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

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

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 BaribaudPer 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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	2101733
Journal	The European respiratory journal
Early online date	25 Nov 2021
DOIs	https://doi.org/10.1183/13993003.01733-2021
Publication status	Published - 25 Nov 2021

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Reinke, S. N., Naz, S., Chaleckis, R., Gallart-Ayala, H., Kolmert, J., Kermani, N. Z., Tiotiu, A., Broadhurst, D. I., Lundqvist, A., Olsson, H., Ström, M., Wheelock, Å. M., Gómez, C., Ericsson, M., Sousa, A. R., Riley, J. H., Bates, S., Scholfield, J., Loza, M., ... Wheelock, C. E. (2021). Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study. The European respiratory journal, Article 2101733. https://doi.org/10.1183/13993003.01733-2021

@article{02f68c057fc240b0bfa0a76889d4747e,

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

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.",

author = "Reinke, {Stacey N} and Shama Naz and Romanas Chaleckis and Hector Gallart-Ayala and Johan Kolmert and Kermani, {Nazanin Z} and Angelica Tiotiu and Broadhurst, {David I} and Anders Lundqvist and Henric Olsson and Marika Str{\"o}m and Wheelock, {{\AA}sa M} and Cristina G{\'o}mez and Magnus Ericsson and Sousa, {Ana R} and Riley, {John H} and Stewart Bates and James Scholfield and Matthew Loza and Fr{\'e}d{\'e}ric Baribaud and Bakke, {Per S} and Massimo Caruso and Pascal Chanez and Fowler, {Stephen J} and Thomas Geiser and Peter Howarth and Ildik{\'o} Horv{\'a}th and Norbert Krug and Paolo Montuschi and Annelie Behndig and Florian Singer and Jacek Musial and Shaw, {Dominick E} and Barbro Dahl{\'e}n and Sile Hu and Jessica Lasky-Su and Sterk, {Peter J} and Chung, {Kian Fan} and Ratko Djukanovic and Sven-Erik Dahl{\'e}n and Adcock, {Ian M} and Wheelock, {Craig E}",

note = "Copyright {\textcopyright}The authors 2021.",

year = "2021",

month = nov,

day = "25",

doi = "10.1183/13993003.01733-2021",

language = "English",

journal = "The European respiratory journal",

issn = "0903-1936",

publisher = "European Respiratory Society",

}

Reinke, SN, Naz, S, Chaleckis, R, Gallart-Ayala, H, Kolmert, J, Kermani, NZ, Tiotiu, A, Broadhurst, DI, Lundqvist, A, Olsson, H, Ström, M, Wheelock, ÅM, Gómez, 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, Horváth, I, Krug, N, Montuschi, P, Behndig, A, Singer, F, Musial, J, Shaw, DE, Dahlén, B, Hu, S, Lasky-Su, J, Sterk, PJ, Chung, KF, Djukanovic, R, Dahlén, S-E, Adcock, IM & Wheelock, CE 2021, 'Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study', The European respiratory journal. https://doi.org/10.1183/13993003.01733-2021

TY - JOUR

T1 - Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study

AU - Reinke, Stacey N

AU - Naz, Shama

AU - Chaleckis, Romanas

AU - Gallart-Ayala, Hector

AU - Kolmert, Johan

AU - Kermani, Nazanin Z

AU - Tiotiu, Angelica

AU - Broadhurst, David I

AU - Lundqvist, Anders

AU - Olsson, Henric

AU - Ström, Marika

AU - Wheelock, Åsa M

AU - Gómez, Cristina

AU - Ericsson, Magnus

AU - Sousa, Ana R

AU - Riley, John H

AU - Bates, Stewart

AU - Scholfield, James

AU - Loza, Matthew

AU - Baribaud, Frédéric

AU - Bakke, Per S

AU - Caruso, Massimo

AU - Chanez, Pascal

AU - Fowler, Stephen J

AU - Geiser, Thomas

AU - Howarth, Peter

AU - Horváth, Ildikó

AU - Krug, Norbert

AU - Montuschi, Paolo

AU - Behndig, Annelie

AU - Singer, Florian

AU - Musial, Jacek

AU - Shaw, Dominick E

AU - Dahlén, Barbro

AU - Hu, Sile

AU - Lasky-Su, Jessica

AU - Sterk, Peter J

AU - Chung, Kian Fan

AU - Djukanovic, Ratko

AU - Dahlén, Sven-Erik

AU - Adcock, Ian M

AU - Wheelock, Craig E

PY - 2021/11/25

Y1 - 2021/11/25

N2 - 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.

AB - 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.

U2 - 10.1183/13993003.01733-2021

DO - 10.1183/13993003.01733-2021

M3 - Article

C2 - 34824054

SN - 0903-1936

JO - The European respiratory journal

JF - The European respiratory journal

M1 - 2101733

ER -

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

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