Cytokines and metabolites are the main descriptors of severe asthma in children when performing multi-omics analysis of bronchoaleveolar lavages

Author:

Briard Mélanie1,Guillon Blanche1,Venot Eric1,Grauso Marta1,Hennequet-Antier Christelle2,Bruneau Aurélia3,Fenaille François4,Castelli Florence4,Thomas Muriel3,Lezmi Guillaume5,Leite-de-Moraes Maria6,Saint-Criq Vinciane3,Adel-Patient Karine1

Affiliation:

1. Université Paris-Saclay, CEA, INRAE, UMR Département Médicaments et Technologies pour la Santé (DMTS)

2. Université Paris-Saclay, MIGALE Bioinformatics Facility

3. Université Paris-Saclay, INRAE, UMR1319 Micalis Institute

4. Université Paris-Saclay, CEA, INRAE, UMR Département Médicaments et Technologies pour la Santé (DMTS)/SPI/Laboratoire innovations en spectrométrie de masse pour la santé

5. AP-HP, Hôpital Necker-Enfants Malades

6. Université de Paris Cité, Institut Necker Enfants Malades, Inserm UMR1151, CNRS UMR8253

Abstract

Abstract Background. Severe asthma (SA) is a heterogeneous condition with multiple phenotypes. There is still an unmet need to characterize and understand underlying mechanisms taking place in the lungs in order to propose the most suitable therapeutic strategies for SA. For this purpose, we aimed to identify a local signature of severe asthma by conducting comprehensive multi-omics analysis of bronchoalveolar lavages fluids (BALs) from children with SA versus non-asthmatic (NA) controls. Method. BALs were collected from twenty children with SA and from ten age-matched NA. We previously analyzed soluble and cellular immune components in those samples, and now propose to perform comprehensive analysis of their microbiota and their metabolome. Briefly, DNA from BALs was extracted and 16S rRNA gene (V3-V4 region) was amplified by PCR and sequenced. In parallel, untargeted metabolomics was performed using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) following an established workflow for sample preparation, data acquisition and treatment. Each microbiome and metabolome dataset was first analysed independently by unsupervised multivariate analyses (Principal component analyses, PCA). Differences between groups for microbiota diversity indices, the relative distribution of each phyla and genera were then analysed. Metabolite set enrichment analysis (MSEA) and univariate supervised analysis were also performed. To identify a local signature of severe asthma, microbiota and metabolome data were further integrated, together with immune and with clinical data, using unsupervised Multi-Omics Factor Analysis (MOFA). Results. Microbiota diversity was higher in children with SA versus NA, with higher relative abundances of Streptococcus, Corynebacterium, Tropheryma whipplei, Dolosigranulum pigrum and Moraxella nonliquefaciens. We identified 88 metabolites in BALs, but unsupervised PCA of corresponding data did not differentiate children with SA from NA. However, MSEA evidenced that biotin and carnitine synthesis, lysine degradation, methionine metabolism and spermidine and spermine biosynthesis pathways were significantly enriched in children with SA. Finally, multiblocks data integration identified a signature of SA, mainly described by metabolites and cytokines. Conclusion. By integrating metabolome, microbiome and cytokines data obtained on BALs from children with severe asthma versus NA, our study uniquely described a local signature of SA.

Publisher

Research Square Platform LLC

Reference57 articles.

1. Global Initiative for Asthma. Global strategy fo asthma management and prevention. 2022.

2. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma;Chung KF;Eur Respir J,2014

3. Assessment of airway inflammation and remodeling in children with severe asthma: The next challenge;Lezmi G;Pediatr Pulmonol,2018

4. Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease;Kuruvilla ME;Clin Rev Allergy Immunol,2019

5. Severe asthma in children: Evaluation and management;Haktanir Abul M;Allergol Int,2019

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