Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study

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Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study

Reinke, SN (författare): Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Perth, Australia; Equal contribution

Naz, S (författare)

Chaleckis, R (författare): Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Gunma Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan

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Gallart-Ayala, H (författare): Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

Kolmert, J (författare): Karolinska Institutet,Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

Kermani, NZ (författare): National Heart and Lung Institute, Imperial College, London, United Kingdom

Tiotiu, A (författare): National Heart and Lung Institute, Imperial College, London, United Kingdom; Dept of Pulmonology, University Hospital of Nancy, Nancy, France

Broadhurst, DI (författare): Karolinska Institutet

Lundqvist, A (författare): DMPK, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Olsson, H (författare): Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

Strom, M (författare): Karolinska Institutet,Respiratory Medicine Unit, K2 Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden

Wheelock, AM (författare): Karolinska Institutet,Respiratory Medicine Unit, K2 Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden

Gomez, C (författare): Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

Ericsson, M (författare): Dept of Clinical Pharmacology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

Sousa, AR (författare): GlaxoSmithKline, London, United Kingdom

Riley, JH (författare): GlaxoSmithKline, London, United Kingdom

Bates, S (författare): GlaxoSmithKline, London, United Kingdom,Faculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom

Scholfield, J (författare)

Loza, M (författare): Janssen Research and Development, High Wycombe, United Kingdom

Baribaud, F (författare): Janssen Research and Development, High Wycombe, United Kingdom

Bakke, PS (författare): Institute of Medicine, University of Bergen, Bergen, Norway

Caruso, M (författare): Dept of Biomedical and Biotechnological Sciences and Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy

Chanez, P (författare): Assistance Publique des Hôpitaux de Marseille, Clinique des Bronches, Allergies et Sommeil, Aix Marseille Université, Marseille, France

Fowler, SJ (författare): Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre and NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom

Geiser, T (författare): Dept of Pulmonary Medicine, University Hospital, University of Bern, Bern, Switzerland

Howarth, P (författare): Faculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom

Horvath, I (författare): Dept of Pulmonology, Semmelweis University, Budapest, Hungary

Krug, N (författare): Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany

Montuschi, P (författare): Pharmacology, Catholic University of the Sacred Heart, Rome, Italy

Behndig, Annelie F., 1963- (författare): Umeå universitet,Lungmedicin

Singer, F (författare): Division of Paediatric Respiratory Medicine and Allergology, Dept of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Musial, J (författare): Dept of Medicine, Jagiellonian University Medical College, Krakow, Poland

Shaw, DE (författare): Karolinska Institutet

Dahlen, B (författare): Karolinska Institutet,Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden

Hu, SL (författare): Data Science Institute, Imperial College, London, United Kingdom

Lasky-Su, J (författare): Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, Boston, United States

Sterk, PJ (författare): Dept of Respiratory Medicine, University of Amsterdam, Amsterdam, Netherlands

Chung, KF (författare): National Heart and Lung Institute, Imperial College, London, United Kingdom

Djukanovic, R (författare): Faculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom

Dahlen, SE (författare): Karolinska Institutet,Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden

Adcock, IM (författare): National Heart and Lung Institute, Imperial College, London, United Kingdom

Wheelock, CE (författare): Karolinska Institutet,Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Gunma Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan; Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden

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(creator_code:org_t)

2021-11-25
2022
Engelska.
Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 59:6

Relaterad länk:: https://erj.ersjourn...; visa fler...; https://doi.org/10.1...; https://umu.diva-por... (primary) (Raw object); http://kipublication...; https://doi.org/10.1...; https://urn.kb.se/re...; visa färre...

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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.MethodsBaseline 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.ResultsA 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.ConclusionsThis 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.

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Av författaren/redakt...: Reinke, SN; Naz, S; Chaleckis, R; Gallart-Ayala, H; Kolmert, J; Kermani, NZ; visa fler...; Tiotiu, A; Broadhurst, DI; Lundqvist, A; Olsson, H; Strom, M; Wheelock, AM; Gomez, C; Ericsson, M; Sousa, AR; Riley, JH; Bates, S; Scholfield, J; Loza, M; Baribaud, F; Bakke, PS; Caruso, M; Chanez, P; Fowler, SJ; Geiser, T; Howarth, P; Horvath, I; Krug, N; Montuschi, P; Behndig, Annelie ...; Singer, F; Musial, J; Shaw, DE; Dahlen, B; Hu, SL; Lasky-Su, J; Sterk, PJ; Chung, KF; Djukanovic, R; Dahlen, SE; Adcock, IM; Wheelock, CE; visa färre...

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Av lärosätet: Karolinska Institutet; Umeå universitet

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Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study

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