Document Type

Journal Article

Publication Title

European Respiratory Journal

Volume

2021

Publisher

European Respiratory Society

School

School of Science / Centre for Integrative Metabolomics and Computational Biology

RAS ID

40493

Comments

Reinke, S. N., Naz, S., Chaleckis, R., Gallart-Ayala, H., Kolmert, J., Kermani, N. Z., ... & Wheelock, C. E. (2021). Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study. European respiratory journal. Advance online publication.

https://doi.org/10.1183/13993003.01733-2021

Note from publisher: This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.

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

Creative Commons Attribution-Noncommercial 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License

Research Themes

Health

Priority Areas

Multidisciplinary biological approaches to personalised disease diagnosis, prognosis and management

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