The Role of the Microbiome in Cystic Fibrosis

Gavillet, Helen (2022) The Role of the Microbiome in Cystic Fibrosis. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Lung Infection is the leading cause of morbidity and mortality for people with Cystic Fibrosis (CF). Infection is monitored by culture-based microbiology and informs subsequent infection management and treatment. Molecular-based methodology have revealed these infections to be polymicrobial. However, how lung infection microbiota change through time is poorly understood, particularly in mild CF. This thesis investigated longitudinal lung pathogen and microbiota dynamics within respiratory samples derived over several years from a cohort of adult and paediatric CF patients with mild disease. First, diagnostic bacterial microbiology was compared to targeted quantitative PCR (qPCR). Prevalence of Pseudomonas aeruginosa and Staphylococcus aureus were significantly under-reported by diagnostic microbiology when compared to targeted qPCR. Further, qPCR revealed most patients were chronically infected with key pathogens which was missed by culture. This has wide-reaching implications for the development of chronic infection and clinical management of infection. Next, bacterial microbiota dynamics through time were investigated. A stable bacterial microbiota was found across adult and paediatric patients, with fluctuations in microbiota composition resulting from changes in acquisition and abundances of transient rare taxa. Furthermore, patients were found to have a tolerance for long-term S. aureus infection and the strict anaerobe Prevotella melaninogenica appeared to be a key component of infection in mild CF disease. Finally, temporal dynamics of the underexplored fungal microbiota were investigated to determine key fungal taxa associated with mild disease, along with comparisons to the bacterial microbiota. Patients were dominated by Candida taxa and new correlations between bacterial and fungal taxa were reported, suggesting a protective role for Candida in paediatric patients. Here molecular-based approaches have revealed novel aspects of pathogen and microbiota dynamics of fundamental importance to our understanding of mild CF lung microbiology. This understanding is important as more patients transition to mild disease phenotypes in the era of effective CF transmembrane conductance regulator (CFTR) modulator therapies.