Inhaled glucocorticoid-induced metabolome changes in asthma

Area of Science:

• Metabolomics
• Pharmacology
• Endocrinology

Background:

• Inhaled glucocorticoids (GCs) are widely used for respiratory conditions.
• Understanding their systemic effects on metabolism is crucial for safety assessment.
• Previous studies have focused on specific metabolic pathways, but a global metabolome analysis is needed.

Purpose of the Study:

• To identify dose-related systemic effects of inhaled GCs on the global metabolome.
• To compare the metabolomic impact of different inhaled GCs at therapeutic and supratherapeutic doses.

Main Methods:

• Plasma metabolomics/lipidomics analysis from 54 subjects receiving escalating doses of fluticasone furoate (FF), fluticasone propionate (FP), budesonide (BUD), or placebo.
• Ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and liquid chromatography-mass spectrometry (LC-MS) were employed for sample analysis.
• Statistical analysis included repeated measures ANOVA, cross-over model, random forest, and principal component analysis.

Main Results:

• Few significant metabolomic changes were observed at therapeutic doses compared to placebo.
• Highest/supratherapeutic doses revealed dose-dependent changes: reduced adrenal steroids (cortisol, cortisone, DHEA-S), increased amino acids and glycolytic intermediates, and decreased fatty acid β-oxidation.
• Notable differences included lowered dopamine metabolites (BUD) and altered bile acid profiles (BUD/FF), suggesting potential CNS and gut microbiome effects.

Conclusions:

• Dose-dependent metabolomic changes with inhaled GCs are predominantly seen at supratherapeutic doses, supporting the safety of lower therapeutic doses.
• At comparable therapeutic doses, FF exhibited the least impact on sensitive markers like adrenal steroids compared to BUD and FP.
• These findings highlight the importance of dose selection and provide insights into the systemic safety profile of different inhaled GCs.