Analysis of microbiome-based asthma phenotypes
File(s)
Author(s)
Versi, Ali
Type
Thesis
Abstract
Background: Asthma encompasses several clinical phenotypes. Metagenomic sequencing enables species-level characterisation and functional profiling. Characterisation of the airway microbiome, dysbiosis phenotypes and host-microbial crosstalk is wanting.
Methods: Metagenomic sequencing of induced sputum from asthmatic patients (n=148) was performed. Patient data was stratified by asthma severity, inflammatory status and human transcriptome-associated clusters (TACs). Dysbiosis phenotypes associated with high abundance bacterial species were determined. A relative dominant species (RDS) was defined and characterised using sputum transcriptomics. Crosstalk between host immune responses and the microbiome was evaluated in early- (EO) and late-onset (LO) asthma.
Results: Reduced alpha-diversity occurred with severity and was accompanied by an increase in Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mc) in non-smokers. Hi and Tropheryma whipplei (Tw) were increased in ex- and current smokers.
53% of samples were classified as RDSs with Hi RDS being most common (31%). Hi RDS had the longest disease duration. Clustering of RDSs revealed a cluster (n=9) of exclusively Hi RDSs with a longer duration of disease, higher sputum neutrophilia associated with enrichment of MAPK, NF-B, TNF, mTOR and necroptosis pathways. This cluster was also enriched for neutrophil extracellular traps (NETosis) and Th-17 activation.
Host-microbial integrative analysis revealed shared pathways between EO and LO phenotypes although the constituent genes and species were different. Barrier function and adhesion molecule-associated pathways were associated with EO asthma. Mc was only associated with pathways in EO and Tw with pathways only in LO.
Conclusions: Hi and Mc were more abundant in neutrophilic asthma and linked to inflammasome. Hi and Tw were linked to TAC1 and ILC2 signatures. A Hi abundant cluster with neutrophilic activation and NETosis driven by host-microbial interaction was elucidated in EO asthma. Shared pathways with unique host-microbe interactions exist between EO and LO asthma indicating distinct mechanisms underpinning the heterogeneity of asthma immunopathophysiology.
Methods: Metagenomic sequencing of induced sputum from asthmatic patients (n=148) was performed. Patient data was stratified by asthma severity, inflammatory status and human transcriptome-associated clusters (TACs). Dysbiosis phenotypes associated with high abundance bacterial species were determined. A relative dominant species (RDS) was defined and characterised using sputum transcriptomics. Crosstalk between host immune responses and the microbiome was evaluated in early- (EO) and late-onset (LO) asthma.
Results: Reduced alpha-diversity occurred with severity and was accompanied by an increase in Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mc) in non-smokers. Hi and Tropheryma whipplei (Tw) were increased in ex- and current smokers.
53% of samples were classified as RDSs with Hi RDS being most common (31%). Hi RDS had the longest disease duration. Clustering of RDSs revealed a cluster (n=9) of exclusively Hi RDSs with a longer duration of disease, higher sputum neutrophilia associated with enrichment of MAPK, NF-B, TNF, mTOR and necroptosis pathways. This cluster was also enriched for neutrophil extracellular traps (NETosis) and Th-17 activation.
Host-microbial integrative analysis revealed shared pathways between EO and LO phenotypes although the constituent genes and species were different. Barrier function and adhesion molecule-associated pathways were associated with EO asthma. Mc was only associated with pathways in EO and Tw with pathways only in LO.
Conclusions: Hi and Mc were more abundant in neutrophilic asthma and linked to inflammasome. Hi and Tw were linked to TAC1 and ILC2 signatures. A Hi abundant cluster with neutrophilic activation and NETosis driven by host-microbial interaction was elucidated in EO asthma. Shared pathways with unique host-microbe interactions exist between EO and LO asthma indicating distinct mechanisms underpinning the heterogeneity of asthma immunopathophysiology.
Version
Open Access
Date Issued
2024-05-30
Date Awarded
01/03/2025
License URL
Advisor
Adcock, Ian Michael
Chung, Kian Fan
Kermani, Nazanin Zounemat
Publisher Department
National Heart & Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)