Metabolomic differences between critically Ill women and men

Abstract

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.

Figure 1

Rain Plot of single time point metabolites Increased in Women. Correlations between individual metabolites and sex at day 0, 3 or 7 were determined utilizing linear regression models correcting for age, SAPS II, admission diagnosis, 25(OH)D at day 0. Day 3 and 7 estimates were also corrected for absolute change in 25(OH)D level at day 3. The magnitude of beta coefficient estimates (effect size) is shown by a color fill scale and the corresponding significance level (− log₁₀(P-value)) is represented by size of the circle. The intensity of the red fill color represents an increase in effect size for that metabolite in women compared to men. Statistical significance is the multiple test-corrected threshold of − log₁₀(P-value) > 4.06 which is equivalent to P-value < 8.65 × 10⁻⁵.

Figure 2

Rain Plot of single time point metabolites Decreased in Women. Correlations between individual metabolites and sex at day 0, 3 or 7 were determined utilizing linear regression models correcting for age, SAPS II, admission diagnosis, 25(OH)D at day 0. Day 3 and 7 estimates were also corrected for absolute change in 25(OH)D level at day 3. The magnitude of beta coefficient estimates (effect size) is shown by a color fill scale and the corresponding significance level (− log₁₀(P-value)) is represented by size of the circle. The blue fill color represents an decrease in effect size for that metabolite in women compared to men. Statistical significance is the multiple test-corrected threshold of − log₁₀(P-value) > 4.06 which is equivalent to P-value < 8.65 × 10^–5.

Figure 3

Circos Plot of metabolites over multiple time points. Bipartite graph of metabolites measured in 1215 plasma samples from 428 subjects. Metabolites shown are determined by mixed-effects linear regression to be significantly increased or decreased in women relative to men over the first seven days following trial enrollment. The graph connects the increase or decrease in metabolite on the left side with individual metabolites on the right side. Width of curves indicates strength of the significance (− log₁₀(P-value)) as determined by mixed-effects regression. Colors differ for each sub-pathway (i.e. all amino acid metabolites are red, all lipids are blue). All curves shown have P-value < 8.65 × 10^–5 in mixed-effects linear regression analysis.