Application of Metabolomics in Pediatric Asthma: Prediction, Diagnosis and Personalized Treatment
Abstract
:1. Introduction
1.1. Strategies in Metabolomics Research
1.2. Application of Metabolomics in Pediatric Asthma Research
2. Results
3. Discussion
3.1. Hypoxia and Energy Deficits
3.1.1. Citric Acid Cycle
3.1.2. Nicotinamide
3.2. Protein Synthesis/Degradation
3.3. One-Carbon Folate Cycle
3.4. Purine Metabolism
3.5. Lipid Metabolism and Inflammation
3.6. Oxidative Stress
3.7. Bile Acids
3.8. Gut Microbiota
3.9. Steroid Hormone Biosynthesis
3.10. Xenobiotics
4. Methods
5. Limitations/Strengths
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Author Year/Study Design/ Country | Follow-Up | Population (n) | Group Allocated | Asthma or Bronchiolitis Diagnosis | Sample/ Metabolomic Technique | Metabolites Isolated | Annotated Pathways | Conclusions |
---|---|---|---|---|---|---|---|---|
NEONATES | ||||||||
Carraro et al., 2018 [19] Birth Cohort Netherlands | 1 year | 292 mothers @ 38–42 weeks gestation 142 analyzed. | wheezers n = 86 non-wheezers n = 56 | Parent’s symptom report | Amniotic fluid (LC-MS) Untargeted | High levels in the wheezing group: Indoxyl sulfate, p-cresol glucuronide, 2-methoxyestrone-3-sulfate, S-adenosylhomocysteine, 1,3,7,12-tetrahydroxycholan- 24-oic acid, glycocholic acid, α- Ν-phenylacetyl-l-glutamine, corticosterone High levels in non-wheezers: 3-hydroxyphenylacetic acid, 3,4-dihydroxyphenyllactic acid methyl ester, ferulic acid 4-O-glucuronide, chenodeoxycholic acid 3- sulfate, 3a-hydroxy-7,12-dioxo-5β- cholan-24-oic acid, 4-hydroxystachydrine, 5-hydroxyindolepyruvate, dehydroepiandrosterone sulfate | Steroid hormone Biosynthesis, Phenylalanine metabolism, gluconeogenesis, bile acid synthesis, products of gut microbiota, oxidative stress and epigenetic dysregulation | Amniotic fluid collected at delivery differed in neonates that experienced wheezing at 1 year than in non-wheezers. |
Chawes et al., 2019 [20] Birth Cohort Denmark | 6 years | Asthmatic mothers COPSA C2000 n = 171 neonates @ 4 weeks of age. COPSAC 2010 n = 161 | Persistent wheezers or asthmatics in the first 6 years of life | Physician | Urine (LC-MS) Untargeted | Higher in asthmatic children vs. healthy controls: Taurochenodeoxycholate-3-sulfate, 3-hydroxy-tetradecanedioic acid Lower in asthmatic children vs. control: Glucoronidated steroid | Steroid, fatty acid metabolism and bile acids | Metabolic profiles discriminated children developing asthma from healthy children. In both cohorts, urine metabolite levels measured at four weeks were related to asthma development before six years of age. |
INFANTS | ||||||||
Chiu et al., 2018 [35] Longitudinal Taiwan | 1, 2, 3, 4 years | PATCH Cohort n = 60 | Asthma n = 30, Healthy controls n = 30 | Physician | Urine (NMR) Untargeted | Lower levels in asthmatic children vs. healthy controls: Dimethylamine, allantoin, guanidoacetic acid, 1-methylnicotinamide | Purine and amino acid metabolism, nicotinamide/ nicotinate metabolism, methane metabolism and gut microbiota imbalance. | Metabolomic profiling provided a link of microbe-environment Interactions in the development of childhood. |
Barlotta et al., 2019 [32] Prospective Italy | 6 months, 12 months, 2 years | n = 52 @ 1 year old patients with acute bronchiolitis | Wheezers Non-wheezers | BronchiolitisPhysician | Urine (LC-MS) Untargeted | Bronchiolitis-induced recurrent wheeze vs. non-wheezers: Isocitrate, citric acid, oxoglutaric acid, lysine, cysteine, methionine. Isobutyrylglycine, N-butyrylglycine. | Citric acid cycle, fatty acid and amino acid metabolism, gut microbial dysbiosis | Metabolomic profiling of urine specimens from infants with bronchiolitis identified children at increased risk of developing recurrent wheezing. |
Atzei et al., 2011 [34] Case-study Italy | N/A | n = 2 @ 33-37 weeks gestation < 28 days Patients with RSV bronchiolitis | Physician | Urine (NMR) | Associated with RSV bronchiolitis: Betaine, creatinine, glycine | Creatine metabolism and epigenetic regulation | 1H-NMR can be potentially applied to identify metabolic alterations in urine samples related to the differences in the inflammation of bronchioles. | |
Turi et al., 2018 [25] INSPIRE Cohort USA | 1, 2, 3 years | n = 140 120 days old | Healthy n = 60, HRV n = 10, RSV n = 70 | Physician | Urine (NMR) Untargeted | 11 metabolites were significantly different between RSV ARI, HRV ARI vs. healthy control infant groups: 1-methylnicotinamide, 4-deoxythreonic acid, citrate, creatine, hypoxanthine, alanine, succinate, 3-hydroxyisovalerate, acetone, valine, 2-aminobutyrate | Citric acid cycle, amino acid metabolism, nicotinamide/ nicotinate metabolism, catecholamine biosynthesis, glucose-alanine cycle, glutamate metabolism, arginine-proline metabolism | Metabolomics may aid in prophylaxis against bronchiolitis in infants. |
PRE-SCHOOL | ||||||||
Carraro et al., 2018 [21] Cohort Italy | 3 years | n = 47 2–5 years | Wheezing n = 34, Healthy n = 13 | Physician | Urine (LC-MS) Untargeted | Higher levels in transient wheezers vs. early-onset asthma: Oxoadipic acid, epinephrine, L-tyrosine, 3-hydroxyhippuric acid, benzoic acid, 3 hydroxy-sebacic acid, dihydroferulic acid 4-sulfate, p-cresol, indolelactic acid, N-acetyl-l-phenylalanine, N2-acetyl-ornithine Higher levels in early-onset asthma vs. transient wheezers: 4-(4-deoxy-α-d-gluc-4-enuronosyl)-d-galacturonate, glutaric acid, 4-hydroxy nonenal, phosphatidylglycerol, 3-methyluridine, steroid O-sulfate, 5-hydroxy-l-tryptophan,3-indoleacetic-acid, tiglylglycine, indole, cytosine, N-acetylputrescine, indole-3-acetamide, 6-methyladenine, 5-methylcytosine, N-acryloylglycine, hydroxyphenyllactic acid. | Tryptophan metabolism, fatty acid metabolism and microbial derivatives | Urine metabolites distinguished between transient wheezers and early-onset asthma. |
Smolinska et al., 2014 [22] Prospective Cohort Netherlands | 6 years | ADEM Study n = 252 2–4 years | Recurrent Wheeze n = 202 Healthy controls n = 50 At age 6 years: Healthy n = 49, Transient wheezers n = 121, Early-onset Asthma n = 76 | Physician | VOC (GC-MS) Targeted | High levels in early-onset asthma vs. transient wheezers: 2,4-dimethylpentane, 2,4-dimethylheptane, 2-undecenal, octane, 2-methylpentane, 2,4-demethylheptane, 2-methylhexane Low levels in early-onset asthma vs. transient wheezers: Acetone, 2,2,4-trimethylheptane, 1-methyl-4-(1-methylethenyl) Cyclohexen, 2, 3, 6-trimethyloctane, biphenyl, 2-ethenylnaptalene, 2, 6, 10-trimethyldodecane | Hydrocarbons produced during lipid peroxidation | VOCs profile in exhaled breath discriminated healthy, transient wheezing and true asthmatic children. VOCs predictive of early-onset asthma. |
Klaassen et al., 2015 [23] Prospective Cohort Netherlands | 6 years | ADEM study n = 202 2–4 years | Recurrent wheezers n= 202 At age 6 years: Healthy n = 4, Asthma n =76, Transient wheeze n =122 | Physician | VOC (GC-TOF-MS) Targeted | High levels in asthmatics: Octane, 2-methylhexane, 2, 3, 6 -trimethyloctane, 2, 4-dimethylheptane Low levels in asthmatics: Acetone, 2-undecenal, 2, 6, 10-trimethyldodecane, 2,4-dimethylpentane, 2-methylpentane | Hydrocarbons produced during airway inflammation | VOCs profile plus Asthma Predictive Index (API) status improved asthma diagnosis at preschool age. VOCs could be a valuable monitoring tool for airway inflammation and in predicting asthma onset. |
Chiu et al., 2020 [26] Cross-sectional Taiwan | N/A | n = 54 3–5 years | Asthma n = 28, Control n = 26 | Physician | Plasma Urine (NMR) Untargeted | Higher in asthma vs. control: Histidine Lower in asthma vs. control: 1-methylnicotinamide, trimethylamine N-oxide (TMAO). Related to allergic sensitization (Ig E)/Food allergy: N-phenylacetylglycine, pyruvate, valine, leucine, isoleucine | Histadine metabolism, nicotinamide and pyruvate metabolism, phenylalanine metabolism, amino acid metabolism and products of microbial metabolism | Plasma pyruvate metabolism associated with Ig E production. Urinary branched-chain amino acids were associated with food allergic reactions. |
SCHOOL CHILDREN | ||||||||
Saude et al., 2011 [27] Cross-sectional Canada | N/A | n = 135 4–16 years SAGE Birth Cohort | Stable n = 73, Unstable asthma n = 20, Healthy controls n = 42 | Physician | Urine (NMR) Targeted | Protective against asthma exacerbation: 1-methylnicotinamide Asthma vs. healthy controls: 1–methylhistamine, 1-methyl-nicotinamide, 2- methylglutarate, 2-oxoglutarate, 3-OH-3-methyl-glutarate, 3-methyladipate, 4-aminohippurate, acetone, adenine, alanine, creatine, dimethylamine, formate, fumarate, glucose, glycolate, imidazole, lactate, methylamine, O-acetylcarnitine, oxaloacetate, phenylacetylglycine, phenylalanine, tryptophan, tyrosine, cis-aconitate, Myo-inositol, trans-aconitate. Separating stable vs. unstable asthma: 2-oxaloglutarate, succinate, fumarate, 3-hydroxy 3-methylglutarate, threonine, aconitate, acetylcarnitine, trimethylamine, threonine, taurine, 4-aminohippurate Stable vs. unstable vs. healthy controls: 4-aminohippurate, carnitine, homovanillate, kynurenine, O-acetylcarnitine, succinate, taurine, threonine, trimethylamine. | Citric acid cycle, nicotinamide metabolism, lipid metabolism, Protein metabolism, purine metabolism, glucose metabolism, tryptophan metabolism, histamine biosynthesis including catecholamine synthesis | 1H-NMR can be used to differentiate stable asthma from controls and unstable asthma. |
Tao et al., 2019 [24] Cohort China | N/A | n = 109 6–11 years | Healthy n = 29, Uncontrolled asthma n = 37, Controlled asthma n = 43 | Physician | Urine (GC-MS) Untargeted | Asthma diagnosis and discrimination of controlled vs. uncontrolled asthma: Uric acid, stearic acid, threitol, acetylgalactosamine, heptadecanoic acid, aspartic acid, xanthosine, hypoxanthine Healthy vs. uncontrolled/ Controlled asthma: Glycine, serine, threonine, Pantothenate and CoA synthesis, BCAA synthesis, tyrosine, inosine, adenosine, arginine, proline, alanine, aspartate, glutamate, pyruvate, tryptophan | Citric acid cycle, purine metabolism, lipid and carbohydrate metabolism, amino acid and phenylalanine metabolism, pantothenate and Coenzyme A biosynthesis | Urine metabolomics discriminated asthma as well as controlled and uncontrolled sub-types and elucidated the biological mechanisms of pediatric asthma. |
Dallinga et al., 2010 [33] Prospective Netherlands | N/A | n = 120 5–16 years | Asthma n = 63, Healthy controls n = 57 | Physician | VOC (GC-TOF-MS) Untargeted | Metabolites differentiated between asthma vs. healthy controls: Branched hydrocarbons (C13H28, C11H24), carbon disulfide, 1-penten-2-on, butanoic acid, 3-(1-methylethyl)-benzene, unsaturated hydrocarbon (C15H26), benzoic acid, p-xylene | Hydrocarbons produced during lipid peroxidation | EBC samples and comparing VOCs differentiated children with asthma from healthy controls. |
Gahleitner et al., 2013 [36] Experimental UK | N/A | n = 23 8–16 years | Asthma n = 11, Healthy n = 12 | Physician | VOC (GC-MS) Targeted | Metabolites differentiated between asthma vs healthy: 1-(methylsulfanyl)propane, ethylbenzene, 1,4-dichlorobenzene, 4-isopropenyl-1-methylcyclohexene, 2-octenal, octadecyne, 1-isopropyl-3-methylbenzene, 1,7 dimethylnaphtalene | Organic compounds from external sources. Used in food manufacturing (flavorings) and disinfectants. | VOCs discriminated between asthmatic and healthy children. The application of breath markers could be a potential non-invasive and low-cost technique for the management of pediatric asthma. |
Asthma Phenotype | Author Year/ Study Design /Country | Population (n) | Group Allocated | Asthma Diagnosis | Sample/ Metabolomic Technique | Metabolites Isolated | Annotated Pathways | Conclusions |
---|---|---|---|---|---|---|---|---|
Mild | Papamichael et al., 2019 [28] Cross-sectional Greece | n = 65 5–12 years | N/A | Physician ACQ | Urine (GC-MS) Targeted | Metabolites correlated with PFTs (FEV1, FVC, FEV1/FVC, PEF, FeNO) and asthma control: Lactic, 4-hydroxyphenylacetic, 5-hydroxyindoleacetic, glycolic, malic acid. | Tryptophan and tyrosine metabolism, lactic acidosis, catecholamine synthesis and alterations in gut microbiota. | Metabolomics is a promising approach in the research for novel biomarkers for asthma monitoring |
Mild-Moderate | Kelly et al., 2017 [29] Cohort Costa Rica | n = 380 6–14 years | N/A | Physician | Plasma (LC-MS) Untargeted | 574 Metabolites isolated in mild-moderate asthmatics. 91 associated with AHR, 102 with pre- FEV1/FVC and 155 with post-FEV1/FVC 24 metabolites common to all 3 parameters | Metabolites common to AHR, pre and post-FEV1/FVC related to: Glycerophospholipids, linoleic acid and pyrimidine metabolism. Metabolites pertaining to AHR: Disturbances in Glycerophospholipid and linoleic acid metabolism, d -glutamine/ glutamate, sphingolipid and pyrimidine metabolism, as well as Nitrogen metabolism. Pre and post bronchodilation FEV1/FVC: Citric acid cycle, lipid metabolism, alanine, aspartate and glutamate metabolism, arginine—proline metabolism, glycine, threonine and serine metabolism, pyrimidine metabolism, BCAA and nitrogen metabolism, pantothenate and CoA biosynthesis and aminoacyl tRNA biosynthesis. Post FEV1/FVC: Pantothenate and CoA biosynthesis | Metabolites and metabolomic profiles distinguished children with asthma by the degree of lung function as reflected by spirometric parameters, thus confirming the existence of an asthma severity metabolome. |
Severe | Carraro et al., 2013 [30] Cross-sectional Italy | n = 57 8–17 years | Severe n = 11, Non-severe n = 31 (17 taking medication) Healthy controls n = 15 | Physician | EBC (LC-MS) Untargeted | Severe asthma: Retinoic acid, deoxyadenosine Non-severe: 20-hydroxy-PGF2a, Thromboxane B2, 6 keto-prostaglandin F1a Healthy controls: Ercalcitriol (active vitamin D2) | Compounds related to: Retinoic acid, adenosine and vitamin D | Breathomics discriminated between severe, non-severe and healthy child asthmatics. |
Cortico- steroid Resistant | Fitzpatrick et al., 2014 [15] Cross-sectional US | n = 57 6–17 years | Mild asthma n = 22, Severe n = 35 | Physician | Plasma (LC-MS) Untargeted | Severe asthma: Glycine, serine, threonine, N-acylethanolamine, N-acyltransferase pathway | Biosynthesis of purine /pyrimidines, phospho-glycerides, sphingo-lipid, glycolipids. Folate cycle, glutathione synthesis. Oxidative stress | Metabolomics revealed that oxidative stress is a contributory factor to corticosteroid refractory severe asthma in children. |
Cortico- steroid Resistant | Park et al., 2017 [31] Cross-sectional US | n = 30 6–17 years | Corticosteroid resistant n = 15, Corticosteroid responders n = 15 | Physician | Urine (LC-MS) Untargeted | Metabolites discriminating corticosteroid responders from non-responders: 3,6-dihydronicotinic, 3-methoxy-4-hydroxyphenyl(ethylene)glycol, 3,4-dihydroxy-phenylalanine, γ-glutamylcysteine, Cys-Gly, reduced Flavin mononucleotide High in the corticosteroid resistant (non-responders) group: Cyst-Gly 3,6-dihydronicotinic, 3,4-dihydroxy-phenylalanine, 1,2-dihydronaphthalene- 1,2-diol, 3-methoxy-4-hydroxyphenyl(ethylene)glycol Low in corticosteroid resistant group (non-responders): γ-glutamylcysteine | Tyrosine metabolism, catecholamine biosynthesis, and glutathione metabolism. 3,6-dihydronicotinic and 1,2-dihydronaphthalene- 1,2-diol are present in cigarette smoke | Putative biomarkers isolated using the metabolomics approach differentiated corticosteroid resistant non-responders) from responders in pediatric asthma. |
Atopic | Mattarucchi et al., 2012 [16] Cross-sectional Italy | Atopic n = 41, Healthy n= 12 Median age 11 years | Well-controlled with β-agonists n = 14, Well-controlled with daily controller drugs n = 16, Poorly-controlled with daily controller drugs n = 11 | Physician | Urine (LC-MS) Untargeted | Low levels in asthmatics: Urocanic, methyl-imidazoleacetic, Ile-Pro fragment | Histamine metabolism. Urocanic acid related to inflammation/immunity and Ile-Pro to prolidase activity. | Metabolic profiling offers the potential of asthma characterization and identification of inflammation- related metabolites. |
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Papamichael, M.M.; Katsardis, C.; Sarandi, E.; Georgaki, S.; Frima, E.-S.; Varvarigou, A.; Tsoukalas, D. Application of Metabolomics in Pediatric Asthma: Prediction, Diagnosis and Personalized Treatment. Metabolites 2021, 11, 251. https://doi.org/10.3390/metabo11040251
Papamichael MM, Katsardis C, Sarandi E, Georgaki S, Frima E-S, Varvarigou A, Tsoukalas D. Application of Metabolomics in Pediatric Asthma: Prediction, Diagnosis and Personalized Treatment. Metabolites. 2021; 11(4):251. https://doi.org/10.3390/metabo11040251
Chicago/Turabian StylePapamichael, Maria Michelle, Charis Katsardis, Evangelia Sarandi, Spyridoula Georgaki, Eirini-Sofia Frima, Anastasia Varvarigou, and Dimitris Tsoukalas. 2021. "Application of Metabolomics in Pediatric Asthma: Prediction, Diagnosis and Personalized Treatment" Metabolites 11, no. 4: 251. https://doi.org/10.3390/metabo11040251
APA StylePapamichael, M. M., Katsardis, C., Sarandi, E., Georgaki, S., Frima, E. -S., Varvarigou, A., & Tsoukalas, D. (2021). Application of Metabolomics in Pediatric Asthma: Prediction, Diagnosis and Personalized Treatment. Metabolites, 11(4), 251. https://doi.org/10.3390/metabo11040251