Sex-Specific Catabolic Metabolism Alterations in the Critically Ill following High Dose Vitamin D.

Pharmacological interventions are essential for the treatment and management of critical illness. Although women comprise a large proportion of the critically ill, sex-specific pharmacological properties are poorly described in critical care. The sex-specific effects of vitamin D3 treatment in the critically ill are not known. Therefore, we performed a metabolomics cohort study with 1215 plasma samples from 428 patients from the VITdAL-ICU trial to study sex-specific differences in the metabolic response to critical illness following high-dose oral vitamin D3 intervention. In women, despite the dose of vitamin D3 being higher, pharmacokinetics demonstrated a lower extent of vitamin D3 absorption compared to men. Metabolic response to high-dose oral vitamin D3 is sex-specific. Sex-stratified individual metabolite associations with elevations in 25(OH)D following intervention showed female-specific positive associations in long-chain acylcarnitines and male-specific positive associations in free fatty acids. In subjects who responded to vitamin D3 intervention, significant negative associations were observed in short-chain acylcarnitines and branched chain amino acid metabolites in women as compared to men. Acylcarnitines and branched chain amino acids are reflective of fatty acid B oxidation, and bioenergesis may represent notable metabolic signatures of the sex-specific response to vitamin D. Demonstrating sex-specific pharmacometabolomics differences following intervention is an important movement towards the understanding of personalized medicine.

Procalcitonin metabolomics in the critically ill reveal relationships between inflammation intensity and energy utilization pathways.

Procalcitonin is a biomarker of systemic inflammation and may have importance in the immune response. The metabolic response to elevated procalcitonin in critical illness is not known. The response to inflammation is vitally important to understanding metabolism alterations during extreme stress. Our aim was to determine if patients with elevated procalcitonin have differences in the metabolomic response to early critical illness. We performed a metabolomics study of the VITdAL-ICU trial where subjects received high dose vitamin D3 or placebo. Mixed-effects modeling was used to study changes in metabolites over time relative to procalcitonin levels adjusted for age, Simplified Acute Physiology Score II, admission diagnosis, day 0 25-hydroxyvitamin D level, and the 25-hydroxyvitamin D response to intervention. With elevated procalcitonin, multiple members of the short and medium chain acylcarnitine, dicarboxylate fatty acid, branched-chain amino acid, and pentose phosphate pathway metabolite classes had significantly positive false discovery rate corrected associations. Further, multiple long chain acylcarnitines and lysophosphatidylcholines had significantly negative false discovery rate corrected associations with elevated procalcitonin. Gaussian graphical model analysis revealed functional modules specific to elevated procalcitonin. Our findings show that metabolite differences exist with increased procalcitonin indicating activation of branched chain amino acid dehydrogenase and a metabolic shift.

Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze.

BACKGROUND: Prenatal vitamin D3 supplementation has been linked to reduced risk of early-life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional single nucleotide polymorphism rs12936231 of the child, which regulates the expression of ORMDL3 (ORM1-like 3) and for which the high-risk CC genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze. METHODS: We determined the rs12936231 genotype of mother-child pairs from two randomised controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010, n=563), to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D3 supplementation versus placebo. RESULTS: Offspring of mothers with the low-risk GG or GC genotype who received high-dose vitamin D3 supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared with the placebo group (hazard ratio (HR) 0.54, 95% CI 0.37-0.77; p<0.001 for VDAART and HR 0.56, 95% CI 0.35-0.92; p=0.021 for COPSAC2010), whereas no difference was observed among the offspring of mothers with the high-risk CC genotype (HR 1.05, 95% CI 0.61-1.84; p=0.853 for VDAART and HR 1.11, 95% CI 0.54-2.28; p=0.785 for COPSAC2010). CONCLUSION: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

Metabolomic differences between critically Ill women and men.

Metabolism differs in women and men at homeostasis. Critically ill patients have profound dysregulation of homeostasis and metabolism. It is not clear if the metabolic response to critical illness differs in women compared to men. Such sex-specific differences in illness response would have consequences for personalized medicine. Our aim was to determine the sex-specific metabolomic response to early critical illness. We performed a post-hoc metabolomics study of the VITdAL-ICU trial where subjects received high dose vitamin D3 or placebo. Using mixed-effects modeling, we studied sex-specific changes in metabolites over time adjusted for age, Simplified Acute Physiology Score II, admission diagnosis, day 0 25-hydroxyvitamin D level, and 25-hydroxyvitamin D response to intervention. In women, multiple members of the sphingomyelin and lysophospholipid metabolite classes had significantly positive Bonferroni corrected associations over time compared to men. Further, multiple representatives of the acylcarnitine, androgenic steroid, bile acid, nucleotide and amino acid metabolite classes had significantly negative Bonferroni corrected associations over time compared to men. Gaussian graphical model analyses revealed sex-specific functional modules. Our findings show that robust and coordinated sex-specific metabolite differences exist early in critical illness.

Metabolomic basis for response to high dose vitamin D in critical illness.

BACKGROUND & AIMS: It is unclear if intervention can mitigate the dramatic alterations of metabolic homeostasis present in critical illness. Our objective was to determine the associations between increased 25-hydroxyvitamin D levels following high dose vitamin D3 and more favorable metabolomic profiles in critical illness. METHODS: We performed a post-hoc metabolomics study of the VITdAL-ICU randomized double-blind, placebo-controlled trial. Trial patients from Medical and Surgical Intensive Care Units at a tertiary university hospital with 25-hydroxyvitamin D level ≤20 ng/mL received either high dose oral vitamin D3 (540,000 IU) or placebo. We performed an analysis of 578 metabolites from 1215 plasma samples from 428 subjects at randomization (day 0), day 3 and 7. Using mixed-effects modeling, we studied changes in metabolite profiles in subjects receiving intervention or placebo relative to absolute increases in 25-hydroxyvitamin D levels from day 0 to day 3. RESULTS: 55.2% of subjects randomized to high dose vitamin D3 demonstrated an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml from day 0 to day 3. With an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml, multiple members of the sphingomyelin, plasmalogen, lysoplasmalogen and lysophospholipid metabolite classes had significantly positive Bonferroni corrected associations over time. Further, multiple representatives of the acylcarnitine and phosphatidylethanolamine metabolite classes had significantly negative Bonferroni corrected associations over time with an absolute increase in 25-hydroxyvitamin D ≥ 15 ng/ml. Changes in these highlighted metabolite classes were associated with decreased 28-day mortality. CONCLUSIONS: Increases in 25-hydroxyvitamin D following vitamin D3 intervention are associated with favorable changes in metabolites involved in endothelial protection, enhanced innate immunity and improved mitochondrial function.

The role of the 17q21 genotype in the prevention of early childhood asthma and recurrent wheeze by vitamin D.

Evidence suggests vitamin D has preventive potential in asthma; however, not all children benefit from this intervention. This study aimed to investigate whether variation in the functional 17q21 single nucleotide polymorphism rs12936231 affects the preventive potential of vitamin D against asthma.A combined secondary analysis of two randomised controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed, stratifying by genotype and integrating metabolite data to explore underlying mechanisms.The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG genotype (hazard ratio (HR) 0.49, 95% CI 0.26-0.94, p=0.032) but not the high-risk CC genotype (HR 1.08, 95% CI 0.69-1.69, p=0.751). In VDAART, in the GG genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate (ß 0.022, 95% CI 0.001-0.044, p=0.038), but this was not evident with the CC genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control human bronchial epithelial cell line and a cell line overexpressing ORMDL3 (p=0.002).Results suggest prenatal vitamin D supplementation may reduce the risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on the 17q21 genotype.

Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y.

Background: Vitamin D deficiency is implicated in a range of common complex diseases that may be prevented by gestational vitamin D repletion. Understanding the metabolic mechanisms related to in utero vitamin D exposure may therefore shed light on complex disease susceptibility.Objective: The goal was to analyze the programming role of in utero vitamin D exposure on children's metabolomics profiles.Design: First, unsupervised clustering was done with plasma metabolomics profiles from a case-control subset of 245 children aged 3 y with and without asthma from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), in which pregnant women were randomly assigned to vitamin D supplementation or placebo. Thereafter, we analyzed the influence of maternal pre- and postsupplement vitamin D concentrations on cluster membership. Finally, we used the metabolites driving the clustering of children to identify the dominant metabolic pathways that were influential in each cluster.Results: We identified 3 clusters of children characterized by 1) high concentrations of fatty acids and amines and low maternal postsupplement vitamin D (mean ± SD; 27.5 ± 11.0 ng/mL), 2) high concentrations of amines, moderate concentrations of fatty acids, and normal maternal postsupplement vitamin D (34.0 ± 14.1 ng/mL), and 3) low concentrations of fatty acids, amines, and normal maternal postsupplement vitamin D (35.2 ± 15.9 ng/mL). Adjusting for sample storage time, maternal age and education, and both child asthma and vitamin D concentration at age 3 y did not modify the association between maternal postsupplement vitamin D and cluster membership (P = 0.0014). Maternal presupplement vitamin D did not influence cluster membership, whereas the combination of pre- and postsupplement concentrations did (P = 0.03).Conclusions: Young children can be clustered into distinct biologically meaningful groups by their metabolomics profiles. The clusters differed in concentrations of inflammatory mediators, and cluster membership was influenced by in utero vitamin D exposure, suggesting a prenatal programming role of vitamin D on the child's metabolome. This trial was registered at clinicaltrials.gov as NCT00920621.