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Nasopharyngeal Microbiome-Epigenome-Wide Association Analysis in Infants With Severe Bronchiolitis
Ryohei Shibata1, Yijun Li2, Anat Yaskolka Meir2
1Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Insights
Severe bronchiolitis in infants is linked to changes in airway bacteria and DNA methylation, potentially increasing asthma risk. These findings highlight microbiota-host interactions influencing immune responses.
Area of Science:
- Epigenetics and Microbiome Research
- Pediatric Respiratory Health
- Infant Health and Development
Background:
- Severe bronchiolitis in infants poses acute risks (hospitalization) and long-term respiratory issues (asthma).
- Microbiota and host genetic/epigenetic factors influence severe bronchiolitis outcomes.
- The link between airway microbiota and DNA methylation in severe bronchiolitis is not well understood.
Purpose of the Study:
- To investigate the association between nasopharyngeal microbiome and blood DNA methylation in infants with severe bronchiolitis.
- To explore DNA methylation age acceleration and its relation to asthma development.
- To functionally analyze asthma-related bacteria and their associated proteins and pathways.
Main Methods:
- Conducted microbiome-epigenome-wide association studies (mbEWAS) in 504 infants hospitalized for severe bronchiolitis.
- Analyzed nasopharyngeal microbiome and blood DNA methylation (Infinium MethylationEPIC BeadChip) data.
- Examined microbiota-associated differentially methylated CpGs (mbDMCs), regions (mbDMRs), DNA methylation age acceleration, and serum proteins.
Main Results:
- Identified 1 microbiota-associated differentially methylated CpG (mbDMC) and 96 differentially methylated regions (mbDMRs).
- Found that higher *Haemophilus influenzae* abundance correlated with DNA methylation age deceleration, a marker associated with increased asthma risk.
- Discovered 156 proteins linked to mbDMRs of asthma-related bacteria, enriched in immune response pathways.
Conclusions:
- Microbiome-epigenome-wide association studies reveal significant microbiota-host associations in severe bronchiolitis.
- These associations appear to play a role in regulating immune responses.
- Findings suggest potential epigenetic mechanisms linking early-life respiratory infections to later asthma development.
Background:
Bronchiolitis exposes infants to both acute burdens (e.g., hospitalization in cases of severe bronchiolitis) and increased risks for chronic respiratory sequelae (e.g., asthma). In severe bronchiolitis, recent evidence suggests distinct pathobiological roles of microbiota (e.g., viruses, bacteria) and host responses influenced by genetic and epigenetic factors. However, the relationship of airway microbiota with host DNA methylation (DNAm) in infants with severe bronchiolitis remains unknown.
Methods:
In a multi-center prospective cohort of 504 multi-ethnic infants with severe bronchiolitis (age < 1 year), using nasopharyngeal microbiome (exposure) and blood DNAm (outcome, Infinium MethylationEPIC BeadChip, Illumina) data within 24 h of the hospitalization, we conducted microbiome-epigenome-wide association studies (mbEWAS). We examined microbiota-associated differentially methylated CpGs (mbDMCs, false discovery rate [FDR] < 0.05), regions (mbDMRs, FDR < 0.05), and DNAm age acceleration. We also determined the associations of DNAm age acceleration with asthma development by age 6 years. Furthermore, we focused on asthma-related pathogenic bacteria-Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae-for functional analyses by examining serum mbDMR-related proteins (Proseek Multiplex, Olink) and their enriched pathways (FDR < 0.10).
Results:
Across 23 common taxa-observed at least in 25% of the infants, we identified 1 mbDMC (S. pneumoniae, cg16594639, chr20: 39528675) and 96 mbDMRs (e.g., S. pneumoniae, chr5:27038497-27038802, CDH9; chr6:48068669-48068940, PTCHD4). A higher H. influenzae abundance was associated with DNAm age deceleration, and the deceleration was associated with a higher risk of developing asthma. In 29 mbDMRs of the asthma-related pathogenic bacteria, we identified 156 mbDMR-related proteins (e.g., MMP9, XCL1). These proteins were enriched in immune response-related pathways (e.g., regulation of ERBB signaling and eosinophil chemotaxis and migration pathways).
Conclusions:
In this multi-center prospective cohort study of severe bronchiolitis, our mbEWAS suggested the microbiota-host associations that regulate immune responses.
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