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

Stacey N Reinke; Shama Naz; Romanas Chaleckis; Hector Gallart-Ayala; Johan Kolmert; Nazanin Z Kermani; Angelica Tiotiu; David I Broadhurst; Anders Lundqvist; Henric Olsson; Marika Ström; Åsa M Wheelock; Cristina Gómez; Magnus Ericsson; Ana R Sousa; John H Riley; Stewart Bates; James Scholfield; Matthew Loza; Frédéric Baribaud; Per S Bakke; Massimo Caruso; Pascal Chanez; Stephen J Fowler; Thomas Geiser; Peter Howarth; Ildikó Horváth; Norbert Krug; Paolo Montuschi; Annelie Behndig; Florian Singer; Jacek Musial; Dominick E Shaw; Barbro Dahlén; Sile Hu; Jessica Lasky-Su; Peter J Sterk; Kian Fan Chung; Ratko Djukanovic; Sven-Erik Dahlén; Ian M Adcock; Craig E Wheelock; U-BIOPRED Study Group

doi:10.1183/13993003.01733-2021

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

Eur Respir J. 2022 Jun 30;59(6):2101733. doi: 10.1183/13993003.01733-2021. Print 2022 Jun.

Authors

Stacey N Reinke^{1

2

3}, Shama Naz^{1

3}, Romanas Chaleckis^{1

4}, Hector Gallart-Ayala¹, Johan Kolmert^{1

5}, Nazanin Z Kermani⁶, Angelica Tiotiu^{6

7}, David I Broadhurst², Anders Lundqvist⁸, Henric Olsson⁹, Marika Ström^{10

11}, Åsa M Wheelock^{10

11}, Cristina Gómez^{1

5}, Magnus Ericsson¹², Ana R Sousa¹³, John H Riley¹³, Stewart Bates¹³, James Scholfield¹⁴, Matthew Loza¹⁵, Frédéric Baribaud¹⁵, Per S Bakke¹⁶, Massimo Caruso¹⁷, Pascal Chanez¹⁸, Stephen J Fowler¹⁹, Thomas Geiser²⁰, Peter Howarth¹⁴, Ildikó Horváth²¹, Norbert Krug²², Paolo Montuschi²³, Annelie Behndig²⁴, Florian Singer²⁵, Jacek Musial²⁶, Dominick E Shaw²⁷, Barbro Dahlén¹¹, Sile Hu²⁸, Jessica Lasky-Su²⁹, Peter J Sterk³⁰, Kian Fan Chung⁶, Ratko Djukanovic¹⁴, Sven-Erik Dahlén^{5

11}, Ian M Adcock⁶, Craig E Wheelock^{31

4

11}; U-BIOPRED Study Group

Affiliations

¹ Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
² Centre for Integrative Metabolomics and Computational Biology, School of Science, Edith Cowan University, Perth, Australia.
³ Equal contribution.
⁴ Gunma Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan.
⁵ The Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁶ National Heart and Lung Institute, Imperial College, London, UK.
⁷ Dept of Pulmonology, University Hospital of Nancy, Nancy, France.
⁸ DMPK, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁹ Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
¹⁰ Respiratory Medicine Unit, K2 Dept of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
¹¹ Dept of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden.
¹² Dept of Clinical Pharmacology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
¹³ GlaxoSmithKline, London, UK.
¹⁴ Faculty of Medicine, Southampton University and NIHR Southampton Respiratory Biomedical Research Centre, University Hospital Southampton, Southampton, UK.
¹⁵ Janssen Research and Development, High Wycombe, UK.
¹⁶ Institute of Medicine, University of Bergen, Bergen, Norway.
¹⁷ Dept of Biomedical and Biotechnological Sciences and Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy.
¹⁸ Assistance Publique des Hôpitaux de Marseille, Clinique des Bronches, Allergies et Sommeil, Aix Marseille Université, Marseille, France.
¹⁹ 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.
²⁰ Dept of Pulmonary Medicine, University Hospital, University of Bern, Bern, Switzerland.
²¹ Dept of Pulmonology, Semmelweis University, Budapest, Hungary.
²² Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
²³ Pharmacology, Catholic University of the Sacred Heart, Rome, Italy.
²⁴ Dept of Public Health and Clinical Medicine, Section of Medicine, Umeå University, Umeå, Sweden.
²⁵ Division of Paediatric Respiratory Medicine and Allergology, Dept of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
²⁶ Dept of Medicine, Jagiellonian University Medical College, Krakow, Poland.
²⁷ Nottingham NIHR Biomedical Research Centre, University of Nottingham, Nottingham, UK.
²⁸ Data Science Institute, Imperial College, London, UK.
²⁹ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³⁰ Dept of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
³¹ Division of Physiological Chemistry 2, Dept of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden craig.wheelock@ki.se.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01976767.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adrenal Cortex Hormones / therapeutic use
Anti-Asthmatic Agents* / therapeutic use
Asthma* / genetics
Carnitine / therapeutic use
Cross-Sectional Studies
Humans
Severity of Illness Index
Solute Carrier Family 22 Member 5

Substances

Adrenal Cortex Hormones
Anti-Asthmatic Agents
SLC22A5 protein, human
Solute Carrier Family 22 Member 5
Carnitine

Associated data

ClinicalTrials.gov/NCT01976767

Grants and funding

CIHR/Canada