Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study - Aix-Marseille Université Access content directly
Journal Articles European Respiratory Journal Year : 2021

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

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

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.

Dates and versions

hal-03654476 , version 1 (28-04-2022)

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Cite

Stacey Reinke, Shama Naz, Romanas Chaleckis, Hector Gallart-Ayala, Johan Kolmert, et al.. Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study. European Respiratory Journal, 2021, pp.2101733. ⟨10.1183/13993003.01733-2021⟩. ⟨hal-03654476⟩
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