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

Abstract

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.

The value of prospective metabolomic susceptibility endotypes: broad applicability for infectious diseases

“…Despite adjustment for sex, the results may be driven by unmeasured confounders related to differences between men and women. 70 Third, we also did not include an strictly independent replication cohort for these findings; however, we generalize this with observe consistent clinical findings to other time point during COVID-19 using an independent group of individuals, which does provide an initial form of validation of these findings. Finally, we extracted clinical data from EMRs; as this captures “real life” clinical data, outcomes measures and other clinical characteristics and are often incomplete.…”

An update on essential micronutrients in critical illness

“…These include a decrease in total 25(OH)D levels but no change in free 25(OH)D levels compared with healthy individuals and a spontaneous increase in vitamin D metabolites after the resolution of critical illness [61,62]. Furthermore, the difference in absorption and metabolic response between men and women was recently reported [63]. Finally, in a posthoc metabolomics study of the VITdAL-ICU trial, an increase of 25(OH)D more than 15 ng/ml after supplementation was associated with favourable changes in metabolites involved in endothelial protection, enhanced innate immunity and improved mitochondrial function.…”

Clarifying the Heterogeneity in Response to Vitamin D in the Development, Prevention, and Treatment of Type 2 Diabetes Mellitus: A Narrative Review

“…Sex differences have also been observed in high-dose VitD supplementation among critically ill men and women in a randomized placebo-controlled trial. In this study, women received higher doses of VitD than their male counterparts but showed significantly lower VitD absorption than males [ 63 ]. Additional research has shown sex-specific differences in coagulation and blood lipids during VitD intervention.…”

“…For instance, VitD enhances tolerance-inducing Treg populations, depresses B cell proliferation, reduces LPS-induced cytotoxicity, skews toward a Th2 response (over Th1, Th17, etc. ), and decreases numerous pro-inflammatory cytokines (MCP-1, IL-1, IL-2, IFN-γ, TNF-α, IL-17, IL-21, and iNOS) while boosting anti-inflammatory cytokines (IL-4, IL-10, and IL-13) [ 29 , 61 , 62 , 63 ]. Even in the absence of T2DM, excess adiposity (roughly estimated by BMI) elevates serum inflammatory markers (IL-6, TNF, and MCP-1) [ 67 , 72 ].…”