Metabolomics in Childhood Asthma

doi:10.12114/j.issn.1007-9572.2021.01.043

Abstract

Abstract:

As the most common chronic disease in children, bronchial asthma is highly underdiagnosed with complex pathogenesis. By qualitative and quantitative analyses of changes in low molecular weight molecules or metabolites in biological samples, metabolomics provides a new method to search biomarkers and pathogenesis. We reviewed the application of metabolomics in childhood asthma, which attempts to find the potential biomarkers and pathogenesis of childhood asthma by analyzing the samples of blood, exhaled breath, feces and urine of asthmatic children and healthy children using targeted or untargeted research approaches, providing help for clinical diagnosis and treatment of childhood asthma. Considerable progress has been made in metabolomics in childhood asthma, but due to factors such as individual differences, sample collection, data analysis, and genomic heterogeneity, metabolomics analysis of childhood asthma is still facing challenges.

Key words: Asthma, Metabolomics, Child, Review

摘要：

支气管哮喘是儿童最常见的慢性疾病，其漏诊率高，发病机制复杂。代谢组学通过定性定量分析生物样品的低分子量分子或代谢产物的变化，为寻找生物标志物和发病机制提供了一种新途径。本文综述了代谢组学技术运用于儿童哮喘的研究，运用靶向或非靶向研究策略，以哮喘儿童及健康儿童的血液、呼出气、粪便及尿液为研究对象，试图寻找儿童哮喘的潜在生物标志物及发病机制，为儿童哮喘的诊断及治疗提供帮助。近年来代谢组学在儿童哮喘方面取得了不小的进展，但受限于个体差异、样品采集、数据分析及组学异质性等因素，代谢组学在儿童哮喘的解释方面仍面临挑战。

关键词: 哮喘, 代谢组学, 儿童, 综述

CLC Number:

R562.25

WU Ruijian, HUANG Yuge, LUO Lianxiang.

Metabolomics in Childhood Asthma [J]. Chinese General Practice, 2022, 25(08): 1014-1020.

吴锐剑,黄宇戈,罗连响. 代谢组学在儿童哮喘中的应用进展[J]. 中国全科医学, 2022, 25(08): 1014-1020. DOI: 10.12114/j.issn.1007-9572.2021.01.043.

Figures/Tables 3

References 90

[1]	BATEMAN E D, HURD S S, BARNES P J，et al. Global strategy for asthma management and prevention：GINA executive summary[J]. Eur Respir J，2008，31(1):143-178. DOI：10.1183/09031936.00138707.
[2]	ASHER I, PEARCE N. Global burden of asthma among children[J]. Int J Tuberc Lung Dis，2014，18(11):1269-1278. DOI：10.5588/ijtld.14.0170.
[3]	BEASLEY R, SEMPRINI A, MITCHELL E A. Risk factors for asthma：is prevention possible?[J]. Lancet，2015，386(9998):1075-1085. DOI：10.1016/s0140-6736(15)00156-7.
[4]	全国儿科哮喘协作组，中国疾病预防控制中心环境与健康相关产品安全所. 第三次中国城市儿童哮喘流行病学调查[J]. 中华儿科杂志，2013，51(10):729-735. DOI：10.3760/cma.j.issn.0578-1310.2013.10.003.
[5]	JOHNSON C H, PATTERSON A D, IDLE J R，et al. Xenobiotic metabolomics：major impact on the metabolome[J]. Annu Rev Pharmacol Toxicol，2012，52:37-56. DOI：10.1146/annurev-pharmtox-010611-134748.
[6]	XIAO M T, YANG H, XU W，et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors[J]. Genes Dev，2012，26(12):1326-1338. DOI：10.1101/gad.191056.112.
[7]	YANG M, SU H Z, SOGA T，et al. Prolyl hydroxylase domain enzymes：important regulators of cancer metabolism[J]. Hypoxia （Auckl），2014，2:127-142. DOI：10.2147/HP.S47968.
[8]	MORRIS C R, POLJAKOVIC M, LAVRISHA L，et al. Decreased arginine bioavailability and increased serum arginase activity in asthma[J]. Am J Respir Crit Care Med，2004，170(2):148-153. DOI：10.1164/rccm.200309-1304OC.
[9]	MATYSIAK J, KLUPCZYNSKA A, PACKI K，et al. Alterations in serum-free amino acid profiles in childhood asthma[J]. Int J Environ Res Public Health，2020，17(13):E4758. DOI：10.3390/ijerph17134758.
[10]	MORRIS C R. Arginine and asthma[J]. Nestle Nutr Inst Work Ser，2013，77:1-15. DOI：10.1159/000351365.
[11]	ZHENG H, YDE C C, ARNBERG K，et al. NMR-based metabolomic profiling of overweight adolescents：an elucidation of the effects of inter-/intraindividual differences，gender，and pubertal development[J]. Biomed Res Int，2014，2014:537157. DOI：10.1155/2014/537157.
[12]	HERTEL J, FRIEDRICH N, WITTFELD K，et al. Measuring biological age via metabonomics：the metabolic age score[J]. Proteome Res，2016，15(2):400-410. DOI：10.1021/acs.jproteome.5b00561.
[13]	PITE H, AGUIAR L, MORELLO J，et al. Metabolic dysfunction and asthma：current perspectives[J]. J Asthma Allergy，2020，13:237-247. DOI：10.2147/JAA.S208823.
[14]	BECKMANN M, LLOYD A J, HALDAR S，et al. Dietary exposure biomarker-lead discovery based on metabolomics analysis of urine samples[J]. Proc Nutr Soc，2013，72(3):352-361. DOI：10.1017/S0029665113001237.
[15]	GRIFFIN J L, BOLLARD M E. Metabonomics：its potential as a tool in toxicology for safety assessment and data integration[J]. Curr Drug Metab，2004，5(5):389-398. DOI：10.2174/1389200043335432.
[16]	FIEHN O. Metabolomics——the link between genotypes and phenotypes[J]. Plant Mol Biol，2002，48(1/2):155-171.
[17]	ROBERTS L D, SOUZA A L, GERSZTEN R E，et al. Targeted metabolomics[J]. Curr Protoc Mol Biol，2012，Chapter 30：Unit30.2.1-30.224. DOI：10.1002/0471142727.mb3002s98.
[18]	ALONSO A, MARSAL S, JULIÀ A. Analytical methods in untargeted metabolomics：state of the art in 2015[J]. Front Bioeng Biotechnol，2015，3:23. DOI：10.3389/fbioe.2015.00023.
[19]	MARKLEY J L, BRÜSCHWEILER R, EDISON A S，et al. The future of NMR-based metabolomics[J]. Curr Opin Biotechnol，2017，43:34-40. DOI：10.1016/j.copbio.2016.08.001.
[20]	DRAPER J, ENOT D P, PARKER D，et al. Metabolite signal identification in accurate mass metabolomics data with MZedDB，an interactive m/z annotation tool utilising predicted ionisation behaviour 'rules'[J]. BMC Bioinformatics，2009，10:227. DOI：10.1186/1471-2105-10-227.
[21]	VEENSTRA T D. Metabolomics：the final frontier?[J]. Genome Med，2012，4(4):40. DOI：10.1186/gm339.
[22]	THEODORIDIS G, GIKA H G, WILSON I D. Mass spectrometry-based holistic analytical approaches for metabolite profiling in systems biology studies[J]. Mass Spectrom Rev，2011，30(5):884-906. DOI：10.1002/mas.20306.
[23]	WISHART D S. Emerging applications of metabolomics in drug discovery and precision medicine[J]. Nat Rev Drug Discov，2016，15(7):473-484. DOI：10.1038/nrd.2016.32.
[24]	PSYCHOGIOS N, HAU D D, PENG J，et al. The human serum metabolome[J]. PLoS One，2011，6(2):e16957. DOI：10.1371/journal.pone.0016957.
[25]	ZHANG A H, SUN H, WANG X J. Serum metabolomics as a novel diagnostic approach for disease：a systematic review[J]. Anal Bioanal Chem，2012，404(4):1239-1245. DOI：10.1007/s00216-012-6117-1.
[26]	BARRI T, DRAGSTED L O. UPLC-ESI-QTOF/MS and multivariate data analysis for blood plasma and serum metabolomics：effect of experimental artefacts and anticoagulant[J]. Anal Chim Acta，2013，768:118-128. DOI：10.1016/j.aca.2013.01.015.
[27]	KUBÁN P, FORET F. Exhaled breath condensate：determination of non-volatile compounds and their potential for clinical diagnosis and monitoring. A review[J]. Anal Chim Acta，2013，805:1-18. DOI：10.1016/j.aca.2013.07.049.
[28]	AHMADZAI H, HUANG S Y, HETTIARACHCHI R，et al. Exhaled breath condensate：a comprehensive update[J]. Clin Chem Lab Med，2013，51(7):1343-1361. DOI：10.1515/cclm-2012-0593.
[29]	GRATTON J, PHETCHARABURANIN J, MULLISH B H，et al. Optimized sample handling strategy for metabolic profiling of human feces[J]. Anal Chem，2016，88(9):4661-4668. DOI：10.1021/acs.analchem.5b04159.
[30]	WU J Q, GAO Y H. Physiological conditions can be reflected in human urine proteome and metabolome[J]. Expert Rev Proteomics，2015，12(6):623-636. DOI：10.1586/14789450.2015.1094380.
[31]	EMWAS A H, ROY R, MCKAY R T，et al. Recommendations and standardization of biomarker quantification using NMR-based metabolomics with particular focus on urinary analysis[J]. J Proteome Res，2016，15(2):360-373. DOI：10.1021/acs.jproteome.5b00885.
[32]	WALSH M C, BRENNAN L, MALTHOUSE J P，et al. Effect of acute dietary standardization on the urinary，plasma，and salivary metabolomic profiles of healthy humans[J]. Am J Clin Nutr，2006，84(3):531-539. DOI：10.1093/ajcn/84.3.531.
[33]	YU Z H, KASTENMÜLLER G, HE Y，et al. Differences between human plasma and serum metabolite profiles[J]. PLoS One，2011，6(7):e21230. DOI：10.1371/journal.pone.0021230.
[34]	BREIER M, WAHL S, PREHN C，et al. Targeted metabolomics identifies reliable and stable metabolites in human serum and plasma samples[J]. PLoS One，2014，9(2):e89728. DOI：10.1371/journal.pone.0089728.
[35]	CHECKLEY W, DEZA M P, KLAWITTER J，et al. Identifying biomarkers for asthma diagnosis using targeted metabolomics approaches[J]. Respir Med，2016，121:59-66. DOI：10.1016/j.rmed.2016.10.011.
[36]	REYNAERT N L. Glutathione biochemistry in asthma[J]. Biochim Biophys Acta，2011，1810(11):1045-1051. DOI：10.1016/j.bbagen.2011.01.010.
[37]	FITZPATRICK A M, PARK Y, BROWN L A，et al. Children with severe asthma have unique oxidative stress-associated metabolomic profiles[J]. J Allergy Clin Immunol，2014，133(1):258-261.e1-8. DOI：10.1016/j.jaci.2013.10.012.
[38]	FITZPATRICK A M, TEAGUE W G, BURWELL L，et al. Glutathione oxidation is associated with airway macrophage functional impairment in children with severe asthma[J]. Pediatr Res，2011，69(2):154-159. DOI：10.1203/PDR.0b013e3182026370.
[39]	FITZPATRICK A M, TEAGUE W G, HOLGUIN F，et al. Airway glutathione homeostasis is altered in children with severe asthma：evidence for oxidant stress[J]. J Allergy Clin Immunol，2009，123(1):146-152.e8. DOI：10.1016/j.jaci.2008.10.047.
[40]	FITZPATRICK A M, STEPHENSON S T, HADLEY G R，et al. Thiol redox disturbances in children with severe asthma are associated with posttranslational modification of the transcription factor nuclear factor （erythroid-derived 2）-like 2[J]. J Allergy Clin Immunol，2011，127(6):1604-1611. DOI：10.1016/j.jaci.2011.03.031.
[41]	COMHAIR S A, RICCI K S, ARROLIGA M，et al. Correlation of systemic superoxide dismutase deficiency to airflow obstruction in asthma[J]. Am J Respir Crit Care Med，2005，172(3):306-313. DOI：10.1164/rccm.200502-180OC.
[42]	KHATRI S B, PEABODY J, BURWELL L，et al. Systemic antioxidants and lung function in asthmatics during high ozone season：a closer look at albumin，glutathione，and associations with lung function[J]. Clin Transl Sci，2014，7(4):314-318. DOI：10.1111/cts.12152.
[43]	NADEEM A, CHHABRA S K, MASOOD A，et al. Increased oxidative stress and altered levels of antioxidants in asthma[J]. J Allergy Clin Immunol，2003，111(1):72-78. DOI：10.1067/mai.2003.17.
[44]	NEERINCX A H, VIJVERBERG S J H, BOS L D J，et al. Breathomics from exhaled volatile organic compounds in pediatric asthma[J]. Pediatr Pulmonol，2017，52(12):1616-1627. DOI：10.1002/ppul.23785.
[45]	ROBROEKS C M, VAN BERKEL J J, JÖBSIS Q，et al. Exhaled volatile organic compounds predict exacerbations of childhood asthma in a 1-year prospective study[J]. Eur Respir J，2013，42(1):98-106. DOI：10.1183/09031936.00010712.
[46]	VAN VLIET D, SMOLINSKA A, JÖBSIS Q，et al. Can exhaled volatile organic compounds predict asthma exacerbations in children?[J]. J Breath Res，2017，11(1):016016. DOI：10.1088/1752-7163/aa5a8b.
[47]	CORRADI M, FOLESANI G, ANDREOLI R，et al. Aldehydes and glutathione in exhaled breath condensate of children with asthma exacerbation[J]. Am J Respir Crit Care Med，2003，167(3):395-399. DOI：10.1164/rccm.200206-507OC.
[48]	PRYOR W A, GODBER S S. Noninvasive measures of oxidative stress status in humans[J]. Free Radic Biol Med，1991，10(3/4):177-184. DOI：10.1016/0891-5849(91)90073-c.
[49]	AMANN A, COSTELLO BDE L, MIEKISCH W，et al. The human volatilome：volatile organic compounds （VOCs） in exhaled breath，skin emanations，urine，feces and saliva[J]. J Breath Res，2014，8(3):034001. DOI：10.1088/1752-7155/8/3/034001.
[50]	BRINKMAN P, VAN DE POL M A, GERRITSEN M G，et al. Exhaled breath profiles in the monitoring of loss of control and clinical recovery in asthma[J]. Clin Exp Allergy，2017，47(9):1159-1169. DOI：10.1111/cea.12965.
[51]	VAN DER SCHEE M P, PALMAY R, COWAN J O，et al. Predicting steroid responsiveness in patients with asthma using exhaled breath profiling[J]. Clin Exp Allergy，2013，43(11):1217-1225. DOI：10.1111/cea.12147.
[52]	LAMICHHANE S, SEN P, DICKENS A M，et al. Gut metabolome meets microbiome：a methodological perspective to understand the relationship between host and microbe[J]. Methods，2018，149:3-12. DOI：10.1016/j.ymeth.2018.04.029.
[53]	HUANG Y J, BOUSHEY H A. The microbiome in asthma[J]. J Allergy Clin Immunol，2015，135(1):25-30. DOI：10.1016/j.jaci.2014.11.011.
[54]	CHIU C Y, CHENG M L, CHIANG M H，et al. Gut microbial-derived butyrate is inversely associated with IgE responses to allergens in childhood asthma[J]. Pediatr Allergy Immunol，2019，30(7):689-697. DOI：10.1111/pai.13096.
[55]	THEILER A, BÄRNTHALER T, PLATZER W，et al. Butyrate ameliorates allergic airway inflammation by limiting eosinophil trafficking and survival[J]. J Allergy Clin Immunol，2019，144(3):764-776. DOI：10.1016/j.jaci.2019.05.002.
[56]	RODUIT C, FREI R, FERSTL R，et al. High levels of butyrate and propionate in early life are associated with protection against atopy[J]. Allergy，2019，74(4):799-809. DOI：10.1111/all.13660.
[57]	DONOHOE D R, GARGE N, ZHANG X X，et al. The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon[J]. Cell Metab，2011，13(5):517-526. DOI：10.1016/j.cmet.2011.02.018.
[58]	THIO C L, CHI P Y, LAI A C，et al. Regulation of type 2 innate lymphoid cell-dependent airway hyperreactivity by butyrate[J]. J Allergy Clin Immunol，2018，142(6):1867-1883.e12. DOI：10.1016/j.jaci.2018.02.032.
[59]	THEILER A, BÄRNTHALER T, PLATZER W，et al. Butyrate ameliorates allergic airway inflammation by limiting eosinophil trafficking and survival[J]. J Allergy Clin Immunol，2019，144(3):764-776. DOI：10.1016/j.jaci.2019.05.002.
[60]	LIAO H Y, TAO L, ZHAO J，et al. Clostridium butyricum in combination with specific immunotherapy converts antigen-specific B cells to regulatory B cells in asthmatic patients[J]. Sci Rep，2016，6:20481. DOI：10.1038/srep20481.
[61]	TEDDER T F. B10 cells：a functionally defined regulatory B cell subset[J]. J Immunol，2015，194(4):1395-1401. DOI：10.4049/jimmunol.1401329.
[62]	KOH A, DE VADDER F, KOVATCHEVA-DATCHARY P，et al. From dietary fiber to host physiology：short-chain fatty acids as key bacterial metabolites[J]. Cell，2016，165(6):1332-1345. DOI：10.1016/j.cell.2016.05.041.
[63]	KIM M, QIE Y Q, PARK J，et al. Gut microbial metabolites fuel host antibody responses[J]. Cell Host Microbe，2016，20(2):202-214. DOI：10.1016/j.chom.2016.07.001.
[64]	TURPEINEN A M, YLÖNEN N, VON WILLEBRAND E，et al. Immunological and metabolic effects of Cis-9，trans-11-conjugated linoleic acid in subjects with birch pollen allergy[J]. Br J Nutr，2008，100(1):112-119. DOI：10.1017/S0007114507886326.
[65]	LEVAN S R, STAMNES K A, LIN D L，et al. Elevated faecal 12，13-diHOME concentration in neonates at high risk for asthma is produced by gut bacteria and impedes immune tolerance[J]. Nat Microbiol，2019，4(11):1851-1861. DOI：10.1038/s41564-019-0498-2.
[66]	YAMAZAKI K, SUZUKI K, NAKAMURA A，et al. Ursodeoxycholic acid inhibits eosinophil degranulation in patients with primary biliary cirrhosis[J]. Hepatology，1999，30(1):71-78. DOI：10.1002/hep.510300121.
[67]	SHAIK F B, PANATI K, NARASIMHA V R，et al. Chenodeoxycholic acid attenuates ovalbumin-induced airway inflammation in murine model of asthma by inhibiting the T（H）2 cytokines[J]. Biochem Biophys Res Commun，2015，463(4):600-605. DOI：10.1016/j.bbrc.2015.05.104.
[68]	MUNN D H, SHAFIZADEH E, ATTWOOD J T，et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism[J]. J Exp Med，1999，189(9):1363-1372. DOI：10.1084/jem.189.9.1363.
[69]	FALLARINO F, GROHMANN U, YOU S，et al. Tryptophan catabolism generates autoimmune-preventive regulatory T cells[J]. Transpl Immunol，2006，17(1):58-60. DOI：10.1016/j.trim.2006.09.017.
[70]	CHENG Y T, JIN U H, ALLRED C D，et al. Aryl hydrocarbon receptor activity of tryptophan metabolites in young adult mouse colonocytes[J]. Drug Metab Dispos，2015，43(10):1536-1543. DOI：10.1124/dmd.115.063677.
[71]	ETTMAYER P, MAYER P, KALTHOFF F，et al. A novel low molecular weight inhibitor of dendritic cells and B cells blocks allergic inflammation[J]. Am J Respir Crit Care Med，2006，173(6):599-606. DOI：10.1164/rccm.200503-468OC.
[72]	QUINTANA F J, BASSO A S, IGLESIAS A H，et al. Control of T（reg） and T（H）17 cell differentiation by the aryl hydrocarbon receptor[J]. Nature，2008，453(7191):65-71. DOI：10.1038/nature06880.
[73]	ALLENDE M L, DREIER J L, MANDALA S，et al. Expression of the sphingosine 1-phosphate receptor，S1P1，on T-cells controls thymic emigration[J]. J Biol Chem，2004，279(15):15396-15401. DOI：10.1074/jbc.M314291200.
[74]	WORGALL T S, VEERAPPAN A, SUNG B，et al. Impaired sphingolipid synthesis in the respiratory tract induces airway hyperreactivity[J]. Sci Transl Med，2013，5(186):186ra67. DOI：10.1126/scitranslmed.3005765.
[75]	KHAMIS M M, ADAMKO D J, EL-ANEED A. Mass spectrometric based approaches in urine metabolomics and biomarker discovery[J]. Mass Spectrom Rev，2017，36(2):115-134. DOI：10.1002/mas.21455.
[76]	SAUDE E J, SKAPPAK C D, REGUSH S，et al. Metabolomic profiling of asthma：diagnostic utility of urine nuclear magnetic resonance spectroscopy[J]. J Allergy Clin Immunol，2011，127(3):757-764.e1-6. DOI：10.1016/j.jaci.2010.12.1077.
[77]	CHAWES B L, GIORDANO G, PIRILLO P，et al. Neonatal urine metabolic profiling and development of childhood asthma[J]. Metabolites，2019，9(9):E185. DOI：10.3390/metabo9090185.
[78]	CHIU C Y, LIN G, CHENG M L，et al. Longitudinal urinary metabolomic profiling reveals metabolites for asthma development in early childhood[J]. Pediatr Allergy Immunol，2018，29(5):496-503. DOI：10.1111/pai.12909.
[79]	TURI K N, ROMICK-ROSENDALE L, GEBRETSADIK T，et al. Using urine metabolomics to understand the pathogenesis of infant respiratory syncytial virus （RSV） infection and its role in childhood wheezing[J]. Metabolomics，2018，14(10):135. DOI：10.1007/s11306-018-1431-z.
[80]	ADAMKO D J, NAIR P, MAYERS I，et al. Metabolomic profiling of asthma and chronic obstructive pulmonary disease：a pilot study differentiating diseases[J]. J Allergy Clin Immunol，2015，136(3):571-580.e3. DOI：10.1016/j.jaci.2015.05.022.
[81]	BÖGER R H. Asymmetric dimethylarginine，an endogenous inhibitor of nitric oxide synthase，explains the "L-arginine paradox" and Acts as a novel cardiovascular risk factor[J]. J Nutr，2004，134(10 ):2842S-2847S;discussion2853S. DOI：10.1093/jn/134.10.2842S.
[82]	KOSKELA H O, SALONEN P H, NISKANEN L. Hyperglycaemia during exacerbations of asthma and chronic obstructive pulmonary disease[J]. Clin Respir J，2013，7(4):382-389. DOI：10.1111/crj.12020.
[83]	BEKIER E, WYCZÓLKOWSKA J, SZYC H，et al. The inhibitory effect of nicotinamide on asthma-like symptoms and eosinophilia in Guinea pigs，anaphylactic mast cell degranulation in mice，and histamine release from rat isolated peritoneal mast cells by compound 48-80[J]. Int Arch Allergy Appl Immunol，1974，47(5):737-748. DOI：10.1159/000231265.
[84]	KELLY R S, DAHLIN A, MCGEACHIE M J，et al. Asthma metabolomics and the potential for integrative omics in research and the clinic[J]. Chest，2017，151(2):262-277. DOI：10.1016/j.chest.2016.10.008.
[85]	GISKEØDEGÅRD G F, DAVIES S K, REVELL V L，et al. Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation[J]. Sci Rep，2015，5:14843. DOI：10.1038/srep14843.
[86]	ANWAR M A, VORKAS P A, LI J V，et al. Optimization of metabolite extraction of human vein tissue for ultra performance liquid chromatography-mass spectrometry and nuclear magnetic resonance-based untargeted metabolic profiling[J]. Analyst，2015，140(22):7586-7597. DOI：10.1039/c5an01041a.
[87]	YIN P Y, LEHMANN R, XU G W. Effects of pre-analytical processes on blood samples used in metabolomics studies[J]. Anal Bioanal Chem，2015，407(17):4879-4892. DOI：10.1007/s00216-015-8565-x.
[88]	NAZ S, GARCÍA A, BARBAS C. Multiplatform analytical methodology for metabolic fingerprinting of lung tissue[J]. Anal Chem，2013，85(22):10941-10948. DOI：10.1021/ac402411n.
[89]	HASIN Y, SELDIN M, LUSIS A. Multi-omics approaches to disease[J]. Genome Biol，2017，18(1):83. DOI：10.1186/s13059-017-1215-1.
[90]	HAAS R, ZELEZNIAK A, IACOVACCI J，et al. Designing and interpreting 'multi-omic' experiments that may change our understanding of biology[J]. Curr Opin Syst Biol，2017，6:37-45. DOI：10.1016/j.coisb.2017.08.009.

生物样本	生理特征	优点	缺点	注意事项
血浆和血清	由不同组织根据不同的生理需要或压力而分泌、排泄或丢弃的所有分子组合^[24]	提供瞬时代谢状态的综合视图，适用于大多数分析技术和平台^[25]	有创，对气道生理缺乏特异性	血浆收集首选肝素，不建议使用柠檬酸盐，血清收集建议使用塑料或玻璃制成的普通无添加剂收集管^[26]
呼出气	组成相对简单，同时包含挥发性和非挥发性分子	无创且易于获得，可重复，与气道生理有关，适合分析挥发性和非挥发性代谢物^[27]	儿童人群难以采集样本，受运动、呼吸方式和速率、鼻污染、环境温度和湿度影响^[28]	需要对样本进行预浓缩，需要高素质的技术人员和昂贵的设备
粪便	粪便由消化物质的残留物或代谢物、肠道菌群代谢物和人体代谢物组成	无创，易于收藏，可重复收集，代谢物代表宿主和肠道菌群之前的相互作用	与呼吸系统无直接关系，难以区分营养、内源和微生物群代谢产物	粪便样品具有高度的不均匀性，取样后在冰上将样品均匀化^[29]
尿液	成分稳定，相对复杂程度不及血清和血浆，反映近端组织和血液灌注远处器官的生理和病理变化^[30]	无创，方便儿科收集，可重复收集，成分丰富^[31]	缺乏与气道生理的接近性和特异性，受饮食摄入影响^[32]	建议禁食样本，建议晨起中段尿^[31]

生物样本	生理特征	优点	缺点	注意事项
血浆和血清	由不同组织根据不同的生理需要或压力而分泌、排泄或丢弃的所有分子组合^[24]	提供瞬时代谢状态的综合视图，适用于大多数分析技术和平台^[25]	有创，对气道生理缺乏特异性	血浆收集首选肝素，不建议使用柠檬酸盐，血清收集建议使用塑料或玻璃制成的普通无添加剂收集管^[26]
呼出气	组成相对简单，同时包含挥发性和非挥发性分子	无创且易于获得，可重复，与气道生理有关，适合分析挥发性和非挥发性代谢物^[27]	儿童人群难以采集样本，受运动、呼吸方式和速率、鼻污染、环境温度和湿度影响^[28]	需要对样本进行预浓缩，需要高素质的技术人员和昂贵的设备
粪便	粪便由消化物质的残留物或代谢物、肠道菌群代谢物和人体代谢物组成	无创，易于收藏，可重复收集，代谢物代表宿主和肠道菌群之前的相互作用	与呼吸系统无直接关系，难以区分营养、内源和微生物群代谢产物	粪便样品具有高度的不均匀性，取样后在冰上将样品均匀化^[29]
尿液	成分稳定，相对复杂程度不及血清和血浆，反映近端组织和血液灌注远处器官的生理和病理变化^[30]	无创，方便儿科收集，可重复收集，成分丰富^[31]	缺乏与气道生理的接近性和特异性，受饮食摄入影响^[32]	建议禁食样本，建议晨起中段尿^[31]

代谢物	机制
短链脂肪酸：乙酸盐、丙酸盐、丁酸盐	直接激活G蛋白偶联受体（如GPR41、GPR43、GRP109A），抑制组蛋白脱乙酰基酶，作为能量底物^[62]；换行诱导T调节细胞分化，减少嗜酸粒细胞运输和存活^[55]，以及促进黏膜抗体产生^[63]
多不饱和脂肪酸：omega-3脂肪酸（二十碳五烯酸和二十二碳六烯酸）、omega-6脂肪酸（亚油酸及其代谢物花生四烯酸）	增加短链脂肪酸的产生，被人体肠道微生物代谢产生共轭亚油酸（CLA）和12，13-二羟基-9-十八烯酸（12，13-diHOME）。换行免疫失衡情况下，补充CLA能减少肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ和白介素（IL）-5的产生以及嗜酸粒细胞来源神经毒素的释放^[64]；12，13-diHOME可激活树突状细胞中的PPARγ调控基因的表达，并减少体外的抗炎细胞因子分泌和Treg细胞数量，从而增加肺部炎症^[65]
胆汁酸：胆酸、鹅脱氧胆酸、脱氧胆酸、石胆酸、熊去氧胆酸	熊去氧胆酸通过连接树突状细胞的法尼醇X受体（FXR），促进IL-12的产生，促进树突状细胞的迁移，减少肺部嗜酸性气道炎症^[66]；鹅去氧胆酸通过阻断炎性细胞浸润，从而抑制Th2细胞因子IL-4、IL-5、IL-13的分泌^[67]
色氨酸：犬尿氨酸、5-羟色胺、褪黑激素、吲哚、吲哚酸、粪臭素、色胺	吲哚胺2，3-双加氧酶-1代谢色氨酸产生犬尿氨酸衍生物，通过降低色氨酸的利用率^[68]和促进T调节细胞来减轻T细胞炎症^[69]；色氨酸衍生物可以激活芳香烃受体^[70]，刺激ILC3细胞产生IL-22并抑制ILC2功能，促进耐受性树突状细胞^[71]、Th17和T调节细胞分化^[72]
鞘脂：1-磷酸鞘氨醇、1-磷酸神经酰胺	1-磷酸鞘氨醇与T细胞表面S1P受体结合，控制T细胞从淋巴结进入血液^[73]；从头合成鞘脂的减少会降低细胞内镁含量并影响平滑肌收缩力^[74]

代谢物	机制
短链脂肪酸：乙酸盐、丙酸盐、丁酸盐	直接激活G蛋白偶联受体（如GPR41、GPR43、GRP109A），抑制组蛋白脱乙酰基酶，作为能量底物^[62]；换行诱导T调节细胞分化，减少嗜酸粒细胞运输和存活^[55]，以及促进黏膜抗体产生^[63]
多不饱和脂肪酸：omega-3脂肪酸（二十碳五烯酸和二十二碳六烯酸）、omega-6脂肪酸（亚油酸及其代谢物花生四烯酸）	增加短链脂肪酸的产生，被人体肠道微生物代谢产生共轭亚油酸（CLA）和12，13-二羟基-9-十八烯酸（12，13-diHOME）。换行免疫失衡情况下，补充CLA能减少肿瘤坏死因子（TNF）-α、干扰素（IFN）-γ和白介素（IL）-5的产生以及嗜酸粒细胞来源神经毒素的释放^[64]；12，13-diHOME可激活树突状细胞中的PPARγ调控基因的表达，并减少体外的抗炎细胞因子分泌和Treg细胞数量，从而增加肺部炎症^[65]
胆汁酸：胆酸、鹅脱氧胆酸、脱氧胆酸、石胆酸、熊去氧胆酸	熊去氧胆酸通过连接树突状细胞的法尼醇X受体（FXR），促进IL-12的产生，促进树突状细胞的迁移，减少肺部嗜酸性气道炎症^[66]；鹅去氧胆酸通过阻断炎性细胞浸润，从而抑制Th2细胞因子IL-4、IL-5、IL-13的分泌^[67]
色氨酸：犬尿氨酸、5-羟色胺、褪黑激素、吲哚、吲哚酸、粪臭素、色胺	吲哚胺2，3-双加氧酶-1代谢色氨酸产生犬尿氨酸衍生物，通过降低色氨酸的利用率^[68]和促进T调节细胞来减轻T细胞炎症^[69]；色氨酸衍生物可以激活芳香烃受体^[70]，刺激ILC3细胞产生IL-22并抑制ILC2功能，促进耐受性树突状细胞^[71]、Th17和T调节细胞分化^[72]
鞘脂：1-磷酸鞘氨醇、1-磷酸神经酰胺	1-磷酸鞘氨醇与T细胞表面S1P受体结合，控制T细胞从淋巴结进入血液^[73]；从头合成鞘脂的减少会降低细胞内镁含量并影响平滑肌收缩力^[74]