Abstract
Introduction
There is limited understanding of how plasma fatty acid levels affect pulmonary function in pediatric years. It has been speculated that polyunsaturated fatty acids influence asthma via anti or pro-inflammatory mechanisms. Metabolomics presents a new and promising resource for identifying molecular processes involved in asthma pathology.
Objectives
We investigated the relationship of plasma fatty acid metabolites as biomarkers of the ‘mild-asthma’ phenotype and lung function including airway inflammation in children.
Methods
This cross-sectional study involved 64 children (5–12 years, 33 male) with mild-asthma phenotype attending an outpatient pediatric clinic in Athens, Greece. Clinical examination included spirometry (FVC, FEV1, FEV1/FVC, PEF, FEF25–75%) and Fractional exhaled Nitric Oxide (FeNO). Targeted metabolomic profiling was used to quantify plasma fatty acid composition. Associations between lipids and pulmonary function indices were investigated applying linear regression.
Results
Targeted GC-MS identified 25 unique plasma fatty acids in mild-asthmatic children. Linear regression revealed significant associations between linoleic, oleic, erucic, cis-11-eicosenoic, arachidic acids and FEV1, FVC, FEV1/FVC, PEF, FEF25–75% and FeNO in the overweight/obese group, adjusting for age and sex; and in the normo-weight between stearic and arachidic acids versus FEV1 and FEV1/FVC respectively. No associations were observed for arachidonic, α-linolenic, EPA and DHA.
Conclusion
Metabolomics is a novel science that is useful to discover metabolic signatures specific to disease. Evaluation of fatty acid status could assist clinicians in decision-making about a dietary modification that can be used for personalized nutrition therapies to achieve better asthma control, optimum lung function, and therapeutic response in children.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data generated or analysed during this study are included in this published article and its supplementary information files.
Abbreviations
- %pred:
-
% Predicted
- FEV1 :
-
Forced expiratory volume in 1 s
- FVC:
-
Forced vital capacity
- FEV1/FVC:
-
Ratio of forced expiratory volume in 1 s and forced vital capacity
- PEF:
-
Peak expiratory flow
- FEF25–75% :
-
Forced expiratory flow at 25–75% of the pulmonary volume
- FeNO:
-
Fractional exhaled Nitric Oxide
- FA:
-
Fatty acid
- ALA:
-
α-Linolenic acid
- ETA:
-
Eicosatrienoic acid
- EPA:
-
Eicosapentaenoic acid
- DHA:
-
Docosahexaenoic acid
- γ-LA:
-
Gamma-linolenic acid
- Homo γ-LA:
-
Gamma-linolenic acid
- AA:
-
Arachidonic acid
- MUFA:
-
Monounsaturated fatty acid
- PUFA:
-
Polyunsaturated fatty acid
- ω6:
-
Οmega 6 fatty acid
- ω3:
-
Οmega 3 fatty acid
References
Bao, X., Pollard, M., & Ohlrogge, J. (1998). The biosynthesis of erucic acid in developing embryos of Brassica rapa. Plant Physiology, 118(1), 183–190. https://doi.org/10.1104/pp.118.1.183.
Beasley, R., Semprini, A., & Mitchell, E. A. (2015). Risk factors for asthma: Is prevention possible? Lancet, 386(9998), 1075–1085. https://doi.org/10.1016/s0140-6736(15)00156-7.
Bedfont Scientific Ltd. (2019). NOBreath, Bedfont Scientific Ltd. Retrieved May, 2020, from https://www.bedfont.com/nobreath.
Best, K. P., Gold, M., Kennedy, D., Martin, J., & Makrides, M. (2016). Omega-3 long-chain PUFA intake during pregnancy and allergic disease outcomes in the offspring: A systematic review and meta-analysis of observational studies and randomized controlled trials. American Journal of Clinical Nutrition, 103(1), 128–143. https://doi.org/10.3945/ajcn.115.111104.
Bolte, G., Kompauer, I., Fobker, M., Cullen, P., Keil, U., Mutius, E., & Weiland, S. K. (2006). Fatty acids in serum cholesteryl esters in relation to asthma and lung function in children. Clinical and Experimental Allergy, 36(3), 293–302. https://doi.org/10.1111/j.1365-2222.2006.02441.x.
Braithwaite, I., Stewart, A. W., Hancox, R. J., Beasley, R., Murphy, R., & Mitchell, E. A. (2014). Fast-food consumption and body mass index in children and adolescents: An international cross-sectional study. British Medical Journal Open, 4(12), e005813. https://doi.org/10.1136/bmjopen-2014-005813.
Brigham, E. P., Woo, H., McCormack, M., Rice, J., Koehler, K., Vulcain, T., Wu, T., Koch, A., Sharma, S., Kolahdooz, F., Bose, S., Hanson, C., Romero, K., Diette, G., & Hansel, N. N. (2019). Omega-3 and omega-6 intake modifies asthma severity and response to indoor air pollution in children. American Journal of Respiratory and Critical Care Medicine, 199(12), 1478–1486. https://doi.org/10.1164/rccm.201808-1474OC.
Calder, P. C. (2013). Omega-3 polyunsaturated fatty acids and inflammatory processes: Nutrition or pharmacology? British Journal of Clinical Pharmacology, 75(3), 645–662. https://doi.org/10.1111/j.1365-2125.2012.04374.x.
Calder, P. C. (2015). Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et Biophysica Acta, 1851(4), 469–484. https://doi.org/10.1016/j.bbalip.2014.08.010.
Chung, K. F. (2017). Personalised medicine in asthma: Time for action: Number 1 in the Series “Personalised medicine in respiratory diseases” Edited by Renaud Louis and Nicolas Roche. European Respiratory Reviews, 26(145), 170064. https://doi.org/10.1183/16000617.0064-2017.
Cole, T. J., & Lobstein, T. (2012). Extended international (IOTF) body mass index cut-offs for thinness, overweight and obesity. Pediatric Obesity, 7(4), 284–294. https://doi.org/10.1111/j.2047-6310.2012.00064.x.
Dweik, R. A., Boggs, P. B., Erzurum, S. C., Irvin, C. G., Leigh, M. W., Lundberg, J. O., Olin, A. C., Plummer, A. L., & Taylor, D. R. (2011). An official ATS clinical practice guideline: Interpretation of exhaled nitric oxide levels (FENO) for clinical applications. American Journal of Respiratory and Critical Care Medicine, 184(5), 602–615. https://doi.org/10.1164/rccm.9120-11ST.
Eichenberger, P. A., Diener, S. N., Kofmehl, R., & Spengler, C. M. (2013). Effects of exercise training on airway hyperreactivity in asthma: A systematic review and meta-analysis. Sports Medicine, 43(11), 1157–1170. https://doi.org/10.1007/s40279-013-0077-2.
Engelkes, M., Janssens, H. M., de Jongste, J. C., Sturkenboom, M. C., & Verhamme, K. M. (2015). Medication adherence and the risk of severe asthma exacerbations: A systematic review. European Respiratory Journal, 45(2), 396–407. https://doi.org/10.1183/09031936.00075614.
Ferrante, G., & La Grutta, S. (2018). The burden of pediatric asthma. Frontiers in Pediatrics, 6, 186. https://doi.org/10.3389/fped.2018.00186.
Fitzpatrick, A. M. (2015). Biomarkers of asthma and allergic airway diseases. Annals of Allergy, Asthma & Immunology, 115(5), 335–340. https://doi.org/10.1016/j.anai.2015.09.003.
Fulco, A. J., & Mead, J. F. (1961). The biosynthesis of lignoceric, cerebronic, and nervonic acids. Journal of Biological Chemistry, 236, 2416–2420.
GINA. (2016). Global Strategy for Asthma Management and Prevention (GINA), global initiative for asthma. Retrieved May, 2020, from http://www.ginasthma.org.
Giudetti, A. M., & Cagnazzo, R. (2012). Beneficial effects of n-3 PUFA on chronic airway inflammatory diseases. Prostaglandins & Other Lipid Mediators, 99(3-4), 57–67. https://doi.org/10.1016/j.prostaglandins.2012.09.006.
Gross, E., Lee, D. S., Hotz, A., Ngo, K. C., & Rastogi, D. (2018). Impact of obesity on asthma morbidity during a hospitalization. Hospital Pediatrics, 8(9), 538–546. https://doi.org/10.1542/hpeds.2017-0265.
Guilbert, T. W., Bacharier, L. B., & Fitzpatrick, A. M. (2014). Severe asthma in children. The Journal of Allergy and Clinical Immunology: In Practice, 2(5), 489–500. https://doi.org/10.1016/j.jaip.2014.06.022.
Gutiérrez, S., Svahn, S. L., & Johansson, M. E. (2019). Effects of omega-3 fatty acids on immune cells. International Journal of Molecular Sciences, 20(20), 5028. https://doi.org/10.3390/ijms20205028.
Haidopoulou, K., Hatzistilianou, M., Petridou, A., Mougios, V., Papastavrou, T., Aivazis, V., & Eboriadou, M. (2009). Plasma fatty acids in asthmatic children of Northern Greece. Archives of Medical Science, 5, 51–56.
Hodson, L., Skeaff, C. M., & Fielding, B. A. (2008). Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Progress in Lipid Research, 47(5), 348–380. https://doi.org/10.1016/j.plipres.2008.03.003.
Katsardis, C. V., Alexandraki, S., & Paraskakis, E. (2015). Chapter 2: Spirometry in children 6-16 years old. In C. Katsardis, A. Koumbourlis, M. Anthracopoulos, & E. Paraskakis (Eds.), Paediatric pulmonary function testing indications and interpretation (pp. 15–42). NOVA Biomedical.
Kelly, R. S., Dahlin, A., McGeachie, M. J., Qiu, W., Sordillo, J., Wan, E. S., Wu, A. C., & Lasky-Su, J. (2017a). Asthma metabolomics and the potential for integrative omics in research and the clinic. Chest, 151(2), 262–277. https://doi.org/10.1016/j.chest.2016.10.008.
Kelly, R. S., Virkud, Y., Giorgio, R., Celedón, J. C., Weiss, S. T., & Lasky-Su, J. (2017b). Metabolomic profiling of lung function in Costa-Rican children with asthma. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1863(6), 1590–1595. https://doi.org/10.1016/j.bbadis.2017.02.006.
Kikukawa, H., Sakuradani, E., Nishibaba, Y., Okuda, T., Ando, A., Shima, J., Shimizu, S., & Ogawa, J. (2015). Production of cis-11-eicosenoic acid by Mortierella fungi. Journal of Applied Microbiology, 118(3), 641–647. https://doi.org/10.1111/jam.12725.
Kim, S. H., Sutherland, E. R., & Gelfand, E. W. (2014). Is there a link between obesity and asthma? Allergy, Asthma & Immunology Research, 6(3), 189–195. https://doi.org/10.4168/aair.2014.6.3.189.
Lee, J. M., Lee, H., Kang, S., & Park, W. J. (2016). Fatty acid desaturases, polyunsaturated fatty acid regulation, and biotechnological advances. Nutrients. https://doi.org/10.3390/nu8010023.
Lord, R., & Bralley, A. (2008). Chapter 5 fatty acids. In Laboratory evaluations for integrative and functional medicine (2nd edn, pp. 269–318). Metametrix Institute.
Mabalirajan, U., Rehman, R., Ahmad, T., Kumar, S., Singh, S., Leishangthem, G. D., Aich, J., Kumar, M., Khanna, K., Singh, V. P., Dinda, A. K., Biswal, S., Agrawal, A., & Ghosh, B. (2013). Linoleic acid metabolite drives severe asthma by causing airway epithelial injury. Scientific Reports, 3(1), 1349. https://doi.org/10.1038/srep01349.
Mafort, T. T., Rufino, R., Costa, C. H., & Lopes, A. J. (2016). Obesity: Systemic and pulmonary complications, biochemical abnormalities, and impairment of lung function. Multidisciplinary Respiratory Medicine, 11(1), 28. https://doi.org/10.1186/s40248-016-0066-z.
Magnusson, J., Kull, I., Rosenlund, H., Hakansson, N., Wolk, A., Melen, E., Wickman, M., & Bergstrom, A. (2013). Fish consumption in infancy and development of allergic disease up to age 12 y. American Journal of Clinical Nutrition, 97(6), 1324–1330. https://doi.org/10.3945/ajcn.112.045377.
Malcicka, M., Visser, B., & Ellers, J. (2018). An evolutionary perspective on linoleic acid synthesis in animals. Evolutionary Biology, 45(1), 15–26. https://doi.org/10.1007/s11692-017-9436-5.
Manion, A. B., & Velsor-Friedrich, B. (2017). Quality of life and health outcomes in overweight and non-overweight children with asthma. Journal of Pediatric Health Care, 31(1), 37–45. https://doi.org/10.1016/j.pedhc.2016.01.005.
Matoba, A., Matsuyama, N., Shibata, S., Masaki, E., Emala, C. W., Sr., & Mizuta, K. (2018). The free fatty acid receptor 1 promotes airway smooth muscle cell proliferation through MEK/ERK and PI3K/Akt signaling pathways. American Journal of Physiology. Lung Cellular and Molecular Physiology, 314(3), L333–L348. https://doi.org/10.1152/ajplung.00129.2017.
McGeachie, M. J., Dahlin, A., Qiu, W., Croteau-Chonka, D. C., Savage, J., Wu, A. C., Wan, E. S., Sordillo, J. E., Al-Garawi, A., Martinez, F. D., Strunk, R. C., Lemanske Jr, R. F., Liu, A. H., Raby, B. A., Weiss, S., Clish, C. B., & Lasky-Su, J. A.. (2015). The metabolomics of asthma control: A promising link between genetics and disease. Immunity, Inflammation and Disease, 3(3), 224–238. https://doi.org/10.1002/iid3.61.
Miller, M. R., Hankinson, J., Brusasco, V., Burgos, F., Casaburi, R., Coates, A., Crapo, R., Enright, P., van der Grinten, C. P. M., Gustafsson, P., Jensen, R., Johnson, D. C., MacIntyre, N., McKay, R., Navajas, D., Pedersen, O. F., Pellegrino, R., Viegi, G., & Wanger, J. (2005). Standardisation of spirometry. European Respiratory Journal, 26(2), 319–338.
Mizuta, K., Zhang, Y., Mizuta, F., Hoshijima, H., Shiga, T., Masaki, E., & Emala, C. W., Sr. (2015). Novel identification of the free fatty acid receptor FFAR1 that promotes contraction in airway smooth muscle. American Journal of Physiology. Lung Cellular and Molecular Physiology, 309(9), L970–L982. https://doi.org/10.1152/ajplung.00041.2015.
Nagel, G., Weinmayr, G., Kleiner, A., Garcia-Marcos, L., Strachan, D. P., & Group, I. P. T. S. (2010). Effect of diet on asthma and allergic sensitisation in the International Study on Allergies and Asthma in Childhood (ISAAC) Phase Two. Thorax, 65(6), 516–522.
Nunes, C., Pereira, A. M., & Morais-Almeida, M. (2017). Asthma costs and social impact. Asthma Research and Practice, 3(1), 1. https://doi.org/10.1186/s40733-016-0029-3.
Okoniewski, W., Lu, K. D., & Forno, E. (2019). Weight loss for children and adults with obesity and asthma. A systematic review of randomized controlled trials. Annals of the American Thoracic Society, 16(5), 613–625. https://doi.org/10.1513/AnnalsATS.201810-651SR.
Papadopoulos, N., Arakawa, H., Carlsen, K. H., Custovic, A., Gern, J., Lemanske, R., Souef, P., Mäkelä, M., Roberts, G., & Wong, G. (2012). International consensus on (ICON) pediatric asthma. Allergy, 67(8), 976–997.
Papamichael, M. M., Katsardis, C., Erbas, B., Itsiopoulos, C., & Tsoukalas, D. (2019a). Urinary organic acids as biomarkers in the assessment of pulmonary function in children with asthma. Nutrition Research, 61, 31–40. https://doi.org/10.1016/j.nutres.2018.10.004.
Papamichael, M. M., Katsardis, C., Lambert, K., Tsoukalas, D., Koutsilieris, M., Erbas, B., & Itsiopoulos, C. (2019b). Efficacy of a Mediterranean diet supplemented with fatty fish in ameliorating inflammation in paediatric asthma: a randomised controlled trial. Journal of Human Nutrition & Dietetics, 32(2), 185–197. https://doi.org/10.1111/jhn.12609.
Paraskakis, E., Katsardis, Ch., & Chatzimichail, A. (2015). Chapter 17: Exhaled NO. In C. Katsardis, A. Koumbourlis, M. Anthracopoulos, & E. Paraskakis (Eds.), Paediatric pulmonary function testing indications and interpretation (pp. 235–248). NOVA Biomedical.
Rastogi, D., Canfield, S. M., Andrade, A., Isasi, C. R., Hall, C. B., Rubinstein, A., & Arens, R. (2012). Obesity-associated asthma in children: A distinct entity. Chest, 141(4), 895–905. https://doi.org/10.1378/chest.11-0930.
Rastogi, D., & Holguin, F. (2017). Metabolic dysregulation, systemic inflammation, and pediatric obesity-related asthma. Annals of the American Thoracic Society, 14(5), S363–S367. https://doi.org/10.1513/AnnalsATS.201703-231AW.
Research, M. M. I. (2020). SPIROBANK II, MIR Medical International Research. Retrieved May, 2020, from https://www.spirometry.com/ENG/Products/spirobank2.asp.
Saadeh, D., Salameh, P., Caillaud, D., Charpin, D., De Blay, F., Kopferschmitt, C., Lavaud, F., Annesi-Maesano, I., Baldi, I., & Raherison, C. (2015). Prevalence and association of asthma and allergic sensitization with dietary factors in schoolchildren: data from the French six cities study. BMC Public Health, 15, 993. https://doi.org/10.1186/s12889-015-2320-2.
Shim, J. S., Oh, K., & Kim, H. C. (2014). Dietary assessment methods in epidemiologic studies. Epidemiol Health, 36, e2014009. https://doi.org/10.4178/epih/e2014009.
Simopoulos, A. P. (2001). The Mediterranean diets: What is so special about the diet of Greece? The scientific evidence. Journal of Nutrition, 131, 3065S–3073S.
Simopoulos, A. P. (2008). The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Experimental Biology and Medicine, 233(6), 674–688. https://doi.org/10.3181/0711-mr-311.
Simopoulos, A. P. (2016). An increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity. Nutrients, 8(3), 128. https://doi.org/10.3390/nu8030128.
Spathopoulos, D., Paraskakis, E., Trypsianis, G., Tsalkidis, A., Arvanitidou, V., Emporiadou, M., Bouros, D., & Chatzimichael, A. (2009). The effect of obesity on pulmonary lung function of school aged children in Greece. Pediatric Pulmonology, 44(3), 273–280. https://doi.org/10.1002/ppul.20995.
Steiner, M. J., Skinner, A. C., & Perrin, E. M. (2011). Fasting might not be necessary before lipid screening: A nationally representative cross-sectional study. Pediatrics, 128(3), 463–470. https://doi.org/10.1542/peds.2011-0844.
Stellaard, F., ten Brink, H. J., Kok, R. M., van den Heuvel, L., & Jakobs, C. (1990). Stable isotope dilution analysis of very long chain fatty acids in plasma, urine and amniotic fluid by electron capture negative ion mass fragmentography. Clinica Chimica Acta, 192(2), 133–144. https://doi.org/10.1016/0009-8981(90)90077-6.
Tiotiu, A. (2018). Biomarkers in asthma: State of the art. Asthma Research and Practice, 4, 10. https://doi.org/10.1186/s40733-018-0047-4.
Zhang, Y., Lin, J., Zhou, R., Zheng, X., & Dai, J. (2020). Effect of omega-3 fatty acids supplementation during childhood in preventing allergic disease: A systematic review and meta-analysis. Journal of Asthma. https://doi.org/10.1080/02770903.2019.1709866.
Acknowledgements
We are grateful to the patients that participated in this study as well as to Sklavenitis and Basilopoulos Supermarkets (Hellas) for their support to economically disadvantaged families.
Funding
This study was an unfunded project. The first author was supported by an Australian Post Graduate Award PhD Scholarship administered by La Trobe University.
Author information
Authors and Affiliations
Contributions
MP was the principal author of the manuscript. CT and BE edited and reviewed the first and final drafts. CK and DT collected the samples and conducted clinical measurements. DT performed the plasma fatty acid targeted metabolomic analysis. MP performed data collection, data entry and the statistical analysis that was supervised by BE. All authors contributed to interpretation of data, revised the paper critically for important intellectual content and approved the final version before submission.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Written informed consent was obtained from all individual participants included in this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Papamichael, M.M., Katsardis, C., Tsoukalas, D. et al. Plasma lipid biomarkers in relation to BMI, lung function, and airway inflammation in pediatric asthma. Metabolomics 17, 63 (2021). https://doi.org/10.1007/s11306-021-01811-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11306-021-01811-5