TY - JOUR

T1 - Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk

AU - Abdel-Aziz, Mahmoud I.

AU - Thorsen, Jonathan

AU - Hashimoto, Simone

AU - Vijverberg, Susanne J.H.

AU - Neerincx, Anne H.

AU - Brinkman, Paul

AU - van Aalderen, Wim

AU - Stokholm, Jakob

AU - Rasmussen, Morten Arendt

AU - Roggenbuck-Wedemeyer, Michael

AU - Vissing, Nadja H.

AU - Mortensen, Martin Steen

AU - Brejnrod, Asker Daniel

AU - Fleming, Louise J.

AU - Murray, Clare S.

AU - Fowler, Stephen J.

AU - Frey, Urs

AU - Bush, Andrew

AU - Singer, Florian

AU - Hedlin, Gunilla

AU - Nordlund, Björn

AU - Shaw, Dominick E.

AU - Chung, Kian Fan

AU - Adcock, Ian M.

AU - Djukanovic, Ratko

AU - Auffray, Charles

AU - Bansal, Aruna T.

AU - Sousa, Ana R.

AU - Wagers, Scott S.

AU - Chawes, Bo Lund

AU - Bønnelykke, Klaus

AU - Sørensen, Søren Johannes

AU - Kraneveld, Aletta D.

AU - Sterk, Peter J.

AU - Roberts, Graham

AU - Bisgaard, Hans

AU - Maitland-van der Zee, Anke H.

AU - U-BIOPRED Study Group

PY - 2023

Y1 - 2023

N2 - Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-β (transforming growth factor-β) (highest in the Veillonella cluster) and Wnt/β-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.

AB - Rationale: Children with preschool wheezing or school-age asthma are reported to have airway microbial imbalances. Objectives: To identify clusters in children with asthma or wheezing using oropharyngeal microbiota profiles. Methods: Oropharyngeal swabs from the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) pediatric asthma or wheezing cohort were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity. Enrichment scores of the Molecular Signatures Database hallmark gene sets were computed from the blood transcriptome using gene set variation analysis. Children with severe asthma or severe wheezing were followed up for 12-18 months, with assessment of the frequency of exacerbations. Measurements and Main Results: Oropharyngeal samples from 241 children (age range, 1-17 years; 40% female) revealed four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The oropharyngeal clusters were different in the enrichment scores of TGF-β (transforming growth factor-β) (highest in the Veillonella cluster) and Wnt/β-catenin signaling (highest in the Haemophilus cluster) transcriptomic pathways in blood (all q values <0.05). Conclusions: Analysis of the oropharyngeal microbiota of children with asthma or wheezing identified four clusters with distinct clinical characteristics (phenotypes) that associate with risk for exacerbation and transcriptomic pathways involved in airway remodeling. This suggests that further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.

KW - asthma

KW - microbiota

KW - phenotype

KW - precision medicine

KW - wheezing

U2 - 10.1164/rccm.202211-2107OC

DO - 10.1164/rccm.202211-2107OC

M3 - Journal article

C2 - 37163754

AN - SCOPUS:85164844622

VL - 208

SP - 142

EP - 154

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 2

ER -