Metabolome alterations in severe critical illness and vitamin D status

BACKGROUND Metabolic homeostasis is substantially disrupted in critical illness. Given the pleiotropic effects of vitamin D, we hypothesized that metabolic profiles differ between critically ill patients relative to their vitamin D status. METHODS We performed a metabolomics study on biorepository samples collected from a single academic medical center on 65 adults with systemic inflammatory response syndrome or sepsis treated in a 20-bed medical ICU between 2008 and 2010. To identify key metabolites and metabolic pathways related to vitamin D status in critical illness, we first generated metabolomic data using gas and liquid chromatography mass spectroscopy. We followed this by partial least squares-discriminant analysis to identify individual metabolites that were significant. We then interrogated the entire metabolomics profile using metabolite set enrichment analysis to identify groups of metabolites and pathways that were differentiates of vitamin D status. Finally we performed logistic regression to construct a network model of chemical-protein target interactions important in vitamin D status. RESULTS Metabolomic profiles significantly differed in critically ill patients with 25(OH)D ≤ 15 ng/ml relative to those with levels >15 ng/ml. In particular, increased 1,5-anhydroglucitol, tryptophan betaine, and 3-hydroxyoctanoate as well as decreased 2-arachidonoyl-glycerophosphocholine and N-6-trimethyllysine were strong predictors of 25(OH)D >15 ng/ml. The combination of these five metabolites led to an area under the curve for discrimination for 25(OH)D > 15 ng/ml of 0.82 (95% CI 0.71-0.93). The metabolite pathways related to glutathione metabolism and glutamate metabolism are significantly enriched with regard to vitamin D status. CONCLUSION Vitamin D status is associated with differential metabolic profiles during critical illness. Glutathione and glutamate pathway metabolism, which play principal roles in redox regulation and immunomodulation, respectively, were significantly altered with vitamin D status.