Vitamin D3 (Immune)

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated neurodegenerative disorder of the central nervous system and a leading cause of disability among young adults. The disease exhibits considerable heterogeneity in clinical progression, with some patients experiencing more aggressive disease activity and a rapid decline in quality of life. Vitamin D plays a key role in immune regulation, and evidence suggests that its deficiency constitutes a significant environmental risk factor for immune-mediated conditions such as MS. While there are controversies regarding the role of serum 25(OH)D in MS as well as vitamin D3 supplements in controlling relapse and disability improvement during treatment. Therefore, our current meta-analysis aims to examine the relationship between serum 25(OH)D levels-and their modulation through supplementation-and multiple sclerosis. METHODS: Comprehensive literature review was performed from conception to November 17, 2025, employing various online databases including PubMed, Cochrane Library, Web of Science, and EMBASE. The relevant studies about MS and serum 25-hydroxyvitamin D (25(OH)D) level or vitamin D3 supplementation. This meta-analysis incorporated 40 research examining the correlation between serum 25(OH)D levels and multiple sclerosis, as well as 22 studies investigating the effects of vitamin D3 supplementation on multiple sclerosis. RESULTS: 1) The 25(OH)D levels in patients with MS were significantly lower than those in healthy controls. In the analysis of disease subtypes, patients with relapsing-remitting MS (RRMS) had significantly higher 25(OH)D levels than those with secondary progressive MS (SPMS), but no significant difference was observed compared to patients with primary progressive MS (PPMS). Additionally, RRMS patients had significantly lower 25(OH)D levels during relapse than during remission. No significant seasonal fluctuation in 25(OH)D levels was observed in MS patients; 2) Multivariable-adjusted analysis comparing the highest versus lowest serum 25(OH)D categories revealed that higher serum 25(OH)D levels were associated with a lower risk of MS onset and lower disability scores (EDSS), but no si

Chronic pruritus is a distressing condition associated with various dermatological and systemic diseases, significantly impairing patients' quality of life. While conventional treatments such as antihistamines and corticosteroids offer relief, their efficacy varies, and long-term use may lead to adverse effects. Emerging evidence suggests that certain vitamins, including vitamin D, vitamin E, vitamin B12, and niacinamide (B3), may play a role in alleviating pruritus through their anti-inflammatory, immune-regulatory, and skin barrier-enhancing properties. However, the effectiveness of these vitamins in managing chronic pruritus remains unclear. This meta-analysis aims to update and expand the evaluation of vitamin supplementation in reducing pruritus severity across different underlying conditions, extending the scope beyond vitamin D to include vitamins B and E. A comprehensive search was performed across PubMed, Embase, Web of Science, and Cochrane Library databases up to January 2025 to identify randomized controlled trials (RCTs) evaluating the effects of vitamin supplementation on chronic pruritus. A total of 21 RCTs (n = 1723) were included in the meta-analysis. Compared to placebo, vitamin supplementation demonstrated a significant reduction in pruritus severity (Standardized Mean Difference [SMD]: -0.578, 95% CI: -0.736 to -0.419, p = 0.000; I2 = 53.630, p = 0.003). Subgroup analysis revealed that topical vitamin B12 and vitamin D3 showed the most pronounced antipruritic effects, particularly in patients with atopic dermatitis and chronic kidney disease-associated pruritus. Sensitivity analysis confirmed the robustness of the findings; however, potential publication bias was suggested by Egger's regression test (p = 0.00979), indicating that the overall effect may be influenced by small-study effects or underreporting of negative results. This meta-analysis indicates that vitamin B, D, and E supplementation may serve as effective adjunct therapies for managing chronic pruritus. However, the variability among the included studies highlights the necessity for well-structured, long-term RCTs to determine the ideal dosage, treatment duration, and target pati

BACKGROUND: Hashimoto's thyroiditis (HT) is the prevailing form of autoimmune thyroiditis and the leading cause of hypothyroidism in iodine-sufficient regions worldwide. This study aims to evaluate the efficacy of vitamin D supplementation on HT through a meta-analysis of randomized controlled trials (RCTs). METHODS: The databases searched included PubMed, and others. We included RCTs that the treatment group received vitamin D, while the control group received either a placebo or no treatment. The studies measured the baseline and endpoint levels of 25-hydroxyvitamin D [25(OH)D], thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), anti-thyroid peroxidase antibody (TPO-Ab), and thyroglobulin antibody (TG-Ab). We performed a meta-analysis to calculate the standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS: A total of 12 studies involving 862 individuals were included. Vitamin D supplementation has a significant impact on reducing the titers of TPO-Ab (SMD = -1.084, 95% CI = -1.624 to -0.545) and TG-Ab (SMD = -0.996, 95% CI = -1.579 to -0.413) in patients with HT, and it also improves thyroid function by decreasing TSH level (SMD = -0.167, 95% CI = -0.302 to 0.031) and increasing FT3 (SMD = 0.549, 95% CI = 0.077-1.020) and FT4 (SMD = 0.734, 95% CI = 0.184-1.285) levels. Active vitamin D (calcitriol) significantly reduces the titer of TPO-Ab compared to naive forms of vitamin D (vitamin D2 or D3); treatment durations > 12 weeks result in a more effective reduction of TPO-Ab levels and a more significant increase in FT4 and FT3 levels in patients with HT (meta-regression P < .05). CONCLUSION: Vitamin D supplementation may have beneficial effects on HT patients by modulating immune responses and improving thyroid function.

Psoriasis is a chronic immune-dysregulated inflammatory disease and hypovitaminosis D is considered a risk factor. We conducted an online database search to review and meta-analyze the relationship between vitamin D, other bone metabolism parameters, and psoriasis. The efficacy of oral vitamin D supplementation in improving Psoriasis Area and Severity Index (PASI) was also evaluated. Non-original articles, case reports, and animal studies were excluded. Bias risk was assessed according to the Cochrane Collaboration's tool and the Newcastle-Ottawa scale in randomized controlled trials (RCTs) and case-control studies, respectively. Unstandardized mean differences were used for data synthesis. Twenty-three studies reported serum 25 hydroxyvitamin D (25(OH)D) levels in 1876 psoriasis patients and 7532 controls. Psoriasis patients had significantly lower 25(OH)D levels than controls (21.0 ± 8.3 vs. 27.3 ± 9.8, p < 0.00001). Conversely, 450 psoriasis patients had lower levels of parathormone than 417 controls (38.7 ± 12.8 vs. 43.7 ± 16.5, p = 0.015). Four RCTs examined the effect of oral vitamin D supplementation on psoriasis for 173 patients and 160 patients were treated with placebo. No significant differences were found in PASI after 3, 6, and 12 months of supplementation. It is shown that 25(OH)D serum levels are significantly lower in psoriasis, but, although the granularity of RCT methodology may have influenced the pooled analysis, vitamin D supplementation did not seem to improve clinical manifestations.

BACKGROUND: Children and young adults with HIV infection may exhibit vitamin D deficiency, which is harmful to bone health as well as the endocrine and immune systems. OBJECTIVES: This study sought to investigate the effect of vitamin D supplementation on children and young adults with HIV infection. METHODS: The PubMed, Embase, and Cochrane databases were searched. Randomized controlled trials that have evaluated the effects of vitamin D supplementation (ergocalciferol or cholecalciferol) at any dose or for any duration in children and young adults with HIV infection, aged 0-25 y, were included. A random-effects model was used, and the standardized mean difference (SMD) and 95% CI were calculated. RESULTS: Ten trials, with 21 publications and 966 participants (mean age: 17.9 y), were included in the meta-analysis. The supplementation dose and the duration of the studies included ranged from 400 to 7000 IU/d and from 6 to 24 mo, respectively. Vitamin D supplementation was associated with a significantly higher serum 25(OH)D concentration at 12 mo (SMD: 1.14; 95% CI: 0.64, 1.65; P < 0.00001) compared with a placebo. No significant difference was observed in spine BMD (SMD: -0.09; 95% CI: -0.47, 0.3; P = 0.65) at 12 mo between these 2 groups. However, participants who received higher doses (1600-4000 IU/d) had significantly higher total BMD (SMD: 0.23; 95% CI: 0.02, 0.44; P = 0.03) and nonsignificantly higher spine BMD (SMD: 0.3; 95% CI: -0.02, 0.61; P = 0.07) at 12 mo compared with those who received standard doses (400-800 IU/d). CONCLUSIONS: Vitamin D supplementation in children and young adults with HIV infection increases the serum 25(OH)D concentration. A relatively high daily dose of vitamin D (1600-4000 IU) improves total BMD at 12 mo and results in sufficient 25(OH)D concentrations.

As vitamin D (VD) plays an essential role in inflammatory bowel diseases (IBD), this systematic review aimed to update the participation of this vitamin in the prevention or remission of these diseases. This review has included studies in MEDLINE-PubMed, EMBASE, and Cochrane databases. The authors have followed PRISMA (Preferred Reporting Items for a Systematic Review and Meta-analysis) guidelines. According to the inclusion and exclusion criteria, twenty-two randomized clinical trials were selected. In total, 1,209 patients were included in this systematic review: 1034 received only VD and 175 received VD in combination with calcium. The average doses of VD supplementation were from oral 400 IU daily to 10,000 IU per kilogram of body weight. Single injection of 300,000 IU of VD was also used. Several studies have shown the crucial role that VD plays in the therapeutic approach of IBD due to its effects on the immune system. It effectively decreased inflammatory cytokines such as TNF-α and IFN-γ (p<0.05) and provided a reduction in disease activity assessed through different scores such as Crohn's Disease Activity Index (CDAI) (p<0.05) and Ulcerative Colitis Disease Activity Index (UCDAI) (p<0.05). Unfortunately, the available clinical trials are not standardized for of doses and routes of administration. Existing meta-analyses are biased because they compare studies using different doses or treatments in combination with different drugs or supplements such as calcium. Even though VD has crucial effects on inflammatory processes, there is still a need for standardized studies to establish how the supplementation should be performed and the doses to be administered.

OBJECTIVE: To perform a meta-analysis of randomized controlled trials to evaluate the efficacy of vitamin D supplementation on thyroid autoimmunity markers in Hashimoto's thyroiditis (HT). METHODS: This meta-analysis included randomized controlled clinical trials identified by a systematic search of electronic databases (PubMed®, MEDLINE®, EMBASE, The Cochrane Library, China National Knowledge Infrastructure) from inception to August 2020. All studies included patients with HT that received vitamin D supplementation irrespective of the doses administered or the duration of treatment. The primary and secondary outcome measures were thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TGAb) titres. RESULTS: Eight studies (n = 652) were included. There was significant heterogeneity between the studies. Using a random-effect model, vitamin D supplementation reduced TPOAb titre (standardized mean difference [SMD]: -1.11; 95% confidence interval [CI]: 1-1.92, -0.29) and TGAb titre (SMD: -1.12; 95% CI: -1.96, -0.28). A subgroup analysis demonstrated that vitamin D supplementation for >3 months resulted in a decrease in TPOAb titre (SMD: -1.66, 95% CI: -2.91, -0.41) but treatment ≤3 months was ineffective. Treatment with vitamin D3 decreased TPOAb titre (SMD: -1.48; 95% CI: -2.53, -0.42) whereas vitamin D did not. CONCLUSION: These data suggest that vitamin D reduces autoantibody titre in patients with HT. Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies. Petrelli F(1), Luciani A(2), Perego G(3), Dognini G(4), Colombelli PL(4), Ghidini A(5). Author information: (1)Oncology Unit, ASST Bergamo Ovest, Treviglio, BG, Italy. Electronic address: [email protected]. (2)Oncology Unit, ASST Bergamo Ovest, Treviglio, BG, Italy. (3)Pharmacy Unit, San Raffaele Hospital, Milano, Italy. (4)Internal Medicine Unit, ASST Bergamo Ovest, Treviglio, BG, Italy. (5)Oncology Unit, Casa di cura Igea, Milano, Italy. Vitamin D modulates the systemic inflammatory response through interaction with immune system. As such, it has a possible protective role against the risk of respiratory tract infect

8. J Steroid Biochem Mol Biol. 2021 Jul;211:105883. doi: 10.1016/j.jsbmb.2021.105883. Epub 2021 Mar 26. Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies. Petrelli F(1), Luciani A(2), Perego G(3), Dognini G(4),

BACKGROUND: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes. METHODS: We searched four databases until December 18th 2020, and trial registries until January 20th 2021. Two reviewers screened the studies, collected data, assessed the risk of bias, and graded the evidence for each outcome across studies, independently and in duplicate. Pre-specified outcomes of interest were mortality, ICU admission, invasive and non-invasive ventilation, hospitalization, time of hospital stay, disease severity and SARS-CoV-2 positivity. We only included data from peer-reviewed articles in our primary analyses. RESULTS: We identified 31 peer-reviewed observational studies. In our primary analysis, there was a positive trend between serum 25(OH)D level <20 ng/ml and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant. Mean 25(OH)D levels was 5.9 ng/ml (95% CI [-9.5, -2.3]) significantly lower in COVID-19 positive, compared to negative patients. The certainty of the evidence was very low. We identified 32 clinical trial protocols, but only three have published results to-date. The trials administer vitamin D doses of 357 to 60,000 IU/day, from one week to 12 months. Eight megatrials investigate the efficacy of vitamin D in outpatient populations. A pilot trial revealed a significant decrease in ICU admission with calcifediol, compared to placebo (OR = 0.003), but the certainty of the evidence was unclear. Another small trial showed that supplementation with cholecalciferol, 60,000 IU/day, decreased fibrinogen levels, but did not have an effect on D-dimer, procalcitonin and CRP levels, compared to placebo. The third trial did not find any effect of vitamin D supplementation on COVID-19 related health outcomes. CONCL

AIMS: Vitamin D deficiency is associated with cardiovascular events in chronic kidney disease (CKD) yet the impact of supplementation is controversial. Previous active vitamin D supplementation studies did not show improvement in cardiac structure or function but the effect of native vitamin D supplementation in CKD patients with low vitamin D levels is unknown. We have addressed this question via both a randomized double-blind prospective study and a meta-analysis of three randomized placebo-controlled studies. METHODS AND RESULTS: We conducted a randomized double-blind, placebo-controlled trial of vitamin D supplementation in stable, non-diabetic, CKD three to four patients with circulating vitamin D <75nmol/L, who were receiving treatment with ACEi or ARB and had high-normal left ventricular (LV) mass. Patients were randomized to receive six directly observed doses of 100 000 IU cholecalciferol (n = 25) or matched placebo (n = 23). The primary endpoint was changed in LV mass index (LVMI) over 52 weeks, as assessed by cardiac magnetic resonance imaging. Secondary endpoints included changes in LV ejection fraction (LVEF); LV and right ventricular volumes and left and right atrial area. Vitamin D concentration increased with the administration of cholecalciferol. The change in LVMI with cholecalciferol [median (inter-quartile range), -0.25 g (-7.20 to 5.30)] was no different from placebo [-4.30 g (9.70 to 2.60)]. There was no difference in changes of LVEF; LV and right ventricular volumes and left and right atrial area. The meta-analysis of three 52-week, randomized placebo-controlled studies using active/native vitamin D supplementation showed no differences in LVMI measurements. CONCLUSION: Vitamin D supplementation does not have beneficial effects on LV mass in CKD patients. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

BACKGROUND: Low vitamin D status and inflammation are associated with poor prognosis among colorectal cancer (CRC) patients. We assessed the efficacy of personalized vitamin D3 supplementation (VIDS) for reducing inflammation in patients with low vitamin D status. METHODS: In an ongoing randomized double-blind, placebo-controlled trial in Germany, CRC patients who underwent surgery in the past year and had serum 25-hydroxyvitamin D levels < 60 nmol/L were randomly assigned to either a personalized loading dose of VIDS, followed by a maintenance dose of 2000 IU/day or a placebo for 12 weeks. Changes in serum interleukin-6 (IL-6), interferon-gamma (IFN-γ), and matrix metalloproteinase (MMP-1) were compared at the end of trial among 126 patients (65 in the placebo and 61 in the intervention group). RESULTS: The VIDS group exhibited 39.3% reduction in IL-6 levels compared to the placebo group (95% CI: -54.9% to -18.2%; p = 0.001). The reductions observed in IFN-γ and MMP-1 due to VIDS were not statistically significant (-6.7%; p = 0.69 and -5.4%; p = 0.23, respectively). CONCLUSION: In CRC patients with low vitamin D status, VIDS reduces serum IL-6, a pro-inflammatory biomarker associated with poor prognosis. Further research should explore a potential supportive therapeutic role of VIDS in managing inflammation and improving CRC outcomes. [Words: 200]. © 2025. The Author(s).

Vitamin D plays a key role in immune modulation, cell proliferation, and hormone regulation. Dysregulated testosterone may contribute to breast cancer progression. We investigated whether long-term vitamin D supplementation affects serum testosterone levels in breast cancer survivors. Complete data at baseline, 12, and 24 months were derived from 253 women with early-stage breast cancer participating in the DEDiCa trial and randomized to receive either a high-dose vitamin D to maintain serum 25(OH)D at 60 ng/mL (group A) or a standard dose to maintain serum levels at 30 ng/mL (group B). Serum 25(OH)D levels significantly increased in both groups (p < 0.001). No significant changes in testosterone concentrations were observed between treatment groups over the 24 month treatment period (A: 0.125 to 0.140 ng/mL; B: 0.162 to 0.193 ng/mL; p = 0.682). Baseline serum testosterone levels emerged as the most significant predictor of testosterone trajectories, possibly modulated by hormone-suppressive therapy. These results are reassuring that vitamin D supplementation did not adversely affect testosterone levels in this population of breast cancer survivors and may partially concur with a healthy lifestyle to equilibrate testosterone levels.

BACKGROUND: Vitamin D plays crucial roles in bone metabolism, growth, and immune response during critical life stages. There is little evidence on the effects of vitamin D supplementation among lactating mothers and their infants in sub-Saharan Africa. OBJECTIVE: We aimed to evaluate the efficacy of maternal vitamin D supplementation during lactation on maternal and infant vitamin D status, biomarkers of bone turnover, and infant anthropometry and motor development in rural Ethiopia. METHODS: In an individually randomized placebo-controlled trial, 126 mothers <2 wk postpartum were allocated to receive either weekly vitamin D3 (15,000 IU cholecalciferol) or placebo capsules for 12 mo. Primary outcomes were maternal and infant plasma 25-hydroxy vitamin D (25(OH)D) concentrations and infant clinical diagnosis for "suspected rickets." Secondary outcomes included biomarkers of bone metabolism, such as maternal plasma concentrations of parathyroid hormone, cross-linked telopeptide type 1 collagen, osteocalcin, and bone-specific alkaline phosphatase (BAP), infant plasma BAP, and maternal urinary concentrations of calcium, phosphorus, and calcium/creatinine ratio. Additional secondary outcomes included infant growth and motor development. RESULTS: Compared with the placebo, weekly cholecalciferol supplementation resulted in greater increases in maternal plasma 25(OH)D concentration at 6 mo [76.6% (95% CI: 56.2, 99.7%); P < 0.001] and 12 mo [68.8% (95% CI: 49.5, 90.7%); P < 0.001]. Maternal vitamin D supplementation also led to significantly higher infant plasma 25(OH)D concentration at 12 mo compared with the placebo group [14.7 nmol/L (95% CI: 5.29, 24.1 nmol/L; P = 0.003)]. There were nonstatistically significant fewer 'suspected rickets' cases in the vitamin D group (8.00%) than the placebo (15.4%) at 12 mo (P = 0.284). However, no significant group differences were observed in infant growth and development. CONCLUSIONS: Maternal cholecalciferol supplementation during lactation using a weekly dose of 15,000 IU safely improves both maternal and infant vitamin D status. The trial was registered at clinicaltrials.gov as NCT02210884.

Parkinson's disease (PD) patients frequently exhibit vitamin D deficiency and an imbalance in T helper 17 (Th17) and regulatory T (Treg) cells, which may contribute to disease pathogenesis. Preclinical evidence suggests vitamin D regulates Th17/Treg balance, but the therapeutic effects of supplementation in PD remain unestablished. This randomized controlled trial investigated peripheral blood levels of vitamin D, Treg, and Th17 cells in PD patients, examined their associations with clinical outcomes, and assessed vitamin D3 supplementation's effects on immunological and motor functions. In this randomized, double-blind, placebo-controlled trial, 51 PD patients and 50 healthy controls (HCs) were enrolled. Thirty PD patients with vitamin D deficiency were randomized to receive vitamin D3 (n = 15) or placebo (vegetable oil, n = 15) for three months. Serum 25(OH)D3 levels were measured by electrochemiluminescence, and Th17/Treg cells were analyzed by flow cytometry. Motor and non-motor symptoms were assessed using standardized scales. Vitamin D3 supplementation significantly increased 25(OH)D3 levels (p < 0.05), reduced Th17 cells (4.62 ± 1.09 to 3.25 ± 1.14, p = 0.003), and elevated Tregs (3.25 ± 0.90 to 4.52 ± 0.95, p = 0.003). Motor function (UPDRS and UPDRS-III) improved in the vitamin D3 group (p < 0.001), while no changes were observed in the placebo group. This preliminary study suggests that vitamin D3 supplementation may restore Th17/Treg balance and potentially alleviate motor symptoms in vitamin D-deficient PD patients, indicating a possible therapeutic strategy.Trial registration: ClinicalTrials.gov: NCT:06539260. Registered 05 August 2024 - Retrospectively registered, https://clinicaltrials.gov/study/NCT06539260 . © 2025. The Author(s).

Recent studies have demonstrated a significant role for gut microbiota dysbiosis in the pathogenesis of various diseases, pregnancy outcomes, and fetal growth. Vitamin D modulates innate immunity and promotes immune tolerance, suggesting involvement in shaping the gut microbiota. However, the relationship between vitamin D and the gut microbiota during pregnancy has not been evaluated in detail. In this study, we administered a vitamin D3 supplement (VD) to pregnant Japanese women, starting during the first trimester of pregnancy, and characterized changes in the circulating concentration of vitamin D and the gut microbiome. Sixty-two pregnant women were randomly allocated to three groups. VD was administered at low (200 IU/d), medium (400 IU/d), or high (1,000 IU/d) doses for 8 wk from 12 to 15 wk of pregnancy, and changes in the serum 25-hydroxyvitamin D (25(OH)D) concentration and the gut microbiome were evaluated. Changes in gut microbial taxa abundance were analyzed by Wilcoxon matched-pairs signed-rank test. Before VD administration, 96.8% of the participants were VD-deficient, and none had a sufficient VD concentration. The serum 25(OH)D concentration increased in a dose-dependent manner in all the dose groups. Additionally, the abundance of Fusicatenibacter in the gut microbiota increased in a VD dosedependent manner, with a significant increase observed in the high-dose group. From these results, in pregnant Japanese women, the administration of high-dose VD increases the prevalence of VD sufficiency and alters the gut microbial composition, suggesting that this has benefits for the maternal and neonatal immune systems.

BACKGROUND: The disruption of the intestinal barrier and the imbalance of the gut microbiota (GM) seem to play a major role in the complex pathogenesis of irritable bowel syndrome (IBS). Specific microbial strains could improve the gut microenvironment, promoting anti-inflammatory pathways; similarly, vitamin D supplementation could play a role in enhancing the barrier integrity and modulating the immune response in the gut. This study aims to evaluate the efficacy of a new multistrain probiotic, combined with vitamin D, in improving gut barrier function in IBS without constipation. METHODS: In this phase IIb double-blind randomized placebo-controlled, parallel-group, multicenter, clinical trial, 35 patients were treated for 12 weeks with OttaBac®, a high concentration multistrain probiotic plus cholecalciferol, or placebo and were followed up until week 16. Symptoms, quality of life, intestinal permeability, fecal biomarkers, and microbiota composition were evaluated at 0, 12, and 16 weeks. RESULTS: Mean zonulin values showed a significant progressive reduction in the active group (-10.2 ng/mL at week 12, p = 0.0375; -19.5 ng/mL at week 16, p = 0.0002), with a significant difference between groups at week 16 in the per-protocol population (-19.01, p = 0.0053). The active group showed a more stable trend toward improvement in stool frequency and consistency at both week 12 and 16, with a significant improvement compared to the baseline and to the placebo group (-23.2, p = 0.0265, and 5.57 vs. -23.2, p = 0.0492, respectively). No differences were found in regards to the lactulose/mannitol ratio, Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) and Short Form Health Survey (SF-36) total scores, plasmalemmal vesicle associated protein-1 (PV-1), and citrulline levels. In the active group, Bifidobacterium animalis subsp. lactis and Streptococcus thermophilus levels were increased (p < 0.05), while those for Lachnospira were decreased (p < 0.05), and significant changes in Actinobacteria and Proteobacteria were observed (p < 0.05). Lactate (p < 0.01) and acetate (p < 0.05) levels increased post-treatment. Correlation analysis pointed out a significant associ

PURPOSE: Vitamin D supplementation during winter may protect children from acute respiratory tract infections (ARTI), especially at Northern latitudes where dermal vitamin D synthesis is negligible. This study aimed to investigate our hypothesis that vitamin D supplementation would have beneficial effects on ARTI in children during extended winter. METHODS: This study includes secondary analyses from a double-blinded, randomized, clinical 24-week trial, which investigated effects of vitamin D supplementation and normal vs. high dairy protein intake on children's growth and health. Baseline visits were conducted in Copenhagen, Denmark (55⁰N) from August-October 2019 and endpoint visits February-April 2020. Parents completed illness questionnaires at baseline and every 4 weeks during the intervention. In total, 200 healthy, white 6-8-y-old children were included and randomized to 20 µg/d vitamin D3 or placebo. RESULTS: Parents of 189 children (100 females (53%); mean (SD) age, 7.7(0.8) years) completed all ARTI questionnaires. Baseline serum 25-hydroxyvitamin D was 79.8(17.2) nmol/L, which increased by 9.4(17.0) nmol/L in the vitamin D group and decreased by 32.7(17.4) nmol/L in the placebo group. The vitamin D-supplemented children had 17% fewer sick days due to ARTI (risk ratio (RR), 0.83; 95% CI, 0.76-0.90; P < 0.001) compared with placebo. Children also had 43% fewer days with ARTI with fever (RR, 0.57; 95% CI, 0.48-0.67; P < 0.001), vitamin D group compared with placebo. No differences were found in any of the other outcomes. CONCLUSION: Vitamin D supplementation reduced the number of days with ARTI. This supports a recommendation of vitamin D supplementation during extended winter at northern latitudes. TRIAL REGISTRATION: Name: Effects of Milk Protein and Vitamin D on Children's Growth and Health (D-pro). Number: NCT03956732. Link: https://clinicaltrials.gov/study/NCT03956732 . © 2025. Springer-Verlag GmbH Germany, part of Springer Nature.

BACKGROUND/OBJECTIVE: Optimal vitamin D levels are required for bone health and proper functionality of the nervous, musculoskeletal and immune systems. The objective of this study was to assess the efficacy and safety profiles of new weekly calcifediol formulations with the potential to improve adherence and outcome. METHODS: A Phase II-III, double-blind, randomized, multicentre trial (EudraCT 2020-001099-14 and NCT04735926). Subjects were randomized 2:2:1 to calcifediol 75 µg, 100 µg and placebo. 25(OH)D levels were measured at 4, 16, 24, 32 and 52 weeks. The main outcome was the percentage of subjects who achieved a response defined as 25(OH)D levels ≥20 ng/mL and/or ≥30 ng/mL at week 16. RESULTS: 398 subjects (51.1 ± 15.96 years, 74.2% females, 98.7% Caucasian) with plasma 25(OH)D levels between 10 and 20 ng/mL were randomized. A total of 376 subjects completed 16 weeks of treatment, and 355 subjects completed the study. Six patients withdrew due to an adverse event, all unrelated to treatment. At week 16, 93.6% and 74.4% of subjects receiving calcifediol 75 µg achieved response levels of ≥20 ng/mL and ≥30 ng/mL, respectively. The calcifediol 100 µg group showed 98.7% and 89.9% of responders for ≥20 ng/mL and ≥30 ng/mL, respectively. Both calcifediol groups showed superiority over placebo at each response level at all time points analyzed (p < 0.0001). Calcifediol treatments increased 25(OH)D levels from baseline to week 24 and remained stable thereafter. The frequency of treatment-emergent adverse events was balanced between groups. CONCLUSIONS: New weekly calcifediol 75 and 100 µg formulations showed an effective and sustained response with a good long-term safety profile.

It was to investigate the clinical efficacy of the combination therapy of fluticasone propionate inhalation aerosol and vitamin D (VD) in pediatric bronchial asthma (BA) and analyze the correlation between serum 25-(OH)-D3 levels and immune function, as well as calcium-phosphorus metabolism. A total of 110 patients with BA were recruited. Regarding treatment plan, patients were randomly rolled into a single-drug treatment group (SDT, treated with fluticasone propionate inhalation aerosol alone) and a dual-drug treatment group (TDT, treated with the combination of fluticasone propionate inhalation aerosol and VD). The changes in serum 25-(OH)-D3 levels, immunoglobulins, T lymphocyte subsets, and inflammatory cytokine levels in children with BA under different treatment modalities were compared. Clinical symptom disappearance, asthma control, and quality of life (QoL) were assessed, and the total effective rate and adverse reactions (ARs) were compared. A control group consisting of 60 healthy children who underwent concurrent physical examinations was included. The differences in serum 25-(OH)-D3 levels, immunoglobulins, and T lymphocyte subset levels between children with BA and healthy controls were compared, and their correlations were analyzed. The TDT group showed a drastic reduction in the disappearance time of lung wheezing and dyspnea relative to the SDT group. Furthermore, the TDT group exhibited notable improvements in lung function parameters, including forced vital capacity (FVC), forced expiratory volume at one second (FEV1), FEV1/FVC, and peak expiratory flow (PEF). Blood gas analysis revealed a great decrease in PaCO2 and an increase in PaO2. The Childhood Asthma Control Test (C-ACT) scores for asthma control and Pediatric Asthma Quality of Life Questionnaire (PAQLQ) scores for QoL showed marked increases in the TDT group. Moreover, the TDT group demonstrated notable increases in serum 25-(OH)-D3 levels, immunoglobulins (IgA, IgG, and IgM), T lymphocyte subsets (CD4+ and CD8+), as well as blood calcium and phosphorus levels. Additionally, the TDT group exhibited a prominent increase in the anti-inflammatory cytokine interleukin (IL)-10 level and a

Background: Critically ill patients with sepsis have a high incidence of vitamin D deficiency. Vitamin D promotes the synthesis of human cathelicidin antimicrobial peptide, a precursor of LL-37, which is a part of the innate immune system. This study investigated the effectiveness and safety of the early administration of high-dose enteral vitamin D3 in comparison with low-dose vitamin D3 in patients with sepsis requiring mechanical ventilation (MV). Methods: Eighty adult patients with sepsis requiring MV with known vitamin D deficiency were randomly assigned to receive either an enteral 50 000 IU (Group I) or 5000 IU (Group II) vitamin D supplementation. Clinical and laboratory parameters were evaluated at baseline and on days 4 and 7 between the study groups. The change in serum procalcitonin (PCT) levels on day 7 was the primary outcome, while the change in serum LL-37 levels on day 7, changes in sequential organ failure assessment (SOFA) score, and clinical pulmonary infection score on day 7, MV duration, and hospital length of stay (LOS) were the secondary outcomes. Results: The (day 7-day 0) change in serum PCT and LL-37 levels and SOFA score were significantly different in Group I (P = .010, P < .001, and P < .001, respectively). The SOFA score was significantly different on days 4 and 7 in Group I (P < .001 and P < .001, respectively). The incidence of early ventilator-associated pneumonia was significantly different between both treatment groups (P = .025). The hospital LOS was shorter in Group I (P < .001). No 25-hydroxyvitamin-D toxicity was observed in either group. Conclusions: Early enteral administration of high-dose vitamin D3 in critically ill patients with sepsis requiring MV along with standard treatment for sepsis decreased serum procalcitonin levels, increased serum LL-37 levels, and ameliorated illness severity scores.

Biofilm formed by Pseudomonas aeruginosa is a three dimensional microbial matrix that confers multidrug resistance properties along with the proficiency to evade the host immune system. The present study aims to determine the combinatorial effects of vitamin D3 (cholecalciferol) with two already reported antibiofilm agents: streptomycin and thymoquinone separately against P. aeruginosa biofilms. The minimum inhibitory concentration of streptomycin, thymoquinone and D3 was found to be 20, 10 and 100 μg/mL respectively. The inhibition of biofilm formation and pre-formed biofilm disintegration properties of streptomycin and thymoquinone alone or in combination with D3 at their sub-MIC concentration was determined by crystal violet staining and confocal laser scanning microscopy. A significant inhibition of metabolic activities like oxygen consumption rate and reduction in quorum sensing related cellular activities like swarming motilities, pyocyanin production and extracellular protease secretion by P. aeruginosa were also observed as a result of this combinatorial effect. Both of these combinatorial applications were found to accumulate ROS in bacterial cells, which has been proved to be one of the main causes of their antibiofilm activity. Effect of these two drug combinations on bacterial lettuce leaf infection was also evaluated. Molecular docking analysis indicated that thymoquinone combined D3 can interact more efficiently with the quorum sensing proteins LasI and LasR. The host cell cytotoxicity of these two combinations was found to be negligible on the murine macrophage cell line. These findings suggest that D3 potentiates the antimicrobial and antibiofilm efficacy of both streptomycin and thymoquinone against P. aeruginosa. Although both combinations have shown significant antibiofilm and antimicrobial potential, combinatorial performances of D3 combined thymoquinone were found to be more promising. © 2025. The Author(s), under exclusive licence to Springer Nature B.V.

BACKGROUND: Aerobic vaginitis (AV) is a state of abnormal vaginal microbiota, which is associated with increased numbers of aerobic, enteric bacteria and inflammation of the vaginal epithelium. Anti-microbial treatment combined with anti-inflammatory therapy could be useful in the treatment of this condition. It is known that calcitriol, the active form of vitamin D, plays an important role in modulating the immune response in several inflammatory diseases. The aim of this preliminary study was to evaluate in vitro the influence of calcitriol on the immune response of human vaginal epithelial cells to bacterial infection. Moreover, we assessed the anti-bacterial properties of calcitriol, as well as its synergistic activity with antibiotics that are used for the treatment of AV. RESULTS: Human vaginal A431 epithelial cells were treated with calcitriol (100 nM) and then stimulated with thermally inactivated strains of AV-associated bacteria (Escherichia coli, Enterococcus faecalis, Streptococcus agalactiae), or first stimulated with heat-treated bacteria and then incubated with calcitriol (30 nM). After 24 h, 48 h, and 72 h post-infection, culture supernatants were collected, and levels of pro-inflammatory cytokines IL-6 and IL-1β were analyzed using enzyme-linked immunosorbent assays (ELISA). As it turned out, calcitriol treatment pre- or post-bacterial stimulation of vaginal epithelial cells significantly decreased the levels of IL-6 and IL-1β compared to cells stimulated only with bacteria. Downregulation of pro-inflammatory cytokines was more frequently significant when cells were pre-treated with calcitriol. Additionally, this study evaluated the anti-bacterial properties and synergistic activity of calcitriol with antibiotics by determining the Minimal Inhibitory Concentration (MIC) using colorimetric, Resazurin-based microdilution method detecting the active metabolism of bacteria. As a result, calcitriol by itself did not exhibit clinically relevant anti-bacterial activity; however, when combined with antibiotics, calcitriol significantly reduced the MIC values. CONCLUSIONS: The results of this preliminary study confirm that calcitriol treatment influences

Vitamin D and beta-glucans are both immunostimulants. Vitamin D exerts its beneficial effects on many components of the immune system. In macrophages, the hormone modulates both phagocytic activity and cytokine production; therefore, it plays an important role in mediating the innate immune response to infection. The immunomodulatory properties of beta-glucans are attributed to the ability of these fungal cell wall polysaccharides to bind to different receptors expressed on the cell surface of phagocytic and cytotoxic innate immune cells, including monocytes and macrophages. The intracellular signaling pathways activated by beta-glucans lead to enhanced phagocytosis and cytokine response. In this study we investigated the possible potentiation of immunomodulatory properties of the combined treatment with vitamin D and beta-glucans. The effects of 100 nM 1,25-dihydroxyvitamin D3 or 100 µg/mL beta-glucans were evaluated in human macrophages in terms of cytokine production, intracellular vesicle acidification and changes in energy metabolism, three hallmarks of macrophage antimicrobial activation. We found that all the analyzed parameters were enhanced by the co-treatment compared to the response to single molecules. The results of this study support the validity of a novel therapeutic approach that could boost the immune response, taking advantage of the synergy between two natural compounds.

The impact of androgens on the thyroid in women is poorly understood. The aim of the present study was to investigate whether vitamin D/dehydroepiandrosterone (DHEA) combination therapy is superior to vitamin D alone in affecting thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity in young women with autoimmune thyroid disease. The study included 35 euthyroid women with untreated Hashimoto's thyroiditis and reduced sexual drive, allocated to one of two treatment groups. The first group (n = 19) received both vitamin D and DHEA, while the second (n = 16) was treated with only vitamin D. Serum thyroid antibody titres and concentrations of thyrotropin, free thyroid hormones, dehydroepiandrosterone-sulphate (DHEA-S), 25-hydroxyvitamin D, testosterone and estradiol were measured at baseline and 6 months later. Vitamin D administered alone or in combination with DHEA decreased serum titres of thyroid peroxidase and thyroglobulin antibodies, which correlated with baseline antibody titres, baseline 25-hydroxyvitamin D levels and treatment-induced increase in 25-hydroxyvitamin D levels. Apart from a stronger effect on antibody titres, vitamin D/DHEA combination therapy slightly decreased thyrotropin levels, as well as increased DHEA-S and testosterone levels. In this group of women, treatment-induced changes in antibody titres and thyrotropin levels correlated with the impact on DHEA-S and testosterone. The obtained results suggest that vitamin D/DHEA combination therapy may be a better treatment option for euthyroid women with Hashimoto's thyroiditis than vitamin D alone. © 2020 John Wiley & Sons Australia, Ltd.

Infections caused by multidrug-resistant (MDR) Klebsiella pneumoniae are difficult to treat with conventional antibiotics. Thus, alternative strategies to control the growth of MDR Klebsiella are warranted. We hypothesized that activation of innate effector systems could sensitize MDR K. pneumoniae to conventional antibiotics. Thus, human primary macrophages were stimulated with compounds known to activate innate immunity (vitamin D3, phenylbutyrate [PBA], and the aroylated phenylenediamine HO53) and then infected with MDR Klebsiella in the presence or absence of antibiotics. Antibiotics alone were ineffective against MDR Klebsiella in the cellular model, whereas vitamin D3, PBA, and HO53 reduced intracellular growth by up to 70%. The effect was further improved when the innate activators were combined with antibiotics. Vitamin D3- and PBA-induced bacterial killing was dependent on CAMP gene expression, whereas HO53 needed the production of reactive oxygen species (ROS), as shown in cells where the CYBB gene was silenced and in cells from a patient with reduced ROS production due to a deletion in the CYBB gene and skewed lyonization. The combination of innate effector activation by vitamin D3, PBA, and HO53 was effective in sensitizing MDR Klebsiella to conventional antibiotics in a primary human macrophage model. This study provides new evidence for future treatment options for K. pneumoniae.

Psoriasis is a T-helper (Th)1/Th17-mediated, chronic inflammatory dermatitis that is commonly treated with topical corticosteroids and vitamin D3 analogs. The combination of a topical corticosteroid and vitamin D3 analog showed superior efficacy to each alone in clinical trials; however, the mechanisms by which the topical corticosteroid and vitamin D3 analog exert their effects on lesional skin in combination and each alone remain unknown. In this study, we examined the effects of combined calcipotriol (Cal)/betamethasone dipropionate (BD) ointment on psoriasis in vivo, utilizing imiquimod (IMQ)-induced murine psoriasiform skin inflammation, compared with each alone. Vehicle, Cal/BD, Cal or BD was applied on the shaved back skin for 3 consecutive days. Then, IMQ was applied for 6 consecutive days. Twenty-four hours after the last IMQ treatment, the murine skin was evaluated clinically and pathologically. mRNA expressions were examined by quantitative polymerase chain reaction. All ointments alleviated IMQ-induced psoriasiform skin inflammation clinically in comparison with vehicle application. Cal/BD suppressed mRNA expressions of cytokines involved in psoriasis pathogenesis such as interleukin (IL)-17A and IL-22 efficiently. Cal alone induced IL-10 expression, whereas BD alone reduced IL-6 mRNA expression and the number of phosphorylated signal transducer and activator of transcription 3-positive cells in lesional skin. Our study revealed that Cal and BD have different effects on IMQ-induced psoriasiform skin. Some of the immune effects of Cal and BD may be additive or synergistic, which may account for the superior clinical efficacy of their combination. © 2019 Japanese Dermatological Association.

Commonly known for its critical role in calcium homeostasis and bone mineralization, more recently vitamin D has been implicated in hematological cancer pathogenesis and shows promise as an anti-cancer therapy. Serum levels of 25(OH)D3 , the precursor to the active form of vitamin D, calcitriol, are frequently lower in patients with hematological disease compared to healthy individuals. This often correlates with worse disease outcome. Furthermore, diseased cells typically highly express the vitamin D receptor, which is required for many of the anti-cancer effects observed in multiple in vivo and in vitro cancer models. In abnormal hematological cells, vitamin D supplementation promotes apoptosis, induces differentiation, inhibits proliferation, sensitizes tumor cells to other anti-cancer therapies, and reduces the production of pro-inflammatory cytokines. Although the dosage of vitamin D required to achieve these effects may induce hypercalcemia in humans, analogs and combinatorial treatments have been developed to circumvent this side effect. Vitamin D and its analogs are well tolerated in clinical trials, and thus, further investigation into the use of these agents in the clinic is warranted. Here, we review the current literature in this field. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A sufficient but balanced vitamin supplementation is a prerequisite for a satisfactory growth pattern and an effective immune system in mink and all other species. The fat-soluble vitamins are very sensitive to over- or under-supply because they interact with each other with respect to dose-response and chemical form. The purpose of the present study was to investigate the effect of increasing the amount of retinol in combination with RRR-α-tocopherol or all-rac-α-tocopherol in the feed given to growing mink on their retinol, cholecalciferol and α-tocopherol concentrations in plasma and selected organs. The results showed that the mink met their retinol requirements from the basal diet, but there were no negative effects of supplying various amounts of retinol on their plasma α-tocopherol concentrations. On the other hand, the study showed that the cholecalciferol status in plasma, assessed as the 25-hydroxycholecalciferol concentration, was low when retinol was supplemented in the feed at high levels. In addition, supplementation with RRR-α-tocopherol in the feed negatively affected the plasma concentration of 25-hydroxycholecalciferol compared with supplementation with all-rac-α-tocopherol. In general, female mink had higher concentrations of fat-soluble vitamins in plasma than male mink.

Calcitriol (1,25-dihydroxyvitamin D3, 1,25D3) and vitamin D side-chain modified analogs (VDAs) have gained considerable attention as potential drugs in the treatment of acute myeloid leukemia (AML), yet studies of the impact of 1,25D3 and VDAs upon other haematological malignancies are more limited. To address this gap in knowledge, we have examined the action of 1,25D3 and VDAs on a human cell line (DOHH2, K422) typifying diffuse large B-cell lymphoma (DLBCL) and also peripheral blood B-cells isolated from healthy donors. 1,25D3 and certain VDAs displayed moderate cytotoxic and pro-apoptotic actions upon DLBCL cells. 1,25D3 and VDAs (100nM) caused the death of approximately 40% DOHH2 cells after 24h stimulation, similar to their impact on HL-60 cells (acute myeloid leukaemia cell line). In addition, 1,25D3 and VDAs displayed concentration and time-dependent anti-proliferative actions upon stimulated B-cells from healthy donors. The VDAs inhibited proliferation by approximately 30%. Hence VDAs may offer therapeutic potential for the treatment of DLBCL or conditions benefitted by B-cell depletion.

BACKGROUND: Retinoic acid (RA), the main biologically active metabolite of vitamin A, is known to promote gut homing of lymphocytes, as well as various regulatory and effector immune responses. In contrast, the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), is predominantly immunosuppressive. Little is known about the direct effects of these vitamins on the recently identified innate lymphoid cells (ILCs). OBJECTIVE: We sought to characterize the effects of RA and 1,25D3 on human ILCs. METHODS: Peripheral blood mononuclear cells were isolated from 27 non-selected blood donor buffy coats, and ILCs were sorted by FACS. ILC1, ILC2, and ILC3 cells were cultured for 5 days with RA, 1,25D3, and various cytokines known to activate ILCs (IL-2, IL-7, IL-12, thymic stromal lymphopoietin (TSLP), IL-25, and IL-33). Cytokines produced by ILCs were measured in culture supernatants, and surface receptor expression was analysed by flow cytometry. RESULTS: Retinoic acid acted synergistically with IL-2 and other activating cytokines to induce expression of the gut-homing integrin α4β7 in ILCs, as well as production of IL-5 and IL-13 in ILC2 cells, and IFN-γ in ILC1 and ILC3 cells. Expression of integrin α4β7 and cytokine production in ILCs stimulated with RA + IL-2 was increased at least fourfold as compared to ILCs cultured with RA or IL-2 alone. In contrast, RA completely inhibited the IL-2-induced expression of cutaneous lymphocyte antigen (CLA) in ILCs. Moreover, addition of 1,25D3 to ILCs cultured with RA + IL-2 inhibited cytokine production and expression of integrin α4β7 by at least 30%. CONCLUSIONS: Retinoic acid and 1,25D3 have antagonistic effects on the expression of effector cytokines and gut-homing integrin by human ILCs. The balance between these vitamins may be an important factor in the functioning of ILCs and the diseases in which ILCs are implicated, such as allergic inflammation. © 2015 John Wiley & Sons Ltd.