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

Abstract

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 D 3 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 D 3 (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 25hydroxyvitamin D levels from day 0 to day 3. Results: 55.2% of subjects randomized to high dose vitamin D 3 demonstrated an absolute increase in 25hydroxyvitamin 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 25hydroxyvitamin 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 D 3 intervention are associated with favorable changes in metabolites involved in endothelial protection, enhanced innate immunity and improved mitochondrial function.

Vitamin D and SARS-CoV-2 infection—evolution of evidence supporting clinical practice and policy development

“…Finally, there is evidence that apart from these immunological effects, high-dose vitamin D supplementation in critical illness can elicit improvements in metabolomic profile. These favourable changes include increases in sphingomyelins, plasmalogens, lysoplasmalogens, and lysophospholipids, and decreases in acylcarnitine, phosphatidylethanolamine, and amino acid class metabolites; alterations which have collectively been associated with reduced 28-day mortality amongst ICU patients [53].…”

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

“…Metabolomics data was produced from 1215 plasma samples obtained from 428 patients: 428 samples were analyzed from day 0, 413 at day 3 and 374 at day 7. Four ultra-high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) methods were utilized by Metabolon, Inc. (Morrisville, NC, USA) to identify 983 metabolites [ 18 , 29 ]. We cube root-transformed and Pareto-scaled the metabolomics data to generate an approximate normal distribution.…”

“…Based on our previous metabolomics analysis of the VITdAL-ICU trial [ 18 ], we considered a response to high-dose oral vitamin D 3 as an absolute increase in 25(OH)D ≥ 7.5 ng/mL from day 0 to day 3. For a sex-stratified analysis of day 0 data, we utilized the Student’s t -test to determine the significance of individual metabolites between vitamin D 3 response groups (25(OH)D< or ≥7.5 ng/mL from day 0 to day 3) using MetaboAnalyst in women and in men [ 70 ].…”

“…Metabolomics before and after intervention can furnish mechanistic insight into drug response and severity of critical illness [ 17 , 18 ]. Sex-specific pharmacokinetics is likely present with oral medication use [ 19 ].…”

Metabolomic differences between critically Ill women and men

“…To generate metabolomic data, a total of 1215 plasma samples from 428 VITdAL-ICU trial subjects at day 0, 413 subjects at day 3 and 374 subjects at day 7 were analyzed using four ultra high-performance liquid chromatography/tandem accurate mass spectrometry methods by Metabolon, Inc 65 . Metabolomic profiling identified 769 metabolites (Supplementary Data 2 ).…”