Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D 3 administration

Abstract

Background Cystic fibrosis (CF) is a chronic catabolic disease often requiring hospitalization for acute episodes of worsening pulmonary exacerbations. Limited data suggest that vitamin D may have beneficial clinical effects, but the impact of vitamin D on systemic metabolism in this setting is unknown. Objective We used high-resolution metabolomics (HRM) to assess the impact of baseline vitamin D status and high-dose vitamin D3 administration on systemic metabolism in adults with CF with an acute pulmonary exacerbation. Design Twenty-five hospitalized adults with CF were enrolled in a randomized trial of high-dose vitamin D3 (250,000 IU vitamin D3 bolus) versus placebo. Age-matched healthy subjects served as a reference group for baseline comparisons. Plasma was analyzed with liquid chromatography/ultra-high resolution mass spectrometry. Using recent HRM bioinformatics and metabolic pathway enrichment methods, we examined associations with baseline vitamin D status (sufficient vs deficient per serum 25-hydroxyvitamin D concentrations) and the 7-day response to vitamin D3 supplementation. Results Several amino acids and lipid metabolites differed between CF and healthy control subjects, indicative of an overall catabolic state. In CF subjects, 343 metabolites differed (P<0.05) by baseline vitamin D status and were enriched within 7 metabolic pathways including fatty acid, amino acid, and carbohydrate metabolism. A total of 316 metabolites, which showed enrichment for 15 metabolic pathways--predominantly representing amino acid pathways-- differed between the vitamin D3- and placebo-treated CF subjects over time (P<0.05). In the placebo group, several tricarboxylic acid cycle intermediates increased while several amino acid-related metabolites decreased; in contrast, little change in these metabolites occurred with vitamin D3 treatment. Conclusions Numerous metabolic pathways detected by HRM varied in association with vitamin D status and high-dose vitamin D3 supplementation in adults with CF experiencing a pulmonary exacerbation. Overall, these pilot data suggest an anti-catabolic effect of high-dose vitamin D3 in this clinical setting.

Metabolomic responses to lumacaftor/ivacaftor in cystic fibrosis

“…This would support a targeted approach which may be useful for metabolic monitoring of treatment responses. Our findings related to pulmonary exacerbation are consistent with other CF metabolomics studies that demonstrate specific patterns related to exacerbation …”

“…Our findings related to pulmonary exacerbation are consistent with other CF metabolomics studies that demonstrate specific patterns related to exacerbation. 30,[36][37][38][39] Significant expertise was needed to develop and complete this study with high level coordination, but we were limited to a single-center cohort of adolescents and adults. Additionally, a lack of comparison to subjects initiating Ivacaftor alone or not initiating therapy, fixed length of treatment follow-up, variable diets, and lack of culture-independent microbiome data availability hinder further comparisons.…”

Targeting Vitamin D Deficiency to Limit Exacerbations in Respiratory Diseases: Utopia or Strategy With Potential?

“…Even though mechanistic studies mostly were done in vitro, few studies in human suggest that the positive effects of vitamin D on exacerbations in CF are mostly attributed to its immunomodulatory properties as reflected by reduced serum IL-6, TNF levels [61], and IL-8 levels [66] or reduced serum Ig(G) levels [45]. A study on metabolomics on plasma of a supplemented CF population revealed that the beneficial effects of high-dose vitamin D in hospitalized CF adults with an acute pulmonary exacerbation may have occurred through a metabolic stabilization of amino acids, lipids, and other metabolites [67].…”

Biological determinants of health: Genes, microbes, and metabolism exemplars of nursing science

“…Metabolomic approaches are increasingly used in the study of diabetes, dyslipidemia, cancer, chronic neurological disorders, pharmaceutics, and nutrition to name a few. Research into the metabotype of individuals during the disease processes has led to new biomarkers of disease status as well as new targets for interventions and the impact of nutritional interventions (Alvarez et al, 2017; McGrath & Young, 2015). Nutritional metabolomics is seeking to identify novel biomarkers of dietary intake to provide objective measures of dietary intake (Schmidt et al, 2015).…”

“…Hypotheses of how diet may improve MS include reduction of inflammation, alteration of the microbiome, increased nutrient provision for cellular healing, epigenetic changes, increased mitochondrial function, among others. Currently, Grossmann and colleagues use a multi-omics approach (metabolome, microbiome and epigenome analyses) to identify potential biomarkers as well as to gain insights into mechanisms related to dietary interventions in MS and cystic fibrosis(Alvarez et al, 2017). …”