Asthma Metabolomics and the Potential for Integrative Omics in Research and the Clinic
2016; Elsevier BV; Volume: 151; Issue: 2 Linguagem: Inglês
10.1016/j.chest.2016.10.008
ISSN1931-3543
AutoresRachel S. Kelly, Amber Dahlin, Michael J. McGeachie, Weiliang Qiu, Joanne E. Sordillo, Emily S. Wan, Ann Chen Wu, Jessica Lasky‐Su,
Tópico(s)Chronic Obstructive Pulmonary Disease (COPD) Research
ResumoAsthma is a complex disease well-suited to metabolomic profiling, both for the development of novel biomarkers and for the improved understanding of pathophysiology. In this review, we summarize the 21 existing metabolomic studies of asthma in humans, all of which reported significant findings and concluded that individual metabolites and metabolomic profiles measured in exhaled breath condensate, urine, plasma, and serum could identify people with asthma and asthma phenotypes with high discriminatory ability. There was considerable consistency across the studies in terms of the reported biomarkers, regardless of biospecimen, profiling technology, and population age. In particular, acetate, adenosine, alanine, hippurate, succinate, threonine, and trans-aconitate, and pathways relating to hypoxia response, oxidative stress, immunity, inflammation, lipid metabolism and the tricarboxylic acid cycle were all identified as significant in at least two studies. There were also a number of nonreplicated results; however, the literature is not yet sufficiently developed to determine whether these represent spurious findings or reflect the substantial heterogeneity and limited statistical power in the studies and their methods to date. This review highlights the need for additional asthma metabolomic studies to explore these issues, and, further, the need for standardized methods in the way these studies are conducted. We conclude by discussing the potential of translation of these metabolomic findings into clinically useful biomarkers and the crucial role that integrated omics is likely to play in this endeavor. Asthma is a complex disease well-suited to metabolomic profiling, both for the development of novel biomarkers and for the improved understanding of pathophysiology. In this review, we summarize the 21 existing metabolomic studies of asthma in humans, all of which reported significant findings and concluded that individual metabolites and metabolomic profiles measured in exhaled breath condensate, urine, plasma, and serum could identify people with asthma and asthma phenotypes with high discriminatory ability. There was considerable consistency across the studies in terms of the reported biomarkers, regardless of biospecimen, profiling technology, and population age. In particular, acetate, adenosine, alanine, hippurate, succinate, threonine, and trans-aconitate, and pathways relating to hypoxia response, oxidative stress, immunity, inflammation, lipid metabolism and the tricarboxylic acid cycle were all identified as significant in at least two studies. There were also a number of nonreplicated results; however, the literature is not yet sufficiently developed to determine whether these represent spurious findings or reflect the substantial heterogeneity and limited statistical power in the studies and their methods to date. This review highlights the need for additional asthma metabolomic studies to explore these issues, and, further, the need for standardized methods in the way these studies are conducted. We conclude by discussing the potential of translation of these metabolomic findings into clinically useful biomarkers and the crucial role that integrated omics is likely to play in this endeavor. Asthma is a complex disease with both environmental and genetic influences; however, the role of molecular determinants as mediators of asthma is not yet fully understood.1Ober C. Yao T.-C. The genetics of asthma and allergic disease: a 21(st) century perspective.Immunol Rev. 2011; 242: 10-30Crossref PubMed Scopus (442) Google Scholar Metabolomics, the systematic analysis of small molecules, including carbohydrates, amino acids, organic acids, nucleotides, and lipids, has identified new biomarkers and novel pathogenic pathways for a number of complex chronic diseases.2Johnson C.H. Ivanisevic J. Siuzdak G. Metabolomics: beyond biomarkers and towards mechanisms.Nat Rev Mol Cell Biol. 2016; 17: 451-459Crossref PubMed Scopus (1168) Google Scholar Metabolomics is well-suited to the study of diseases with an environmental etiological component because it has the potential to capture the history of the cellular response to past exposures. Metabolite fluctuations represent an integrated pathophysiologic profile encompassing genetic and environmental interactions; therefore, metabolic profiles can be instrumental in elucidating the understanding of the biologic mechanisms of asthma. Although the application of metabolomics to study asthma is recent, the body of literature is rapidly growing. Critical analysis of this literature will afford an improved understanding of the status of asthma metabolomics and help to inform future studies. The National Center for Biotechnology Information PubMed database was searched to identify studies of asthma in humans using mass spectrometry (MS) or nuclear magnetic resonance spectroscopy (NMR) to identify and quantify metabolites associated with asthma or asthma-related outcomes. The references of each identified study were evaluated to identify additional qualifying manuscripts. Twenty-one studies using metabolomic profiling of exhaled breathe condensate (EBC) (n = 11),3Esther C.R. Boysen G. Olsen B.M. et al.Mass spectrometric analysis of biomarkers and dilution markers in exhaled breath condensate reveals elevated purines in asthma and cystic fibrosis.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L987-L993Crossref PubMed Scopus (71) Google Scholar, 4Montuschi P. LC/MS/MS analysis of leukotriene B4 and other eicosanoids in exhaled breath condensate for assessing lung inflammation.J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877: 1272-1280Crossref PubMed Scopus (83) Google Scholar, 5Carraro S. Giordano G. Reniero F. et al.Asthma severity in childhood and metabolomic profiling of breath condensate.Allergy. 2012; 68: 110-117Crossref PubMed Scopus (101) Google Scholar, 6Caldeira M. Perestrelo R. Barros A.S. et al.Allergic asthma exhaled breath metabolome: a challenge for comprehensive two-dimensional gas chromatography.Jf Chromatogr A. 2012; 1254: 87-97Crossref PubMed Scopus (92) Google Scholar, 7van de Kant K.D.G. van Berkel J.J.B.N. Jöbsis Q. et al.Exhaled breath profiling in diagnosing wheezy preschool children.Eur Resp J. 2013; 41: 183-188Crossref PubMed Scopus (49) Google Scholar, 8Gahleitner F. Guallar-Hoyas C. Beardsmore C.S. Pandya H.C. Thomas C.P. Metabolomics pilot study to identify volatile organic compound markers of childhood asthma in exhaled breath.Bioanalysis. 2013; 5: 2239-2247Crossref PubMed Scopus (52) Google Scholar, 9Smolinska A. Klaassen E.M.M. Dallinga J.W. et al.Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children.PLoS ONE. 2014; 9: e95668Crossref PubMed Scopus (103) Google Scholar, 10Carraro S. Rezzi S. Reniero F. et al.Metabolomics applied to exhaled breath condensate in childhood asthma.Am J Respir Crit Care Med. 2007; 175: 986-990Crossref PubMed Scopus (201) Google Scholar, 11Sinha A. Krishnan V. Sethi T. et al.Metabolomic signatures in nuclear magnetic resonance spectra of exhaled breath condensate identify asthma.Eur Respir J. 2012; 39: 500-502Crossref PubMed Scopus (27) Google Scholar, 12Ibrahim B. Marsden P. Smith J.A. Custovic A. Nilsson M. Fowler S.J. Breath metabolomic profiling by nuclear magnetic resonance spectroscopy in asthma.Allergy. 2013; 68: 1050-1056Crossref PubMed Scopus (43) Google Scholar, 13Motta A. Paris D. D’Amato M. et al.NMR metabolomic analysis of exhaled breath condensate of asthmatic patients at two different temperatures.J Proteome Res. 2014; 13: 6107-6120Crossref PubMed Scopus (47) Google Scholar urine (n = 4),14Mattarucchi E. Baraldi E. Guillou C. Metabolomics applied to urine samples in childhood asthma; differentiation between asthma phenotypes and identification of relevant metabolites.Biomed Chromatogr. 2012; 26: 89-94Crossref PubMed Scopus (79) Google Scholar, 15Saude E.J. Skappak C.D. Regush S. et al.Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy.J Allergy Clin Immunol. 2011; 127: 757-764.e1-6Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 16Loureiro C.C. Duarte I.F. Gomes J. et al.Urinary metabolomic changes as a predictive biomarker of asthma exacerbation.J Allergy Clin Immunol. 2014; 133: 261-263.e265Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 17Loureiro C.C. Oliveira A.S. Santos M. et al.Urinary metabolomic profiling of asthmatics can be related to clinical characteristics.Allergy. 2016; 71: 1362-1365Crossref PubMed Scopus (33) Google Scholar serum (n = 3),18Ried J.S. Baurecht H. Stückler F. et al.Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma.Allergy. 2013; 68: 629-636Crossref PubMed Scopus (63) Google Scholar, 19Chang C. Guo Z-g He B. Yao W-z Metabolic alterations in the sera of Chinese patients with mild persistent asthma: a GC-MS-based metabolomics analysis.Acta Pharmacol Sinica. 2015; 36: 1356-1366Crossref PubMed Scopus (51) Google Scholar, 20Jung J. Kim S.H. Lee H.S. et al.Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis.Clin Exp Allergy. 2013; 43: 425-433Crossref PubMed Scopus (123) Google Scholar and plasma (n = 3)21McGeachie M.J. Dahlin A. Qiu W. et al.The metabolomics of asthma control: a promising link between genetics and disease.Immun Inflamm Dis. 2015; 3: 224-238Crossref PubMed Scopus (62) Google Scholar, 22Fitzpatrick A.M. Park Y. Brown L.A. Jones D.P. Children with severe asthma have unique oxidative stress-associated metabolomic profiles.J Allergy Clin Immunol. 2014; 133: 258-261.e258Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 23Comhair S.A.A. McDunn J. Bennett C. Fettig J. Erzurum S.C. Kalhan S.C. Metabolomic endotype of asthma.J Immunol. 2015; 195: 643-650Crossref PubMed Scopus (92) Google Scholar were identified (Table 1). Twelve studies evaluated children,3Esther C.R. Boysen G. Olsen B.M. et al.Mass spectrometric analysis of biomarkers and dilution markers in exhaled breath condensate reveals elevated purines in asthma and cystic fibrosis.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L987-L993Crossref PubMed Scopus (71) Google Scholar, 4Montuschi P. LC/MS/MS analysis of leukotriene B4 and other eicosanoids in exhaled breath condensate for assessing lung inflammation.J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877: 1272-1280Crossref PubMed Scopus (83) Google Scholar, 5Carraro S. Giordano G. Reniero F. et al.Asthma severity in childhood and metabolomic profiling of breath condensate.Allergy. 2012; 68: 110-117Crossref PubMed Scopus (101) Google Scholar, 6Caldeira M. Perestrelo R. Barros A.S. et al.Allergic asthma exhaled breath metabolome: a challenge for comprehensive two-dimensional gas chromatography.Jf Chromatogr A. 2012; 1254: 87-97Crossref PubMed Scopus (92) Google Scholar, 7van de Kant K.D.G. van Berkel J.J.B.N. Jöbsis Q. et al.Exhaled breath profiling in diagnosing wheezy preschool children.Eur Resp J. 2013; 41: 183-188Crossref PubMed Scopus (49) Google Scholar, 8Gahleitner F. Guallar-Hoyas C. Beardsmore C.S. Pandya H.C. Thomas C.P. Metabolomics pilot study to identify volatile organic compound markers of childhood asthma in exhaled breath.Bioanalysis. 2013; 5: 2239-2247Crossref PubMed Scopus (52) Google Scholar, 9Smolinska A. Klaassen E.M.M. Dallinga J.W. et al.Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children.PLoS ONE. 2014; 9: e95668Crossref PubMed Scopus (103) Google Scholar, 10Carraro S. Rezzi S. Reniero F. et al.Metabolomics applied to exhaled breath condensate in childhood asthma.Am J Respir Crit Care Med. 2007; 175: 986-990Crossref PubMed Scopus (201) Google Scholar, 14Mattarucchi E. Baraldi E. Guillou C. Metabolomics applied to urine samples in childhood asthma; differentiation between asthma phenotypes and identification of relevant metabolites.Biomed Chromatogr. 2012; 26: 89-94Crossref PubMed Scopus (79) Google Scholar, 15Saude E.J. Skappak C.D. Regush S. et al.Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy.J Allergy Clin Immunol. 2011; 127: 757-764.e1-6Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 21McGeachie M.J. Dahlin A. Qiu W. et al.The metabolomics of asthma control: a promising link between genetics and disease.Immun Inflamm Dis. 2015; 3: 224-238Crossref PubMed Scopus (62) Google Scholar, 22Fitzpatrick A.M. Park Y. Brown L.A. Jones D.P. Children with severe asthma have unique oxidative stress-associated metabolomic profiles.J Allergy Clin Immunol. 2014; 133: 258-261.e258Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar eight evaluated adults,12Ibrahim B. Marsden P. Smith J.A. Custovic A. Nilsson M. Fowler S.J. Breath metabolomic profiling by nuclear magnetic resonance spectroscopy in asthma.Allergy. 2013; 68: 1050-1056Crossref PubMed Scopus (43) Google Scholar, 13Motta A. Paris D. D’Amato M. et al.NMR metabolomic analysis of exhaled breath condensate of asthmatic patients at two different temperatures.J Proteome Res. 2014; 13: 6107-6120Crossref PubMed Scopus (47) Google Scholar, 16Loureiro C.C. Duarte I.F. Gomes J. et al.Urinary metabolomic changes as a predictive biomarker of asthma exacerbation.J Allergy Clin Immunol. 2014; 133: 261-263.e265Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 17Loureiro C.C. Oliveira A.S. Santos M. et al.Urinary metabolomic profiling of asthmatics can be related to clinical characteristics.Allergy. 2016; 71: 1362-1365Crossref PubMed Scopus (33) Google Scholar, 18Ried J.S. Baurecht H. Stückler F. et al.Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma.Allergy. 2013; 68: 629-636Crossref PubMed Scopus (63) Google Scholar, 19Chang C. Guo Z-g He B. Yao W-z Metabolic alterations in the sera of Chinese patients with mild persistent asthma: a GC-MS-based metabolomics analysis.Acta Pharmacol Sinica. 2015; 36: 1356-1366Crossref PubMed Scopus (51) Google Scholar, 20Jung J. Kim S.H. Lee H.S. et al.Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis.Clin Exp Allergy. 2013; 43: 425-433Crossref PubMed Scopus (123) Google Scholar, 23Comhair S.A.A. McDunn J. Bennett C. Fettig J. Erzurum S.C. Kalhan S.C. Metabolomic endotype of asthma.J Immunol. 2015; 195: 643-650Crossref PubMed Scopus (92) Google Scholar and one included both.11Sinha A. Krishnan V. Sethi T. et al.Metabolomic signatures in nuclear magnetic resonance spectra of exhaled breath condensate identify asthma.Eur Respir J. 2012; 39: 500-502Crossref PubMed Scopus (27) Google Scholar The majority used MS-based methods; six used NMR.10Carraro S. Rezzi S. Reniero F. et al.Metabolomics applied to exhaled breath condensate in childhood asthma.Am J Respir Crit Care Med. 2007; 175: 986-990Crossref PubMed Scopus (201) Google Scholar, 11Sinha A. Krishnan V. Sethi T. et al.Metabolomic signatures in nuclear magnetic resonance spectra of exhaled breath condensate identify asthma.Eur Respir J. 2012; 39: 500-502Crossref PubMed Scopus (27) Google Scholar, 12Ibrahim B. Marsden P. Smith J.A. Custovic A. Nilsson M. Fowler S.J. Breath metabolomic profiling by nuclear magnetic resonance spectroscopy in asthma.Allergy. 2013; 68: 1050-1056Crossref PubMed Scopus (43) Google Scholar, 13Motta A. Paris D. D’Amato M. et al.NMR metabolomic analysis of exhaled breath condensate of asthmatic patients at two different temperatures.J Proteome Res. 2014; 13: 6107-6120Crossref PubMed Scopus (47) Google Scholar, 15Saude E.J. Skappak C.D. Regush S. et al.Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy.J Allergy Clin Immunol. 2011; 127: 757-764.e1-6Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 20Jung J. Kim S.H. Lee H.S. et al.Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis.Clin Exp Allergy. 2013; 43: 425-433Crossref PubMed Scopus (123) Google Scholar All but four16Loureiro C.C. Duarte I.F. Gomes J. et al.Urinary metabolomic changes as a predictive biomarker of asthma exacerbation.J Allergy Clin Immunol. 2014; 133: 261-263.e265Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 17Loureiro C.C. Oliveira A.S. Santos M. et al.Urinary metabolomic profiling of asthmatics can be related to clinical characteristics.Allergy. 2016; 71: 1362-1365Crossref PubMed Scopus (33) Google Scholar, 21McGeachie M.J. Dahlin A. Qiu W. et al.The metabolomics of asthma control: a promising link between genetics and disease.Immun Inflamm Dis. 2015; 3: 224-238Crossref PubMed Scopus (62) Google Scholar, 22Fitzpatrick A.M. Park Y. Brown L.A. Jones D.P. Children with severe asthma have unique oxidative stress-associated metabolomic profiles.J Allergy Clin Immunol. 2014; 133: 258-261.e258Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar were case-control in design, and the total number of people with asthma ranged from 1016 to 343.9Smolinska A. Klaassen E.M.M. Dallinga J.W. et al.Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children.PLoS ONE. 2014; 9: e95668Crossref PubMed Scopus (103) Google Scholar The primary aim of most studies was to examine the differences between asthma cases and healthy control patients, with a smaller number of studies examining disease severity or phenotypes. One study of recurrent wheeze was also included.7van de Kant K.D.G. van Berkel J.J.B.N. Jöbsis Q. et al.Exhaled breath profiling in diagnosing wheezy preschool children.Eur Resp J. 2013; 41: 183-188Crossref PubMed Scopus (49) Google ScholarTable 1Characteristics of the 21 Asthma Metabolomic Studies Conducted in HumansBiological SampleAge GroupMethodAuthorsNo. of CasesNo. of Control PatientsDiagnostic CriteriaMain AimPopulationMetabolomic ProfilingEBCChildrenLC-MSEsther et al (2009)3Esther C.R. Boysen G. Olsen B.M. et al.Mass spectrometric analysis of biomarkers and dilution markers in exhaled breath condensate reveals elevated purines in asthma and cystic fibrosis.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L987-L993Crossref PubMed Scopus (71) Google Scholar1128PDMetabolomic profile of asthma vs healthyUnited StatesTargeted: adenosine, AMP, and purine biomarkersMontuschi (2009)4Montuschi P. LC/MS/MS analysis of leukotriene B4 and other eicosanoids in exhaled breath condensate for assessing lung inflammation.J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877: 1272-1280Crossref PubMed Scopus (83) Google Scholar20 atopic patients without asthma, 25 steroid-naïve atopic mild patients with asthma, 22 atopic mild-to-moderate patients with asthma15PD; skin-prick testingLeukotriene profile of asthma vs healthyItalyTargeted: leukotrienesCarraro et al (2012)5Carraro S. Giordano G. Reniero F. et al.Asthma severity in childhood and metabolomic profiling of breath condensate.Allergy. 2012; 68: 110-117Crossref PubMed Scopus (101) Google Scholar31 patients with nonsevere asthma, 11 patients with severe asthma15PD; GINA guidelinesDiscrimination of different asthma phenotypesItalyUntargetedGC-MSCaldeira et al (2012)6Caldeira M. Perestrelo R. Barros A.S. et al.Allergic asthma exhaled breath metabolome: a challenge for comprehensive two-dimensional gas chromatography.Jf Chromatogr A. 2012; 1254: 87-97Crossref PubMed Scopus (92) Google Scholar32 atopic patients with asthma27PDMetabolomic profile of asthma vs healthyPortugalTargeted: alkanes, alkenes, aldehydes, and ketonesvan de Kant et al (2013)7van de Kant K.D.G. van Berkel J.J.B.N. Jöbsis Q. et al.Exhaled breath profiling in diagnosing wheezy preschool children.Eur Resp J. 2013; 41: 183-188Crossref PubMed Scopus (49) Google Scholar202 recurrent wheezers50≥ 2 parental-reported episodes of wheeze during lifeMetabolomic profile of recurrent wheeze vs no recurrent wheezeADEM study, NetherlandsTargeted: VOCsGahleitner et al (2013)8Gahleitner F. Guallar-Hoyas C. Beardsmore C.S. Pandya H.C. Thomas C.P. Metabolomics pilot study to identify volatile organic compound markers of childhood asthma in exhaled breath.Bioanalysis. 2013; 5: 2239-2247Crossref PubMed Scopus (52) Google Scholar1112Health questionnaire; respiratory examinationMetabolomic profile of asthma vs healthyUnited KingdomTargeted: VOCsEBCChildrenGC-MSSmolinska et al (2014)9Smolinska A. Klaassen E.M.M. Dallinga J.W. et al.Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children.PLoS ONE. 2014; 9: e95668Crossref PubMed Scopus (103) Google Scholar343185 healthy and 546 transient wheezersPDMetabolomic profile of asthma vs transient wheezeADEM study, NetherlandsTargeted: VOCsNMRCarraro et al (2007)10Carraro S. Rezzi S. Reniero F. et al.Metabolomics applied to exhaled breath condensate in childhood asthma.Am J Respir Crit Care Med. 2007; 175: 986-990Crossref PubMed Scopus (201) Google Scholar17 patients with persistent asthma treated with inhaled corticosteroids, 8 corticosteroid-naïve intermittent patients with asthma11PD; GINA guidelinesMetabolomic profile of asthma vs healthyItalyUntargetedAll agesNMRSinha et al (2012)11Sinha A. Krishnan V. Sethi T. et al.Metabolomic signatures in nuclear magnetic resonance spectra of exhaled breath condensate identify asthma.Eur Respir J. 2012; 39: 500-502Crossref PubMed Scopus (27) Google Scholar7 adults with asthma, 58 children with asthma10PDMetabolomic profile of asthma vs healthyIndiaUntargetedAdultsNMRIbrahim et al (2013)12Ibrahim B. Marsden P. Smith J.A. Custovic A. Nilsson M. Fowler S.J. Breath metabolomic profiling by nuclear magnetic resonance spectroscopy in asthma.Allergy. 2013; 68: 1050-1056Crossref PubMed Scopus (43) Google Scholar8235Reported symptoms; treatmentMetabolomic profile of asthma vs healthyASMAL study, United KingdomUntargetedMotta et al (2014)13Motta A. Paris D. D’Amato M. et al.NMR metabolomic analysis of exhaled breath condensate of asthmatic patients at two different temperatures.J Proteome Res. 2014; 13: 6107-6120Crossref PubMed Scopus (47) Google Scholar35 patients with mild asthma35PD; GINA guidelines; DSSMetabolomic profile of asthma vs healthyItalyTargeted and untargetedUrineChildrenLC-MSMattarucchi et al (2012)14Mattarucchi E. Baraldi E. Guillou C. Metabolomics applied to urine samples in childhood asthma; differentiation between asthma phenotypes and identification of relevant metabolites.Biomed Chromatogr. 2012; 26: 89-94Crossref PubMed Scopus (79) Google Scholar4112PD; GINA guidelinesMetabolomic profile of asthma vs healthyItalyUntargetedNMRSaude et al (2011)15Saude E.J. Skappak C.D. Regush S. et al.Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy.J Allergy Clin Immunol. 2011; 127: 757-764.e1-6Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar73 patients with stable asthma, 20 patients with unstable asthma42PDMetabolomic profile of asthma vs healthy, and of different asthma endotypesCanadaTargetedAdultsGC-MSLoureiro et al (2014)16Loureiro C.C. Duarte I.F. Gomes J. et al.Urinary metabolomic changes as a predictive biomarker of asthma exacerbation.J Allergy Clin Immunol. 2014; 133: 261-263.e265Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar7 patients with allergic asthma, 3 patients with nonallergic asthmaNAPDMetabolomic changes with asthma exacerbationPortugalTargeted: aldehydes and alkanes and central metabolitesLoureiro et al (2016)17Loureiro C.C. Oliveira A.S. Santos M. et al.Urinary metabolomic profiling of asthmatics can be related to clinical characteristics.Allergy. 2016; 71: 1362-1365Crossref PubMed Scopus (33) Google Scholar57NAPDMetabolomic profile of asthma severityPortugalTargeted: aliphatic aldehydes and alkanesSerumAdultsGC-MSRied et al (2013)18Ried J.S. Baurecht H. Stückler F. et al.Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma.Allergy. 2013; 68: 629-636Crossref PubMed Scopus (63) Google Scholar1472,778Self-report and medical examinationMetabolomic profile of asthma vs healthyKORA Study, GermanyTargetedChang et al (2015)19Chang C. Guo Z-g He B. Yao W-z Metabolic alterations in the sera of Chinese patients with mild persistent asthma: a GC-MS-based metabolomics analysis.Acta Pharmacol Sinica. 2015; 36: 1356-1366Crossref PubMed Scopus (51) Google Scholar17 patients with mild persistent asthma17PD; GINA guidelinesMetabolomic profile of asthma vs healthyChinaUntargetedPlasmaChildrenLC-MSMcGeachie et al (2015)21McGeachie M.J. Dahlin A. Qiu W. et al.The metabolomics of asthma control: a promising link between genetics and disease.Immun Inflamm Dis. 2015; 3: 224-238Crossref PubMed Scopus (62) Google Scholar20NAPDIdentification of predictors of asthma controlCARE Network cohort, United StatesTargeted lipidomicsFitzpatrick et al (2014)22Fitzpatrick A.M. Park Y. Brown L.A. Jones D.P. Children with severe asthma have unique oxidative stress-associated metabolomic profiles.J Allergy Clin Immunol. 2014; 133: 258-261.e258Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar22 patients with mild/moderate asthma, 35 patients with severe asthmaNASpirometryMetabolomic profile of mild-moderate vs severe asthmaUnited StatesUntargetedPlasmaAdultsNMRJung et al (2013)20Jung J. Kim S.H. Lee H.S. et al.Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis.Clin Exp Allergy. 2013; 43: 425-433Crossref PubMed Scopus (123) Google Scholar3926PDMetabolomic profile of asthma vs healthySouth KoreaUntargeted and targetedMSComhair et al (2015)23Comhair S.A.A. McDunn J. Bennett C. Fettig J. Erzurum S.C. Kalhan S.C. Metabolomic endotype of asthma.J Immunol. 2015; 195: 643-650Crossref PubMed Scopus (92) Google Scholar2010ATS Workshop on Refractory Asthma GuidelinesMetabolomic profile of asthma vs healthy, and of different asthma endotypesUnited StatesUntargeted and targetedADEM = Asthma Detection and Monitoring Study; AMP = adenosine monophosphate; ASMAL = Assessment of Manchester Asthmatics Longitudinally Study; ATS = American Thoracic Society; CARE = Childhood Asthma Research and Education Study; DSS = disease severity score; EBC = exhaled breath condensate; GC-MS = gas chromatography–mass spectrometry; GINA = Global Initiative for Asthma; KORA = Cooperative Health Research in the Region Augsburg Study; LC-MS = liquid chromatography–mass spectrometry; NA = not applicable; NMR = nuclear magnetic resonance spectroscopy; PD = physician diagnosed; VOC = volatile organic compounds. Open table in a new tab ADEM = Asthma Detection and Monitoring Study; AMP = adenosine monophosphate; ASMAL = Assessment of Manchester Asthmatics Longitudinally Study; ATS = American Thoracic Society; CARE = Childhood Asthma Research and Education Study; DSS = disease severity score; EBC = exhaled breath condensate; GC-MS = gas chromatography–mass spectrometry; GINA = Global Initiative for Asthma; KORA = Cooperative Health Research in the Region Augsburg Study; LC-MS = liquid chromatography–mass spectrometry; NA = not applicable; NMR = nuclear magnetic resonance spectroscopy; PD = physician diagnosed; VOC = volatile organic compounds. All 21 studies reported significant findings and concluded that metabolomic profiles in EBC, urine, and blood could distinguish asthma and asthma phenotypes (Table 2). The utility of such profiles is twofold: (1) the identification of metabolite biomarkers for asthma and (2) the improved understanding of the pathophysiology of asthma. The majority of the studies focused on the former by building metabolomic signatures that were subsequently assessed for discriminative ability. These signatures were created by identifying associated metabolites from the total number measured, which ranged by study from two4Montuschi P. LC/MS/MS analysis of leukotriene B4 and other eicosanoids in exhaled breath condensate for assessing lung inflammation.J Chromatogr B Analyt Technol Biomed Life Sci. 2009; 877: 1272-1280Crossref PubMed Scopus (83) Google Scholar to almost 9,000.14Mattarucchi E. Baraldi E. Guillou C. Metabolomics applied to urine samples in childhood asthma; differentiation between asthma phenotypes and identification of relevant metabolites.Biomed Chromatogr. 2012; 26: 89-94Crossref PubMed Scopus (79) Google Scholar However, the interrogation of the metabolites and pathways composing these signatures also provided important insights into asthma pathophysiology. In this review, we compare the metabolomic signatures and the biological information they impart. In particular, we focus on how different methods and techniques may affect metabolomic signatures, and the implications thereof, as the metabolomics field begins to shift toward clinical translation.Table 2Summary of Results for the 21 Asthma Metabolomic Studies in HumansAuthorsNo. of MetabolitesResultsSignificant MetabolitesImplicated PathwaysConclusionsValidationEsther et al (2009)3Esther C.R. Boysen G. Olsen B.M. et al.Mass spectrometric analysis of biomarkers and dilution markers in exhaled breath condensate reveals elevated purines in asthma and cystic fibrosis.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L987-L993Crossref PubMed Scopus (71) Google Scholar6Adenosine-to-urea ratio elevated in asthma (median, 1.5) vs control (median, 0.4) (P < .05)AdenosineNeutrophilic airway inflammationEBC adenosine-to-urea ratio is a potential noninvasive biomarker of airways diseaseNoMontuschi et al (2009)4Montuschi P. LC/MS/MS analysis of leukotriene B4 and other eicosanoids in exhaled breath condensate for assessing lung inflamm
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