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

Autor:	Reinke SN; 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; Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.; Equal contribution., Chaleckis R; 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., Gallart-Ayala H; Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden., Kolmert J; Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.; The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden., Kermani NZ; National Heart and Lung Institute, Imperial College, London, UK., Tiotiu A; National Heart and Lung Institute, Imperial College, London, UK.; Dept of Pulmonology, University Hospital of Nancy, Nancy, France., Broadhurst DI; Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Perth, Australia., Lundqvist A; DMPK, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Olsson H; Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Ström M; 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 ÅM; 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., Gómez C; Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.; The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden., Ericsson M; Dept of Clinical Pharmacology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden., Sousa AR; GlaxoSmithKline, London, UK., Riley JH; GlaxoSmithKline, London, UK., Bates S; GlaxoSmithKline, London, UK., Scholfield J; Faculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, UK., Loza M; Janssen Research and Development, High Wycombe, UK., Baribaud F; Janssen Research and Development, High Wycombe, UK., Bakke PS; Institute of Medicine, University of Bergen, Bergen, Norway., Caruso M; Dept of Biomedical and Biotechnological Sciences and Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy., Chanez P; Assistance Publique des Hôpitaux de Marseille, Clinique des Bronches, Allergies et Sommeil, Aix Marseille Université, Marseille, France., Fowler SJ; Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, and Manchester Academic Health Science Centre and NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, UK., Geiser T; Dept of Pulmonary Medicine, University Hospital, University of Bern, Bern, Switzerland., Howarth P; Faculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, UK., Horváth I; Dept of Pulmonology, Semmelweis University, Budapest, Hungary., Krug N; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany., Montuschi P; Pharmacology, Catholic University of the Sacred Heart, Rome, Italy., Behndig A; Dept of Public Health and Clinical Medicine, Section of Medicine, Umeå University, Umeå, Sweden., Singer F; Division of Paediatric Respiratory Medicine and Allergology, Dept of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Musial J; Dept of Medicine, Jagiellonian University Medical College, Krakow, Poland., Shaw DE; Nottingham NIHR Biomedical Research Centre, University of Nottingham, Nottingham, UK., Dahlén B; Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden., Hu S; Data Science Institute, Imperial College, London, UK., Lasky-Su J; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Sterk PJ; Dept of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands., Chung KF; National Heart and Lung Institute, Imperial College, London, UK., Djukanovic R; Faculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, UK., Dahlén SE; The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden., Adcock IM; National Heart and Lung Institute, Imperial College, London, UK., Wheelock CE; Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden craig.wheelock@ki.se.; Gunma Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan.; Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2022 Jun 30; Vol. 59 (6). Date of Electronic Publication: 2022 Jun 30 (Print Publication: 2022).
DOI:	10.1183/13993003.01733-2021
Abstrakt:	Introduction: 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. Methods: Baseline 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. Results: A 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. 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 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. Competing Interests: Conflict of interest: S.N. Reinke reports grants from Canadian Institutes of Health Research, during the conduct of the study. Conflict of interest: S. Naz has nothing to disclose. Conflict of interest: R. Chaleckis has nothing to disclose. Conflict of interest: H. Gallart-Ayala has nothing to disclose. Conflict of interest: J. Kolmert reports personal fees for consultancy from Gesynta Pharma AB, outside the submitted work. Conflict of interest: N.Z. Kermani has nothing to disclose. Conflict of interest: A. Tiotiu has nothing to disclose. Conflict of interest: D.I. Broadhurst has nothing to disclose. Conflict of interest: A. Lundqvist has nothing to disclose. Conflict of interest: H. Olsson is an employee and shareholder of AstraZeneca. Conflict of interest: M. Ström has nothing to disclose. Conflict of interest: Å.M. Wheelock has nothing to disclose. Conflict of interest: C. Gómez has nothing to disclose. Conflict of interest: M. Ericsson has nothing to disclose. Conflict of interest: A.R. Sousa has nothing to disclose. Conflict of interest: J.H. Riley works for and own shares in GlaxoSmithKline. Conflict of interest: S. Bates is an employee of Johnson & Johnson and has previously worked for and holds stock in GlaxoSmithKline. Conflict of interest: J. Scholfield reports grants from Innovative Medicines Initiative, during the conduct of the study; and is director and employee of TopMD Precision Medicine Ltd. Conflict of interest: M. Loza is an employee of and owns stock in Johnson & Johnson. Conflict of interest: F. Baribaud is a shareholder of Johnson & Johnson and a current employee of Bristol Myers Squibb. Conflict of interest: P.S. Bakke reports personal fees for advisory board work and lectures from AstraZeneca, and personal fees for lectures from Novartis and Boehringer Ingelheim, outside the submitted work. Conflict of interest: M. Caruso has nothing to disclose. Conflict of interest: P. Chanez reports grants and personal fees from AstraZeneca, ALK, Boehringer Ingelheim, Chiesi, Sanofi-Aventis, Novartis and GlaxoSmithKline, outside the submitted work. Conflict of interest: S.J. Fowler reports personal fees from AstraZeneca, Novartis, TEVA and Chiesi, outside the submitted work. Conflict of interest: T. Geiser has nothing to disclose. Conflict of interest: P. Howarth has nothing to disclose. Conflict of interest: I. Horvath has nothing to disclose. Conflict of interest: N. Krug has nothing to disclose. Conflict of interest: P. Montuschi has nothing to disclose. Conflict of interest: A. Behndig has nothing to disclose. Conflict of interest: F. Singer reports personal fees from Vertex Pharmaceuticals (CH) and Novartis, outside the submitted work. Conflict of interest: J. Musial has nothing to disclose. Conflict of interest: D.E. Shaw has nothing to disclose. Conflict of interest: B. Dahlén reports personal fees for advisory board work and lectures from AstraZeneca, TEVA and Sanofi, and grants from Novartis and GlaxoSmithKline, outside the submitted work. Conflict of interest: S. Hu has nothing to disclose. Conflict of interest: J. Lasky-Su has nothing to disclose. Conflict of interest: P.J. Sterk reports a public private grant from the Innovative Medicines Initiative (IMI) covered by the EU and EFPIA, during the conduct of the study. Conflict of interest: K.F. Chung has received honoraria for participating in advisory board meetings of GlaxoSmithKline, AstraZeneca, Roche, Novartis, Merck, Nocion and Shionogi regarding treatments for asthma, COPD and chronic cough and has also been remunerated for speaking engagements. Conflict of interest: R. 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; and is a co-founder and current consultant, and has shares in Synairgen, a University of Southampton spin out company. Conflict of interest: S-E. Dahlén reports personal fees for consultancy from AstraZeneca, Cayman Chemical, GlaxoSmithKline, Novartis, Merck, Regeneron, Sanofi and TEVA, outside the submitted work. Conflict of interest: I.M. Adcock has nothing to disclose. Conflict of interest: C.E. Wheelock has nothing to disclose. (Copyright ©The authors 2022.)
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