Dietary spermidine improves cognitive function.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.

Morphometric parameters of muscle and bone in critically ill patients : Post hoc analysis of the VITdAL-ICU trial.

BACKGROUND: Sarcopenia, defined as loss of muscle mass, quality and function, is a part of the frailty syndrome. In critical illness, sarcopenia has rarely been evaluated regarding clinical outcomes. Therefore, we evaluated the association of sarcopenia with both hospital length of stay (HLOS) and 6­month mortality in critically ill patients using abdominal computed tomography (CT) scans. METHODS: In a post hoc analysis from the high dose vitamin D3 vs. placebo in adult vitamin D deficient patients (VITdAL-ICU) trial, we retrospectively reviewed all available abdominal CT scans (18 women, 19 men). We measured and calculated total psoas area (TPA), psoas muscle density (PMD), skeletal muscle index (SMI) and bone mineral density (BMD) and analyzed the relation of these endpoints with HLOS and mortality. Defining sarcopenia we used cut-off values for TPA as 642.1 mm2/m2 in women and 784 mm2/m2 in men and PMD as 31.1 Hounsfield units (HU) in women and 33.3 HU in men, both measured at the level of L3, as well as for SMI (38.5 cm2/m2 in women and 52.4 cm2/m2 in men). Likely osteoporosis was defined by L1 trabecular attenuation of ≤110 HU. Values for TPA, PMD and SMI could not be obtained in 11 patients and BMD in 1 patient. RESULTS: Mean adjusted TPA was lower in women versus men (478 vs. 749 mm2/m2) as well as PMD (34.6 vs. 41.3 HU), SMI (62.36 vs. 76.81 cm2/m2) and BMD (141.1 vs. 157.2 HU). No significant influence on hospital length of stay and on 6­month mortality was found, irrespective of the morphometric parameter used (TPA, PMD, SMI, BMD; p > 0.05). Survivors showed statistically nonsignificantly better values than nonsurvivors: TPA: 652 vs. 530 mm2/m2 (p = 0.27); PMD: 38.4 vs. 37.4 HU (p = 0.85); SMI: 70.32 vs. 69.54 cm2/m2 (p = 0.91); BMD: 156 vs. 145.8 HU (p = 0.81). CONCLUSION: Although the study is limited by the small sample size, our data do not support a strong predictive value for TPA/PMD/SMI or BMD for HLOS or mortality in critically ill patients with vitamin D deficiency.

Stratifying nutritional restriction in cancer therapy: Next stop, personalized medicine.

Dietary interventions combined with cancer drugs represent a clinically valid polytherapy. In particular nutrient restriction (NR) in the form of varied fasting or caloric restriction regimens holds great clinical promise, conceptually due to the voracious anabolic appetite of cancer cells. This metabolic dependency is driven by a strong selective pressure to increasingly acquire biomass of a proliferating tumor and can be therapeutically exploited as vulnerability. A host of preclinical data suggest that NR can potentiate the efficacy of, or alleviate resistance to, cancer drugs. However, complicating clinical implementation are the many variables involved, such as host biology, cancer stage and type, oncogenic mutation landscape, tumor heterogeneity, variations in treatment modalities, and patient compliance to NR protocols. This calls for systematic preclinical screens and co-clinical studies to predict effective combinations of NR with cancer drugs and to allow for patient stratification regarding responsiveness to polytherapy. Such screen-and-stratify pipelines should consider tumor heterogeneity as well as the role of immune effectors in the tumor microenvironment and may lead to biomarker discovery advancing the oncology field toward personalized options with improved translatability to clinical settings. This opinion-based review provides a critical overview of recent literature investigating NR for cancer treatment, pinpoints limitations of current studies, and suggests standardizations and refinements for future studies and trials. The proposed measures aim to increase the translational value of preclinical data and effectively harness the vast potential of NR as adjuvant for cancer therapy.

The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron-Deficient Blood Donors: A Secondary Analysis of the IronWoMan RCT.

Background: Besides anemia, iron deficiency may cause more subtle symptoms, including the restless legs syndrome (RLS), the chronic fatigue syndrome (CFS) or sleeping disorders. Objective: The aim of this pre-planned secondary analysis of the IronWoMan randomized controlled trial (RCT) was to compare the frequency and severity of symptoms associated with iron deficiency before and after (intravenous or oral) iron supplementation in iron deficient blood donors. METHODS/DESIGN: Prospective, randomized, controlled, single-centre trial. (ClinicalTrials.gov: NCT01787526). SETTING: Tertiary care center in Graz, Austria. PARTICIPANTS: 176 (138 female and 38 male) whole-blood and platelet apheresis donors aged ≥ 18 and ≤ 65 years with iron deficiency (ferritin ≤ 30ng/mL at the time of blood donation). INTERVENTIONS: Intravenous iron (1 g ferric carboxymaltose, n = 86) or oral iron supplementation (10 g iron fumarate, 100 capsules, n = 90). MEASUREMENTS: Clinical symptoms were evaluated by a survey before iron therapy (visit 0, V0) and after 8-12 weeks (visit 1, V1), including questions about symptoms of restless legs syndrome (RLS), chronic fatigue syndrome (CFS), sleeping disorders, quality of life and symptoms like headaches, dyspnoea, dizziness, palpitations, pica and trophic changes in fingernails or hair. RESULTS: We found a significant improvement in the severity of symptoms for RLS, fatigue and sleep quality (p < 0.001). Furthermore, a significant decrease in headaches, dyspnoea, dizziness and palpitations was reported (p < 0.05). There was no difference between the type of iron supplementation (intravenous versus oral) and clinical outcome data. CONCLUSION: Iron supplementation in iron-deficient blood donors may be an effective strategy to improve symptoms related to iron deficiency and the wellbeing of blood donors.

Genetic Components of 25-Hydroxyvitamin D Increase in Three Randomized Controlled Trials.

The 25-Hydroxyvitamin D (25[OH)D) serum concentration depends on vitamin D intake, endogenous vitamin D production and genetic factors. The latter have been demonstrated in large genome-wide association studies indicating that single nucleotide polymorphisms (SNPs) in genes related to the vitamin D metabolism are as important for serum 25(OH)D levels as the influence of season. The mechanism on how these SNPs influence serum 25(OH)D levels are still unclear. The aim of the present study was to investigate the genetic effects of ten selected SNPs related to vitamin D metabolism on 25-hydroxyvitamin D increase (∆25(OH)D) after vitamin D supplementation in three randomized controlled trials. Genotypes of SNPs related to vitamin D metabolism were determined in 411 participants with 25(OH)D concentrations < 75 nmol/l receiving 20,000 IU cholecalciferol per week for 8 or 12 weeks after study inclusion. For the vitamin D receptor (VDR) rs10783219 polymorphism, the minor A-allele was associated with lower ∆25(OH)D values in the entire study population (p = 0.022), which was not consistent in all three cohorts when analysed separately. VDR rs10783219 might therefore be a genetic modulator of increasing 25-hydroxyvitamin D concentrations. Considering the wide-spread use of vitamin D supplementation, future large and well-designed randomized controlled trials (RCTs) should investigate the clinical impact of this polymorphism.

High-dose intravenous versus oral iron in blood donors with iron deficiency: The IronWoMan randomized, controlled clinical trial.

INTRODUCTION: Frequent blood donation often leads to iron deficiency and even anemia but appropriate strategies for detection and prevention are currently not mandatory. At the Medical University of Graz, we conducted a single-center prospective clinical trial to compare oral and IV iron supplementation in iron deficient blood donors including Austrian regular whole blood and platelet apheresis donors. We aimed to determine the difference of transferrin saturation between the treatment groups 8-12 weeks iron administration besides other parameters of iron status and blood count. METHODS: 176 healthy male and female blood donors with iron deficiency (ferritin ≤30 ng/mL) were randomized to either a single dose of IV ferric carboxymaltose (1000 mg, n = 86) or oral iron (II)fumarate (100 tablets of 100 mg [10 per week], n = 90). RESULTS: Between 2014 and 2016, 172 donors (137 women) completed the study; 4 in the oral group were lost to follow-up. At follow-up, median (IQR) transferrin saturation and ferritin were significantly higher in the intravenous group (27 [23-35]%, vs 21.0 [16-32]%; p < 0.001 and 105 [75-145] ng/mL vs 25 [17-34] ng/mL; p < 0.001, respectively) while median (IQR) hemoglobin levels were comparable (IV, 13.6 [13.0-14.4] g/dL vs oral, 13.6 [13.0-14.2] g/dL). The frequency of adverse effects was comparable (38% in both groups) and no serious adverse events occurred. CONCLUSIONS: A single dose of 1000 mg of intravenous iron is highly effective to counteract iatrogenic iron deficiency in blood donors. Oral iron appears to be an acceptable alternative. The assessment of body iron stores should play a key role in maintaining blood donors' health. This trial was registered at www.clinicaltrials.gov as NCT01787526 on February 8, 2013 and at www.clinicaltrialsregister.eu (EudraCT identifier: 2013-000327-14) on September 24, 2013.

Effects of vitamin D supplementation on metabolic and endocrine parameters in healthy premenopausal women: A randomized controlled trial.

BACKGROUND & AIMS: Vitamin D supplementation may affect glycemic as well as hormonal regulation. Thus, the aim of the current study was to investigate whether vitamin D supplementation has any significant effects on metabolic and endocrine parameters in healthy premenopausal women. Primary outcome measure was the plasma glucose area under the curve (AUCgluc). METHODS: The current study was a single-center, double-blind, randomized placebo-controlled trial that was conducted at the Medical University of Graz, Austria, between March 2013 and October 2017. One-hundred and fifty healthy premenopausal women with 25-hydroxyvitamin D [25(OH)D] concentrations <75 nmol/L once weekly received either 20,000 IU of cholecalciferol or placebo (2:1 ratio) over a total of 24 weeks. RESULTS: In total, 127 women [age 36.2 ± 8.7 years; BMI 25.3 ± 5.6 kg/m2; baseline 25(OH)D 55.8 ± 19.7 nmol/L] completed the study. Vitamin D supplementation had no significant effect on AUCgluc (mean treatment effect 11.70; p = 0.069), while it had a significant treatment effect on homeostatic model assessment-insulin resistance (HOMA-IR; mean treatment effect 0.31; p = 0.019) and quantitative insulin-sensitivity check index (QUICKI; mean treatment effect -0.019; p = 0.013). There was no significant effect on the remaining secondary outcome parameters. CONCLUSIONS: In this randomized-controlled trial in healthy premenopausal women, there was a significant treatment effect of vitamin D supplementation on HOMA-IR and QUICKI, while there was no significant treatment effect on AUCgluc.

The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species.

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.

Effects of vitamin D supplementation on metabolic and endocrine parameters in PCOS: a randomized-controlled trial.

PURPOSE: Vitamin D status may be associated with insulin resistance and other key features of polycystic ovary syndrome (PCOS), but data from preliminary randomized controlled trials (RCTs) are conflicting. Therefore, we aimed to investigate the effects of vitamin D supplementation on plasma glucose area under the curve (AUCgluc, primary outcome measure) and on other metabolic and endocrine parameters (secondary outcome measures). METHODS: This study was a single-center, double-blind, randomized placebo-controlled trial conducted between December 2011 and July 2017 at the Medical University of Graz, Austria. One-hundred and eighty women with PCOS and 25-hydroxyvitamin D [25(OH)D] concentrations < 75 nmol/L were randomized in a 2:1 ratio to either receive 20,000 IU of cholecalciferol weekly or placebo over 24 weeks. Primary outcome was the between-group difference in AUCgluc at study end while adjusting for baseline values. RESULTS: In total, 123 participants completed the study [age 25.9 ± 4.7 years; BMI 27.5 ± 7.3 kg/m2; baseline 25(OH)D 48.8 ± 16.9 nmol/L, baseline fasting glucose 84 ± 8 mg/dL]. Vitamin D supplementation lead to a significant increase in 25(OH)D [mean treatment effect 33.4 nmol/L; 95% confidence interval (CI) 24.5 to 42.2; p < 0.001] but had no significant effect on AUCgluc (mean treatment effect - 9.19; 95% CI - 21.40 to 3.02; p = 0.139). Regarding secondary outcome measures, we observed a significant decrease in plasma glucose at 60 min during oral glucose tolerance test (mean treatment effect - 10.2 mg/dL; 95% CI - 20.2 to - 0.3; p = 0.045). CONCLUSIONS: Vitamin D supplementation had no significant effect on metabolic and endocrine parameters in PCOS with the exception of a reduced plasma glucose during OGTT.

Effects of vitamin D supplementation on FGF23: a randomized-controlled trial.

PURPOSE: Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations. METHODS: This is a post-hoc analysis of the Styrian Vitamin D Hypertension trial, a single-center, double-blind, randomized, placebo-controlled trial, conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two hundred subjects with 25(OH)D concentrations < 30 ng/mL and arterial hypertension were randomized to receive either 2800 IU of vitamin D3 daily or placebo over 8 weeks. Primary outcome was the between-group difference in FGF23 levels at study end while adjusting for baseline values. RESULTS: Overall, 181 participants (mean ± standard deviation age, 60.1 ± 11.3; 48% women) with available c-term FGF23 concentrations were considered for the present analysis. Mean treatment duration was 54 ± 10 days in the vitamin D3 group and 54 ± 9 days in the placebo group. At baseline, FGF23 was significantly correlated with serum phosphate (r = 0.135; p = 0.002). Vitamin D3 supplementation had no significant effect on FGF23 in the entire cohort (mean treatment effect 0.374 pmol/L; 95% confidence interval - 0.024 to 0.772 pmol/L; p = 0.065), but increased FGF23 concentrations in subgroups with baseline 25(OH)D concentrations below 20 ng/mL (n = 70; mean treatment effect 0.973 pmol/L; 95% confidence interval - 0.032 to 1.979 pmol/L; p = 0.019) and 16 ng/mL (n = 40; mean treatment effect 0.593 pmol/L; 95% confidence interval 0.076 to 1.109; p = 0.022). CONCLUSIONS: Vitamin D3 supplementation had no significant effect on FGF23 in the entire study cohort. We did, however, observe an increase of FGF23 concentrations in subgroups with low baseline 25(OH)D.

Hormonal Contraceptive Use Is Associated With Higher Total but Unaltered Free 25-Hydroxyvitamin D Serum Concentrations.

Context: Intake of hormonal contraceptives (HC) is associated with higher total 25-hydroxyvitamin D [25(OH)D] concentrations, but the effect of HC on free 25(OH)D is unclear. Objective: We investigated whether free 25(OH)D concentrations differ according to use of HC. Design: This is a post hoc analysis of a randomized open trial. Setting: This study was conducted from 13 January to 9 May, 2016, at a clinical research organization in Esslingen, Germany. Participants: We included 201 apparently healthy women of childbearing age. Intervention: Participants were randomly assigned to receive a daily multimicronutrient supplement for 8 weeks; the supplement contained 200 IU (n =100) or 800 IU (n = 101) of vitamin D3. Main Outcome Measures: Primary outcome was the difference in free 25(OH)D between users and nonusers of HC. Results: Overall, 176 participants [median (25th to 75th percentiles) age: 25 (22 to 29) years] with available free 25(OH)D were included in the present analysis. At baseline, total 25(OH)D was significantly higher in users (n = 110) than in nonusers (n = 66) of HC [49.2 (33.4 to 63.4) vs 39.1 (23.8 to 52.5) nmol/L; P < 0.001], whereas there was no difference in free 25(OH)D [7.87 (6.50 to 10.11) vs 7.88 (6.35 to 10.12) pmol/L; P = 0.923]. These results were confirmed after multimicronutrient supplementation and in subgroups according to treatment allocation. Conclusions: Use of HC was associated with, on average, 26% higher total 25(OH)D, whereas free 25(OH)D values did not differ according to use of HC. These findings are relevant for epidemiological studies, but the physiological implications remain to be clarified.

Vitamin D supplementation and lipoprotein metabolism: A randomized controlled trial.

BACKGROUND: Vitamin D deficiency is associated with an unfavorable lipid profile, but whether and how vitamin D supplementation affects lipid metabolism is unclear. OBJECTIVE: To examine the effects of vitamin D supplementation on lipid and lipoprotein parameters. METHODS: This is a post hoc analysis of the single-center, double-blind, randomized, placebo-controlled Styrian Vitamin D Hypertension Trial (2011-2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D concentrations of <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for 8 weeks. RESULTS: One hundred sixty-three participants (62.2 [53.1-68.4] years of age; 46% women) had available lipid data and were included in this analysis. Vitamin D supplementation significantly increased total cholesterol, triglycerides, very-low-density lipoprotein (VLDL) triglycerides, low-density lipoprotein (LDL) triglycerides, high-density lipoprotein (HDL) triglycerides, apolipoprotein B (ApoB), LDL-ApoB, ApoCII, ApoCIII, phospholipids, and ApoE (P < .05 for all). Except for ApoCII and ApoCIII and HDL-triglycerides, all other treatment effects remained statistically significant after adjustment for multiple testing with the Benjamini and Hochberg false discovery rate method. There was a nonsignificant increase in LDL cholesterol. Furthermore, no significant effects were seen on free fatty acids, lipoprotein (a), ApoAI, ApoAII, VLDL cholesterol, VLDL-ApoB, HDL cholesterol, LDL diameter, and VLDL diameter. CONCLUSIONS: The effects of vitamin D on lipid metabolism are potentially unfavorable. They require further investigation in view of the wide use of vitamin D testing and treatment.

Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings allow for longer-term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.

Effects of Vitamin D Supplementation on IGF-1 and Calcitriol: A Randomized-Controlled Trial.

Increasing evidence suggests a possible interaction between vitamin D and insulin-like growth factor-1 (IGF-1). We aimed to investigate effects of vitamin D supplementation on IGF-1 (primary outcome) and calcitriol (1,25(OH)2D) concentrations (secondary outcome). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial-a single-center, double-blind, randomized, placebo-controlled trial (RCT) conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two-hundred subjects with arterial hypertension and 25(OH)D concentrations <30 ng/mL were randomized to either receive 2800 IU of vitamin D daily or placebo for eight weeks. A total of 175 participants (mean ± standard deviation age, 60 ± 11 years; 49% women) with available IGF-1 concentrations were included in the present analysis. At baseline, IGF-1 concentrations were significantly correlated with 1,25(OH)2D (r = 0.21; p = 0.005) but not with 25(OH)D (r = -0.008; p = 0.91). In the RCT, vitamin D had no significant effect on IGF-1 (mean treatment effect 3.1; 95% confidence interval -5.6 to 11.9 ng/mL; p = 0.48), but it increased 1,25(OH)2D concentrations (mean treatment effect 9.2; 95% confidence interval 4.4 to 13.9 pg/mL; p ≤ 0.001). In this RCT, in hypertensive patients with low 25(OH)D concentrations, there was no significant effect of vitamin D supplementation on IGF-1 concentrations. However, we observed a cross-sectional correlation between 1,25(OH)2D and IGF-1 and an increase of 1,25(OH)2D after vitamin D supplementation.

Effects of Vitamin D Supplementation on Bone Turnover Markers: A Randomized Controlled Trial.

Bone turnover markers (BTMs) are used to evaluate bone health together with bone mineral density and fracture assessment. Vitamin D supplementation is widely used to prevent and treat musculoskeletal diseases but existing data on vitamin D effects on markers of bone resorption and formation are inconsistent. We therefore examined the effects of vitamin D supplementation on bone-specific alkaline phosphatase (bALP), osteocalcin (OC), C-terminal telopeptide (CTX), and procollagen type 1 N-terminal propeptide (P1NP). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial, a single-center, double-blind, randomized, placebo-controlled trial (RCT) performed at the Medical University of Graz, Austria (2011-2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D (25[OH]D) levels <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for eight weeks. One hundred ninety-seven participants (60.2 ± 11.1 years; 47% women) were included in this analysis. Vitamin D had no significant effect on bALP (mean treatment effect (MTE) 0.013, 95% CI -0.029 to 0.056 µg/L; p = 0.533), CTX (MTE 0.024, 95% CI -0.163 to 0.210 ng/mL, p = 0.802), OC (MTE 0.020, 95% CI -0.062 to 0.103 ng/mL, p = 0.626), or P1NP (MTE -0.021, 95% CI -0.099 to 0.057 ng/mL, p = 0.597). Analyzing patients with 25(OH)D levels <50 nmol/L separately (n = 74) left results largely unchanged. In hypertensive patients with low 25(OH)D levels, we observed no significant effect of vitamin D supplementation for eight weeks on BTMs.

Beneficial Effects of UV-Radiation: Vitamin D and beyond.

Aside from its well-known effects on bone and mineral metabolism, vitamin D may also play an important role in extra-skeletal processes like immunologic diseases, cancer, or cardiovascular diseases. Even though meta-analyses showed that vitamin D supplementation reduces fractures, falls, and overall mortality, its potential benefits did not find universal acclaim. Several health care authorities published Recommended Dietary Allowances (RDAs) for vitamin D, most of them ranging from 600 to 800 international units (IU) per day, corresponding to a serum level of 25-hydroxyvitamin D of at least 20 ng/mL (50 nmol/L). However, studies conducted in the general population revealed a much lower overall intake of vitamin D than the proposed RDAs. Thus, strategies to increase the vitamin D intake in the general population, e.g., food fortification or vitamin D supplementation, are needed to match the existing evidence and recommendations. Therefore, several currently ongoing projects aim to investigate the effect of vitamin D supplementation in the general population and try to establish food-based solutions to improve vitamin D status.

Effects of high doses of vitamin D3 on mucosa-associated gut microbiome vary between regions of the human gastrointestinal tract.

PURPOSE: Vitamin D is well known for its effects on bone mineralisation but has also been attributed immunomodulatory properties. It positively influences human health, but in vivo data describing vitamin D effects on the human gut microbiome are missing. We aimed to investigate the effects of oral vitamin D3 supplementation on the human mucosa-associated and stool microbiome as well as CD8(+) T cells in healthy volunteers. METHODS: This was an interventional, open-label, pilot study. Sixteen healthy volunteers (7 females, 9 males) were endoscopically examined to access a total of 7 sites. We sampled stomach, small bowel, colon, and stools before and after 8 weeks of vitamin D3 supplementation. Bacterial composition was assessed by pyrosequencing the 16S rRNA gene (V1-2), and CD8(+) T cell counts were determined by flow cytometry. RESULTS: Vitamin D3 supplementation changed the gut microbiome in the upper GI tract (gastric corpus, antrum, and duodenum). We found a decreased relative abundance of Gammaproteobacteria including Pseudomonas spp. and Escherichia/Shigella spp. and increased bacterial richness. No major changes occurred in the terminal ileum, appendiceal orifice, ascending colon, and sigmoid colon or in stools, but the CD8(+) T cell fraction was significantly increased in the terminal ileum. CONCLUSION: Vitamin D3 modulates the gut microbiome of the upper GI tract which might explain its positive influence on gastrointestinal diseases, such as inflammatory bowel disease or bacterial infections. The local effects of vitamin D demonstrate pronounced regional differences in the response of the GI microbiome to external factors, which should be considered in future studies investigating the human microbiome.

Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus - A randomized clinical trial.

It is unknown if cholecalciferol is able to modify defects in regulatory T cells (Tregs) in type 1 diabetes (T1D). In this randomized, double-blind, placebo controlled trial 30 young patients with new-onset T1D were assigned to cholecalciferol (70IU/kgbodyweight/day) or placebo for 12months. Tregs were determined by FACS-analysis and functional tests were assessed with ex vivo suppression co-cultures at months 0, 3, 6 and 12. Suppressive capacity of Tregs increased (p<0.001) with cholecalciferol from baseline (-1.59±25.6%) to 3 (30.5±39.4%), 6 (44.6±23.8%) and 12months (37.2±25.0%) and change of suppression capacity from baseline to 12months was significantly higher (p<0.05) with cholecalciferol (22.2±47.2%) than placebo (-16.6±21.1%). Serum calcium and parathormone stayed within normal range. This is the first study, which showed that cholecalciferol improved suppressor function of Tregs in patients with T1D and vitamin D could serve as one possible agent in the development of immunomodulatory combination therapies for T1D.