Mitochondrial beta-oxidation is altered in response to prednisolone intervention in mepolizumab treated severe eosinophilic asthma

<bold>Background:</bold> Treatment with prednisolone following interleukin-5 (IL-5) inhibition with mepolizumab further reduced Th2 inflammation but had limited clinical benefits in stable severe eosinophilic asthma. <bold>Aim:</bold> To investigate the effects of prednisolone treatment after IL-5 inhibition on observed asthma metabotypes. <bold>Methods:</bold> Urine was collected as part of the MAPLE study; a randomised placebo-controlled crossover trial (Yang et al. J Allergy Clin Immunol Pract 2022;10(11):2925.e12). 30 mepolizumab-treated severe asthmatics underwent 2-week interventions of placebo and prednisolone. Metabolomic data were acquired using mass spectrometry and analysed using univariate and multivariate statistics. <bold>Results:</bold> 158 metabolites were identified, with 25 being altered following prednisolone (p<0.05, FDR<0.05) and 0 being altered following placebo intervention. Multivariate modelling corroborated these findings. The metabotypes of pre-intervention and post-placebo timepoints were similar, and the post-prednisolone timepoint was significantly different (p<0.05). Acylglycines (biomarkers of beta-oxidation deficiency, FC=1.55-2.06) increased while medium chain acylcarnitines and citric acid (central energy, FC=0.66-0.77), taurine (anti-inflammatory and antioxidant, FC=0.25), and imidazoleacetic acid (catabolic product of histamine, FC=0.85) decreased following prednisolone intervention. <bold>Conclusion:</bold> Metabolomics revealed significant changes to fatty acid beta-oxidation and central energy metabolism after 2 weeks of prednisolone. Results suggest altered mitochondrial function as a potential mechanism through which corticosteroids mediate airway inflammation following IL5 inhibition.