may play a critical role in the development of inflammatory bowel disease (IBD). This review presents advances in the molecular mechanisms of vitamin D and vitamin D receptor (VDR) signaling with respect to barrier integrity and innate/adaptive immunity in the gut, as well as recent findings in uncovering the biological link between vitamin D-associated genetic variants and IBD. Experimental data have revealed a mechanistic basis for the contribution of vitamin D to the pathogenesis of IBD. The vitamin D/VDR complex is involved in the regulation of innate and adaptive immune responses to pathogenic threats by acting as an immunomodulator and alleviating inflammation in experimental IBD models and IBD patients, contributing to intestinal homeostasis. Vitamin D has been associated with the promotion of antimicrobial peptide secretion, down-regulation of dendritic cell activity, induction of tolerogenic rather than pro-inflammatory T-cell differentiation and function, and increased production of anti-inflammatory cytokines, highlighting its potential therapeutic value for IBD. Elucidating the complex interplay between vitamin D/VDR and the pathogenesis of IBD is critical for the development of novel therapeutic interventions and for the potential use of this molecule as a prognostic and diagnostic tool in clinical practice.

Vitamin D/vitamin D receptor, autophagy, and infection. / ç»´ç”Ÿç´ D/ç»´ç”Ÿç´ D受体、自噬与感染.

Vitamin D plays an important role in mineral and bone homeostasis, immune responses, cardiovascular function and keratinocyte proliferation and differentiation. Vitamin D performs most of its functions by binding to vitamin D receptors (VDR), which interact with other intracellular signaling pathways to regulate bone metabolism, inflammation, immunity, cell cycle progression and apoptosis. Autophagy is a basic stress response in yeast, plants and mammals, and plays a critical role in maintaining optimal functional states at the level of cells and organs. Vitamin D/VDR plays an anti-infection role via inducing and regulating autophagy.

Experimental Testing of the Action of Vitamin D and Silicon Chelates in Bone Fracture Healing and Bone Turnover in Mice and Rats.

This study presents findings on the biological action of an integrated supplement containing the following components involved in osteogenesis and mineralization: vitamin D and silicon in the bioavailable and soluble form. A hypothesis that these components potentiate one another's action and make calcium absorption by the body more efficient was tested. Biological tests of the effect of vitamin D and silicon chelates on bone fracture healing and bone turnover were conducted using ICR mice and albino Wistar rats. Radiographic and biochemical studies show that the supplement simultaneously containing silicon chelates and vitamin D stimulates bone tissue regeneration upon mechanical defects and accelerates differentiation of osteogenic cells, regeneration of spongy and compact bones, and restoration of bone structure due to activation of osteoblast performance. Bone structure restoration was accompanied by less damage to skeletal bones, apparently due to better absorption of calcium from food. The studied supplement has a similar effect when used to manage physiologically induced decalcification, thus holding potential for the treatment of osteomalacia during pregnancy or occupational diseases (e.g., for managing bone decalcification in astronauts).

Paraventricular Vitamin D Receptors Are Required for Glucose Tolerance in Males but Not Females.

When delivered directly into the brain, vitamin D, can improve glucose levels in male mice. Additionally, the loss of the vitamin D receptor (VDR) in male mice's paraventricular hypothalamus (PVH) results in impaired glucose tolerance. Data in humans shows that low vitamin D levels are detrimental to glucose homeostasis, an effect that may be more prominent in men. However, it is unknown if vitamin D action in the brain is required for normal glucose regulation in female mice. This study shows that in both viral and genetic models, male mice with obesity and PVH VDR loss have impaired glucose tolerance while female mice are unaffected. Weights were unaltered in both sexes by PVH VDR loss. Additionally, PVH VDR loss did not cause any glucose abnormalities in either sex when the mice were on a chow diet. Utilizing electrophysiology studies, we show PVH VDR loss resulted in decreased baseline firing frequency and resting membrane potential in males, but not females. Additionally, male mice with PVH VDR loss had impaired miniature excitatory postsynaptic currents (mEPSC), while females were unaffected. Interestingly, the PVH neurons of both sexes were activated by exogenous vitamin D (1,25-dihydroxyvitamin D3), an effect dependent upon the VDR. Thus, there is sexual dimorphism, for the actions of the PVH VDR on glucose regulation. PVH VDRs are necessary for normal glucose homeostasis in males but not females and this may be secondary to actions of the VDR on neuronal activity.

The role of vitamin D in cardiovascular disease and COVID-19.

Patients with pre-existing cardiovascular disease (CVD) are at high risk for adverse outcomes with coronavirus disease 2019 (COVID-19). Further, COVID-19 infection is associated with numerous cardiovascular (CV) complications including arrhythmia, myocardial injury, cardiomyopathy, and thrombotic events. Increased susceptibility to COVID-19 and CV complications related to COVID-19 may be in part related to immune dysregulation and inflammation associated with CV disease which is exacerbated with viral infection. Vitamin D plays a major role in immune function and exerts anti-inflammatory effects, which may prove important in the context of CVD and COVID-19. To date, studies have shown minimal benefit for vitamin D supplementation in patients with COVID-19, though there are no studies specific to patients with CVD and related complications. Further, given that vitamin D has important protective effects on the CV system, including augmentation of myocardial contractility and anti-thrombotic effects, it is unknown if supplementation with vitamin D can mitigate CVD complications associated with COVID-19.

Vitamin D Implications and Effect of Supplementation in Endocrine Disorders: Autoimmune Thyroid Disorders (Hashimoto's Disease and Grave's Disease), Diabetes Mellitus and Obesity.

Background and Objectives: Vitamin D deficiency is involved in numerous pathologies, including endocrine pathology. The purpose of this review consists of presenting the role of vitamin D in the pathophysiology of certain endocrine disorders, autoimmune thyroid disorders (Hashimoto's disease and Grave's disease), diabetes mellitus, and obesity, and whether its supplementation can influence the outcome of these diseases. Materials and Methods: Review articles and original articles from the literature were consulted that corresponded with the thematic. Results: Vitamin D deficiency is frequently encountered in endocrine disorders and supplementation restores the normal values. In Hashimoto's disease, vitamin D deficiency appears to be correlated with a higher titer of anti-TPO antibodies and with thyroid volume, and supplementation was associated with reduction of antibodies in some studies. In other studies, supplementation appeared to reduce TSH levels. In Grave's disease, there was a significant correlation regarding vitamin D levels and thyroid volume respective to the degree of exophthalmos. In diabetes mellitus type 2 patients, supplementation led to some improvement of the HOMA-IR index and HbA1c, whereas obesity data from literature do not report significant beneficial findings. Conclusions: Vitamin D deficiency is highly prevalent in endocrine disorders and its supplementation appears to have numerous beneficial effects.

Vitamin D/vitamin D receptor, autophagy, and infection / 中南大学学报(医学版)

Vitamin D plays an important role in mineral and bone homeostasis, immune responses, cardiovascular function and keratinocyte proliferation and differentiation. Vitamin D performs most of its functions by binding to vitamin D receptors (VDR), which interact with other intracellular signaling pathways to regulate bone metabolism, inflammation, immunity, cell cycle progression and apoptosis. Autophagy is a basic stress response in yeast, plants and mammals, and plays a critical role in maintaining optimal functional states at the level of cells and organs. Vitamin D/VDR plays an anti-infection role via inducing and regulating autophagy.

Vitamin D deficiency: concern for rheumatoid arthritis and COVID-19?

Vitamin D is an immunomodulatory hormone with an established role in calcium and phosphate metabolism and skeletal mineralization. Evidence showing its immunological benefits by regulating essential components of the innate and adaptive immune system is prevalent. Vitamin D deficiency is reported worldwide and is thereby found to be associated with various immune-related diseases. Rheumatoid Arthritis and COVID-19 are two such diseases, sharing a similar hyperinflammatory response. Various studies have found an association of lower Vitamin D levels to be associated with both these diseases. However, contrasting data is also reported. We review here the available scientific data on risk factor association and supplementation benefits of Vitamin D in Rheumatoid Arthritis and COVID-19, intending to critically evaluate the literature.

Vitamin D alleviates hypoxia/reoxygenation-induced injury of human trophoblast HTR-8 cells by activating autophagy.

INTRODUCTION: Attenuation of trophoblast cell dysfunction would be beneficial for retarding pre-eclampsia (PE). Vitamin D has been reported to improve trophoblast cell function in early PE, but the mechanism involved is not fully elucidated. This study is aimed to investigate whether vitamin D alleviates trophoblast cell dysfunction via regulating autophagy. METHODS: Human trophoblast HTR-8 cells were cultured in hypoxia/reoxygenation (H/R) condition to simulate the oxidative stress state of early PE in vitro. MTT, Transwell and tube formation assays were respectively applied to assess cell proliferation, invasion, and angiogenesis abilities. DCFH-DA staining was performed to detect cellular reactive oxygen species levels. GFP-RFP-LC3 plasmid transfection and transmission electron microscopy were subjected to monitor autophagy. Enzyme-linked immunosorbent assay and Western blot analysis were used to detect autophagy-related and pyroptosis-associated molecules. RESULTS: H/R led to severe impairments on the bio-function of HTR-8 cells, as evidenced by the deficiency of cell proliferation, invasion, and angiogenesis abilities, and the increase of cellular ROS production. Simultaneously, H/R inhibited autophagy and triggered pyroptosis. 1,25(OH)2D3, the hormonally active form of vitamin D, dramatically attenuated H/R-induced trophoblast dysfunction. Also, 1,25(OH)2D3 activated autophagy and inhibited pyroptosis. Additionally, autophagy-enhancer rapamycin exerted similar protective effect to that of 1,25(OH)2D3, whereas autophagy-inhibitor 3-methyladenine blocked the protective effect of 1,25(OH)2D3. DISCUSSION: The mechanism that vitamin D alleviates trophoblast cell dysfunction is associated with autophagy induction and pyroptosis inhibition.

The role of vitamin D in selected autoimmune diseases.

The authors of recently published scientific papers are focusing increasingly often on the effect of vitamin D on immune processes. In the case of deficiencies of this vitamin, an imbalance in the immune system is observed, which is associated with the intensification of the inflammatory reaction in the body and the increased possibility of an autoimmune reaction. Therefore, due to the growing interest of scientists in the relationship between the effects of vitamin D and the development of autoimmune diseases, this paper considers the use of Vitamin D in autoimmune therapies. However, the mechanism of vitamin D on individual autoimmune diseases has not been elucidated so far, therefore there is a need for further research. The importance of maintaining normal plasma vitamin D levels to reduce the risk of developing autoimmune diseases has been demonstrated by the authors of other studies. They showed that vitamin D levels influenced the course, severity of symptoms and frequency of relapses of autoimmune thyroid disease, inflammatory bowel disease, and rheumatoid arthritis.

The relationship between vitamin D status, intake and exercise performance in UK University-level athletes and healthy inactive controls.

The potential ergogenic effects of vitamin D (vitD) in high performing athletes has received considerable attention in the literature and media. However, little is known about non-supplemented university athletes and students residing at a higher latitude. This study aimed to investigate the effects of vitD (biochemical status and dietary intake) on exercise performance in UK university athletes and sedentary students. A total of 34 athletes and 16 sedentary controls were studied during the spring and summer months. Serum vitD status and sunlight exposure were assessed using LC-MS/MS and dosimetry, respectively. Muscular strength of the upper and lower body was assessed using handgrip and knee extensor dynamometry (KE). Countermovement jump (CMJ) and aerobic fitness were measured using an Optojump and VO2max test, respectively. Statistical analysis was performed using paired/ independent t-tests, ANCOVA and Pearson/ Spearman correlations, depending on normality. VitD status increased significantly over the seasons, with athletes measuring higher status both in spring (51.7±20.5 vs. 37.2±18.9 nmol/L, p = 0.03) and summer (66.7±15.8 vs 55.6±18.8 nmol/L, p = 0.04) when compared to controls, respectively. Notably, 22% of the subjects recruited were vitD deficient during the spring term only (<25nmol/L, n 9). Subjects with 'insufficient' vitD status (<50nmol/L) elicited significantly lower CMJ when contrasted to the vitD 'sufficient' (>50nmol/l) group (p = 0.055) and a lower VO2 max (p = 0.05) in the spring and summer term (p = 0.05 and p = 0.01, respectively). However, an ANCOVA test showed no significant difference detected for either CMJ or VO2max following adjustments for co-variates. In conclusion, we provide novel information on the vitD status, dietary intake, physical fitness and sunlight exposure of UK young adults across two separate seasons, for which there is limited data at present.

The Influence of Vitamin D Intake and Status on Mental Health in Children: A Systematic Review.

A potential role of vitamin D in some components of mental health is currently suggested, but the analyses are conducted mainly for adults, while for young individuals mental health is especially important, due to its lifelong effects. The aim of the study was to analyze the association between vitamin D intake or status and mental health in children within a systematic review of literature, including both intervention and observational studies. The literature search was conducted according to the PRISMA guidelines and it covered peer-reviewed studies included in databases of PubMed and Web of Science until October 2019. The studies presenting either vitamin D intake, or vitamin D status in human subjects were allowed (excluding subjects with intellectual disabilities, eating disorders and neurological disorders), while for mental health the various methods of assessment and wide scope of factors were included. The bias was assessed using the Newcastle-Ottawa Scale (NOS). The review was registered in the PROSPERO database (CRD42020155779). A number of 7613 studies after duplicate removing were extracted by two independent researchers, followed by screening and assessment for eligibility, conducted by two independent researchers in two steps (based on title and abstract). Afterwards, the full texts were obtained and after reviewing, a number of 24 studies were included. The synthetic description of the results was prepared, structured around exposure (vitamin D supplementation/status) and outcome (components of mental health). The included studies were conducted either in groups of healthy individuals, or individuals with mental health problems, and they assessed following issues: behavior problems, violence behaviors, anxiety, depressive symptoms/depression, aggressive disorder, psychotic features, bipolar disorder, obsessive compulsive disorder, suicidal incident, as well as general patterns, as follows: mental health, level of distress, quality of life, well-being, mood, sleep patterns. The vast majority of assessed studies, including the most prominent ones (based on the NOS score) supported potential positive influence of vitamin D on mental health in children. As a limitation of the analysis, it should be indicated that studies conducted so far presented various studied groups, outcomes and psychological measures, so more studies are necessary to facilitate comparisons and deepen the observations. Nevertheless, vitamin D intake within a properly balanced diet or as a supplementation, except for a safe sun exposure, should be indicated as an element supporting mental health in children, so it should be recommended to meet the required 25(OH)cholecalciferol blood level in order to prevent or alleviate mental health problems.

New Roles for Vitamin D Superagonists: From COVID to Cancer.

Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity.