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. 2025 Aug;156(2):339-351.
doi: 10.1016/j.jaci.2025.04.017. Epub 2025 Apr 23.

Metabotypes are linked to uncontrolled childhood asthma, gut microbiota, and systemic inflammation

Mahmoud I Abdel-Aziz  1 , Simone Hashimoto  2 , Anne H Neerincx  3 , Eric G Haarman  4 , Alexander Cecil  5 , Jutta Lintelmann  5 , Michael Witting  6 , Stefanie M Hauck  5 , Nikki Kerssemakers  7 , Joris C Verster  8 , Corinna Bang  9 , Andre Franke  9 , Barbara S Dierdorp  10 , Tamara Dekker  10 , Nariman K A Metwally  3 , Jan Willem Duitman  11 , René Lutter  11 , Mario Gorenjak  12 , Antoaneta A Toncheva  13 , Parastoo Kheiroddin  13 , Susanne Harner  13 , Susanne Brandstetter  14 , Christine Wolff  14 , Paula Corcuera-Elosegui  15 , Leyre López-Fernández  15 , Javier Perez-Garcia  16 , Mario Martin-Almeida  16 , Olaia Sardón-Prado  17 , Maria Pino-Yanes  18 , Uroš Potočnik  19 , Michael Kabesch  20 , Susanne J H Vijverberg  21 , Aletta D Kraneveld  7 , Anke H Maitland-van der Zee  2 ; SysPharmPediA Consortium
Affiliations
Free article

Metabotypes are linked to uncontrolled childhood asthma, gut microbiota, and systemic inflammation

Mahmoud I Abdel-Aziz et al. J Allergy Clin Immunol. 2025 Aug.
Free article

Abstract

Background: Childhood asthma has been linked to distinct metabolomic profiles.

Objective: We sought to identify phenotypes (metabotypes) in children with moderate to severe asthma through integrative fecal and serum metabolome analysis.

Methods: Children from the Systems Pharmacology Approach to Uncontrolled Pediatric Asthma cohort with Global Initiative for Asthma treatment step 3 or higher were recruited. Asthma control was defined by the Asthma Control Test and annual exacerbation history. Targeted metabolomic profiling of feces and serum was performed using liquid chromatography and flow injection electrospray ionization-triple quadrupole mass spectrometry. Similarity network fusion integrated fecal and serum metabolome profiles, followed by spectral clustering. Clusters were analyzed for differences in asthma characteristics, food diaries, fecal microbiota composition, and levels of serum inflammatory markers and blood cells.

Results: Integrative fecal and serum metabolome analysis of 92 children with moderate to severe asthma (median age, 11.5 years, 34% female) revealed 3 metabotypes. Metabotype 1 had the lowest percentage of allergic rhinitis, with elevated serum ceramides and triglycerides. Metabotype 2 had higher odds of asthma control, the highest percentage of children with 4 or more months of breast-feeding, reduced sugar intake, lowest levels of blood neutrophils and serum inflammatory markers, and elevated serum acylcarnitines and ω-3 fatty acids. Metabotype 3 included the highest percentage of uncontrolled asthma patients, with decreased serum cholesteryl esters, phosphatidylcholines, and sphingomyelins, elevated fecal amino acids, and reduced fecal microbiota diversity.

Conclusions: Metabotypes in children with moderate to severe asthma are linked to asthma control, distinct fecal microbiota, and systemic inflammatory patterns. The findings suggest that metabotyping can be valuable in precision medicine approaches for asthma.

Keywords: Moderate to severe childhood asthma; gut microbiota; inflammatory markers; metabotyping; precision medicine.

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Conflict of interest statement

Disclosure statement The SysPharmPediA consortium has been supported by The Netherlands Organisation for Health Research and Development (ZonMW; project no. 9003035001), Ministry of Higher Education, Science and Innovation of the Republic of Slovenia (MVZI; contract no. C330-16-500106); the German Ministry of Education and Research (BMBF; project no. FKZ 031 L0088); and Instituto de Salud Carlos III through Strategic Action for Health Research (AES) and European Community within the Active and Assisted Living Program framework (award nos. AC15/00015 and AC15/00058) under the frame of the ERACoSysMed JTC-1 Call. M.I.A.-A. is supported by the Longfonds, Stichting Astma Bestrijding, and Amsterdam Public Health Institute (Netherlands) and was funded by a full PhD scholarship from the Ministry of Higher Education (Egypt), in relation to this work. M.M.-A. is funded by fellowship FPU23/02667 from the Spanish Ministry of Science, Innovation, and Universities. Disclosure of potential conflict of interest: J. C. Verster reports receiving consulting fees from Eisai, KNMP, Med Solutions, Red Bull, and Toast and receiving travel support from Sen-Jam Pharmaceutical and personal stock options from Sen-Jam Pharmaceutical, outside the submitted work. J. W. Duitman reports receiving grants paid to institution from Abbvie and Boehringer Ingelheim, outside of this submitted work. R. Lutter reports receiving grants paid to institution from Amsterdam UMC Foundation, Foresee, and Eurostar, receiving fees for webinar contribution from Pfizer, receiving support for attending meeting/travel from the European Society for Clinical Investigation (ESCI), receiving fees from Sanofi for participation on a Data Safety Monitoring/Advisory Board (DSMB), and unpaid secretary/treasurer Trust of ESCI, outside of this submitted work. S. Harner reports receiving payment or honoraria from Nutricia and Allergopharma, outside of this submitted work. O. Sardón-Prado reports receiving support from Faes Farma for traveling to Spanish Society of Pediatric Pulmonology congress June 2024, outside of the submitted work. M. Pino-Yanes was funded by grants PID2020-116274RB-I00, SAF2017-83417R, and the Ramon y Cajal program RYC-2015-17205 from the Spanish Ministry of Science, Innovation, and Universities (MICIU/AEI/10.13039/501100011033) and the European Regional Development Fund “ERDF A way of making Europe” by the European Union, was funded by Instituto de Salud Carlos III (ISCIII) through AES and the European Community within the Active Assisted Living (AAL) framework, and was funded by GlaxoSmithKline, Spain, and CSL Behring, outside the submitted work. M. Kabesch reports grants from the European Union, German Ministry of Education and Research, Bavarian Ministry of Health, receiving consulting fees from AstaZeneca, and receiving honoria from the European Academy of Allergy and Clinical Immunology (EAACI), Novartis, Nutricia, and Pari, outside the submitted work. S. J. H. Vijverberg reports receiving support for attending meeting/travel from the European Respiratory Society (ERS), being ERS officer Pediatric Assembly, and receiving payment paid to institution for involvement in 3TR ABC (IMI project), which includes funding from AstraZeneca, GlaxoSmithKline (GSK), and Sanofi, outside the submitted work. A. D. Kraneveld reports leadership role by being dean of the Faculty of Science, Vrije Universiteit Amsterdam. A. H. Maitland-van der Zee is the PI of a public-private consortium (P4O2 [Precision Medicine for More Oxygen]) sponsored by Health∼Holland involving many private partners that contribute in cash and/or in kind (AbbVie, Boehringer Ingelheim, Breathomix, Clear, Fluidda, Ortec Logiqcare, Olive, Philips, Quantib-U, Smartfish, Clear, SODAQ, Thirona, Roche, TopMD, Novartis, RespiQ), received unrestricted research grant from GSK and Boehringer Ingelheim, received Vertex Innovation Award Grant, received honoraria paid to institution from Boehringer Ingelheim, Astra Zeneca, and GSK, and reports that she is the Chair of DSMB of a study on bronchopulmonary dysplasia in neonates, outside of the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.