TY - JOUR T1 - Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01733-2021 VL - 59 IS - 6 SP - 2101733 AU - Stacey N. Reinke AU - Shama Naz AU - Romanas Chaleckis AU - Hector Gallart-Ayala AU - Johan Kolmert AU - Nazanin Z. Kermani AU - Angelica Tiotiu AU - David I. Broadhurst AU - Anders Lundqvist AU - Henric Olsson AU - Marika Ström AU - Åsa M. Wheelock AU - Cristina Gómez AU - Magnus Ericsson AU - Ana R. Sousa AU - John H. Riley AU - Stewart Bates AU - James Scholfield AU - Matthew Loza AU - Frédéric Baribaud AU - Per S. Bakke AU - Massimo Caruso AU - Pascal Chanez AU - Stephen J. Fowler AU - Thomas Geiser AU - Peter Howarth AU - Ildikó Horváth AU - Norbert Krug AU - Paolo Montuschi AU - Annelie Behndig AU - Florian Singer AU - Jacek Musial AU - Dominick E. Shaw AU - Barbro Dahlén AU - Sile Hu AU - Jessica Lasky-Su AU - Peter J. Sterk AU - Kian Fan Chung AU - Ratko Djukanovic AU - Sven-Erik Dahlén AU - Ian M. Adcock AU - Craig E. Wheelock A2 - , Y1 - 2022/06/01 UR - http://erj.ersjournals.com/content/59/6/2101733.abstract N2 - Introduction Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication.Methods Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods.Results A total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10−20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10−4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings.Conclusions This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.Metabolomics identified a urinary metabotype of asthma driven by lower carnitine levels in an oral corticosteroid-independent manner. The carnitine transporter SLC22A5 was also decreased, suggesting carnitine metabolism as a potential therapeutic target. https://bit.ly/3BJfvT0 ER -