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  • Reinke, SNDivision 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 (author)

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

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2021-11-25
  • European Respiratory Society (ERS),2022

Numbers

  • LIBRIS-ID:oai:prod.swepub.kib.ki.se:150324797
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:150324797URI
  • https://doi.org/10.1183/13993003.01733-2021DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-198227URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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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  • Naz, S (author)
  • Chaleckis, RDivision of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Gunma Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan (author)
  • Gallart-Ayala, HDivision of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden (author)
  • Kolmert, JKarolinska Institutet,Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (author)
  • Kermani, NZNational Heart and Lung Institute, Imperial College, London, United Kingdom (author)
  • Tiotiu, ANational Heart and Lung Institute, Imperial College, London, United Kingdom; Dept of Pulmonology, University Hospital of Nancy, Nancy, France (author)
  • Broadhurst, DIKarolinska Institutet (author)
  • Lundqvist, ADMPK, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (author)
  • Olsson, HTranslational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (author)
  • Strom, MKarolinska 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 (author)
  • Wheelock, AMKarolinska 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 (author)
  • Gomez, CDivision of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (author)
  • Ericsson, MDept of Clinical Pharmacology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (author)
  • Sousa, ARGlaxoSmithKline, London, United Kingdom (author)
  • Riley, JHGlaxoSmithKline, London, United Kingdom (author)
  • Bates, SGlaxoSmithKline, London, United Kingdom,Faculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom (author)
  • Scholfield, J (author)
  • Loza, MJanssen Research and Development, High Wycombe, United Kingdom (author)
  • Baribaud, FJanssen Research and Development, High Wycombe, United Kingdom (author)
  • Bakke, PSInstitute of Medicine, University of Bergen, Bergen, Norway (author)
  • Caruso, MDept of Biomedical and Biotechnological Sciences and Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy (author)
  • Chanez, PAssistance Publique des Hôpitaux de Marseille, Clinique des Bronches, Allergies et Sommeil, Aix Marseille Université, Marseille, France (author)
  • Fowler, SJDivision 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 (author)
  • Geiser, TDept of Pulmonary Medicine, University Hospital, University of Bern, Bern, Switzerland (author)
  • Howarth, PFaculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom (author)
  • Horvath, IDept of Pulmonology, Semmelweis University, Budapest, Hungary (author)
  • Krug, NFraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany (author)
  • Montuschi, PPharmacology, Catholic University of the Sacred Heart, Rome, Italy (author)
  • Behndig, Annelie F.,1963-Umeå universitet,Lungmedicin(Swepub:umu)anbe0145 (author)
  • Singer, FDivision of Paediatric Respiratory Medicine and Allergology, Dept of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland (author)
  • Musial, JDept of Medicine, Jagiellonian University Medical College, Krakow, Poland (author)
  • Shaw, DEKarolinska Institutet (author)
  • Dahlen, BKarolinska Institutet,Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden (author)
  • Hu, SLData Science Institute, Imperial College, London, United Kingdom (author)
  • Lasky-Su, JChanning Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, Boston, United States (author)
  • Sterk, PJDept of Respiratory Medicine, University of Amsterdam, Amsterdam, Netherlands (author)
  • Chung, KFNational Heart and Lung Institute, Imperial College, London, United Kingdom (author)
  • Djukanovic, RFaculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, United Kingdom (author)
  • Dahlen, SEKarolinska Institutet,Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden (author)
  • Adcock, IMNational Heart and Lung Institute, Imperial College, London, United Kingdom (author)
  • Wheelock, CEKarolinska 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 (author)
  • 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 contributionDivision of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Gunma Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan (creator_code:org_t)

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  • In:The European respiratory journal: European Respiratory Society (ERS)59:61399-30030903-1936

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