The organisation and function of the gut microbiota in cystic fibrosis

Marsh, Ryan (2024) The organisation and function of the gut microbiota in cystic fibrosis. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

People with cystic fibrosis (pwCF) suffer from a range of gastrointestinal manifestations of disease, which has increased in prevalence as respiratory outcomes improve and life expectancy raises. This translates to the occurrence of daily GI symptoms for many pwCF, which is a top research priority to alleviate. The gut microbiota is altered in CF and has been shown to associate with intestinal abnormalities, therefore offers a potential avenue of therapeutic intervention by its modulation. This thesis investigated relationships between the microbiota and associated functions, intestinal outcomes, and cystic fibrosis transmembrane regulator (CFTR) modulator usage. Initially, relationships between altered intestinal function and physiology in CF were revealed with microbiota, by combining 16S rRNA gene sequencing data with magnetic resonance imaging (MRI) results and clinical metadata across pwCF and healthy controls. Significant differences in diversity and composition were observed between groups, which further associated with clinical factors and markers of intestinal function. To understand how microbiota function might be compromised in CF, a sensitive method to profile and quantify faecal short-chain fatty acids (SCFAs) using gas chromatography-mass spectrometry (GC-MS) was validated. This was subsequently used to demonstrate that overall SCFA compositional differences persist between healthy controls pwCF receiving Tezacaftor/Ivacaftor CFTR modulator therapy, further extending to microbiota compositional differences, which were also not significantly altered by treatment. Finally, microbiota composition and function were assessed across pwCF receiving more efficacious Elexacaftor/Tezacaftor/Ivacaftor (ETI) therapy. Subtle differences were observed following extended ETI administration, yet microbiota and SCFA compositions remained significantly different from controls. Interestingly, there were no differences across the most abundant SCFAs, indicating possible functional redundancy in the CF microbiota. Overall, the results obtained in this thesis advocate for further investigation of microbiota function through more sophisticated metagenomic and untargeted metabolomic approaches, to unravel the complex relationships between the microbiota, gastrointestinal (GI) manifestations, and patient symptoms in CF.