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.
Footnotes
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Conflict of interest: Dr. Reinke reports grants from Canadian Institutes of Health Research, during the conduct of the study;.
Conflict of interest: Dr. naz has nothing to disclose.
Conflict of interest: Dr. Chaleckis has nothing to disclose.
Conflict of interest: Dr. Gallart-Ayala has nothing to disclose.
Conflict of interest: Dr. Kolmert reports personal fees from Gesynta Pharma AB, outside the submitted work;.
Conflict of interest: Dr. Kermani has nothing to disclose.
Conflict of interest: Dr. Tiotiu has nothing to disclose.
Conflict of interest: Dr. Broadhurst has nothing to disclose.
Conflict of interest: Dr. Lundqvist has nothing to disclose.
Conflict of interest: Dr. Olsson reports other from AstraZeneca, other from AstraZeneca, outside the submitted work; .
Conflict of interest: Dr. Marika Ström has nothing to disclose.
Conflict of interest: Dr. ÅM Wheelock has nothing to disclose.
Conflict of interest: Dr. Gómez has nothing to disclose.
Conflict of interest: Dr. Ericsson has nothing to disclose.
Conflict of interest: Dr. Sousa has nothing to disclose.
Conflict of interest: Dr. Riley reports and he works for and own shares in GSK.
Conflict of interest: Dr. Bates reports to be an employee of Johnson & Johnson and to have previously worked and holds stock in GSK.
Conflict of interest: Dr. James Scholfield reports grants from Innovative Medicines Initiative, during the conduct of the study; and Director & employee of TopMD Precision Medicine Ltd.
Conflict of interest: Dr. Loza reports other from Johnson & Johnson, outside the submitted work;.
Conflict of interest: Dr. Baribaud is a share holder of Johnson & Johnson and a current employee of Bristol Myers Squibb.
Conflict of interest: Dr. Bakke reports personal fees from AstraZeneca, personal fees from AstraZeneca, personal fees from Novartis, personal fees from Boehringer-Ingelheim, outside the submitted work;.
Conflict of interest: Dr. Caruso has nothing to disclose.
Conflict of interest: Dr. Chanez reports grants and personal fees from AstraZeneca, grants and personal fees from ALK, grants and personal fees from Boehringer-Ingelheim, grants and personal fees from Chiesi, grants and personal fees from Sanofi-Aventis, grants and personal fees from Novartis, grants and personal fees from GSK, outside the submitted work; .
Conflict of interest: Dr. Fowler reports personal fees from AstraZeneca, personal fees from Novartis, personal fees from Teva, personal fees from Chiesi, outside the submitted work; .
Conflict of interest: Dr. Thomas Geiser has nothing to disclose.
Conflict of interest: Dr. Howarth has nothing to disclose.
Conflict of interest: Dr. Horvath has nothing to disclose.
Conflict of interest: Dr. Krug has nothing to disclose.
Conflict of interest: Dr. Montuschi has nothing to disclose.
Conflict of interest: Dr. Behndig has nothing to disclose.
Conflict of interest: Dr. Singer reports personal fees from Vertex Pharmaceuticals (CH), personal fees from Novartis, outside the submitted work.
Conflict of interest: Dr. Jacek Musial has nothing to disclose.
Conflict of interest: Dr. Shaw has nothing to disclose.
Conflict of interest: Dr. Dahlén reports personal fees from AstraZeneca, Teva, Sanofi, grants from Novartis, GSK, outside the submitted work; .
Conflict of interest: Dr. Hu has nothing to disclose.
Conflict of interest: Dr. Lasky-Su has nothing to disclose.
Conflict of interest: Dr. Sterk reports grants from public private grant by the Innovative Medicines Initiative (IMI) covered by the EU and EFPIA, during the conduct of the study; .
Conflict of interest: KFC has received honoraria for participating in Advisory Board meetings of GSK, AZ, Roche, Novartis, Merck, Nocion, and Shionogi regarding treatments for asthma, chronic obstructive pulmonary disease and chronic cough and has also been renumerated for speaking engagements.
Conflict of interest: Dr Djukanovic reports receiving fees for lectures at symposia organised by Novartis, AstraZeneca and TEVA, consultation for TEVA and Novartis as member of advisory boards, and participation in a scientific discussion about asthma organised by GlaxoSmithKline. He is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin out company.
Conflict of interest: - Dr. Sven-Erik Dahlén reports personal fees from AZ, Cayman Chemical, GSK, Novartis, Merck, Regeneron, Sanofi, TEVA, outside the submitted work; .
Conflict of interest: Dr. Adcock has nothing to disclose.
Conflict of interest: Dr. Wheelock has nothing to disclose.
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- Received June 18, 2021.
- Accepted October 28, 2021.
- Copyright ©The authors 2021.
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