Document Type
Journal Article
Publication Title
European Respiratory Journal
Volume
59
Issue
6
Publisher
European Respiratory Society
School
School of Science / Centre for Integrative Metabolomics and Computational Biology
RAS ID
40493
Funders
Konsul Th C Berghs Stiftelse
ChAMP (Centre for Allergy Research Highlights Asthma Markers of Phenotype) consortium
Hjärt-Lungfonden HLF 20180290
Stockholms Läns Landsting
Stiftelsen för Strategisk Forskning
Canadian Institutes of Health Research MFE-135481
Innovative Medicines Initiative no. 115010
Vårdalstiftelsen
Vetenskapsrådet
2014-3281; 2016-02798; 2016-0338
Abstract
Introduction: Asthma is a heterogeneous disease with poorly defined phenotypes. Severe asthmatics 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), mild-to-moderate asthmatics (n=87) and severe asthmatics (n=418) in the cross-sectional U-BIOPRED cohort; 12–18-month longitudinal samples were collected from severe asthmatics (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods. Results: Ninety metabolites were identified, with 40 significantly altered (p<0.05, FDR<0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and mild-to-moderate asthmatics differed significantly from severe asthmatics (p=2.6×10−20), OCS-treated asthmatics differed significantly from non-treated (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 necessity 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.
DOI
10.1183/13993003.01733-2021
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Comments
Reinke, S. N., Naz, S., Chaleckis, R., Gallart-Ayala, H., Kolmert, J., Kermani, N. Z., ... & Wheelock, C. E. (2022). Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study. European respiratory journal.
https://doi.org/10.1183/13993003.01733-2021