Impact of Vitamin D Status and High‐dose Vitamin D3 Administration on the Plasma Metabolome in Critically Ill Adults
Authors: Perry‐Walker Kayla , Walker Douglas I. , Alvarez Jessica A. , Han Jenny E. , Jones Jennifer L. , Hao Li , Li Shuzhao , Uppal Karan , Tran ViLinh T. , Brown LouAnn , Tangpricha Vin , Martin Gregory S. , Jones Dean P. , Ziegler Thomas R. 
Published: November 2023

Objective

Vitamin D deficiency is common in critical illness but the metabolic effects of vitamin D deficiency or supplementation in critical illness are little understood. Our objective was to use high‐resolution metabolomics of plasma to explore the impact on metabolism of vitamin D status and after high‐dose vitamin D3 treatment in critically ill adults.

Methods

Adults requiring mechanical ventilation in the intensive care unit were randomized to enterally receive vitamin D3 250,000 IU (n=9), vitamin D3 500,000 IU (n=11), or placebo (n=10) in divided doses for 5 days. Non‐targeted metabolite profiling of plasma obtained at baseline and weekly for up to 28 days was performed. Time series metabolome‐wide association studies (MWAS) were conducted using total 25‐hydroxyvitamin D (25(OH)D) concentrations and concomitant plasma metabolomic profiling determined serially. Metabolites were detected as mass‐to‐charge (m/z) features after C18 chromatography using a high‐resolution mass spectrometer (positive and negative ionization mode). Tentative metabolite matches were completed using METLIN. False discovery rate (FDR) and hierarchical cluster analysis (HCA) was used and pathway enrichment analysis was performed using the Mummichog program (Li S, et al. 2013). MWAS were performed in: 1) using all available plasma in which concomitant plasma 25(OH)D and metabolomics was measured; 2) as a function of baseline vitamin D deficiency (plasma 25(OH)D levels < 20 vs ≥ 20 ng/mL); and 3) in control (placebo) subjects vs those receiving either of the high‐dose vitamin D3 regimens at 7 days after entry. Data were analyzed using a mixed effects model, corrected for sex, BMI, race, age, and APACHE II score at baseline.

Results

The time‐series study identified 336 metabolites significant at P< 0.05 (FDR=0.2), suggesting a vitamin D dose‐dependent effect on the metabolome. Identification of altered metabolic pathways using Mummichog pathway and KEGG metabolic modeling programs indicated a significant impact of plasma 25(OH)D levels on metabolic pathways involving energy metabolism, including constituents of the TCA cycle, biosynthesis and/or degradation of conditionally essential amino acids (arginine, glutamine, and tyrosine) and pathways associated with inflammation (e.g. leukotriene and vitamin B6 metabolism). A total of 14 metabolites at baseline were differentially expressed in subjects with compared to without vitamin D deficiency, including gamma‐glutamyl‐cysteine, a precursor to glutathione, which was upregulated in vitamin D‐deficient subjects. At day 7 after high‐dose vitamin D3, 22 metabolites were differentially expressed compared to controls, including those linked to inflammatory signaling, antioxidants, nucleosides, amino acids and uremic toxins.

Conclusion

These pilot results suggest that vitamin D status is associated with alterations in numerous nutrient‐ and energy‐related metabolic processes, some of which have been linked to clinical outcomes in individuals requiring critical care.

Support or Funding Information

NIH R21 HL110044 (GSM, VT, LAB, TRZ), K24 DK096574 (TRZ), T32 AA013528 (JEH), T32 DK007298 (JLJ), K01 DK102851 (JAA), P30 ES019776 (DPJ, TRZ) and UL1 TR000454.