Date of Award

Summer 5-29-2024

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Benjamin D. Ross

Abstract

Cystic Fibrosis (CF) is a progressive genetic disease that leads to dysfunction of ion transport across epithelial cell membranes. A major hallmark in CF is chronic inflammation in the intestine, though the mechanisms by which this occurs are still unknown. Here, we describe the developing microbiome in CF infants. We first performed metagenomic sequencing on a longitudinal cohort of CF infants and compared the microbial dynamics of these samples to multiple non-CF cohorts. Through various computational approaches, we reveal a delay in the maturation of the microbiome in CF compared to non-CF, characterized by shifts in abundance and prevalence of species identified as biomarkers of age progression. These results motivate future mechanistic studies to determine whether this delay can be corrected using our age model species.

We then expanded upon this work to explore a specific metabolic pathway in CF. Indole is a beneficial derivative of the tryptophan metabolism pathway that is known to modulate intestinal inflammation. Metabolomics was performed on nine indole pathway metabolites and showed no differences between CF and non-CF samples in the first year. Machine learning was used to determine whether metabolite and metagenomic data are predictive of age and disease state. Metagenomic data was more predictive of both conditions, and non-CF machine learning models are more predictive than CF models. Reiterating the developmental delay in the CF microbiome, we emphasize the importance of correcting dysbiosis in future work.

Finally, we look at B. fragilis, which is altered in CF and investigate the effects of an associated zinc-metalloprotease toxin, B. fragilis toxin (BFT) on non-CF primary colonoids. Our preliminary results contradict the existing body of BFT literature; thus, further exploration is required prior to making any definitive conclusions on the impact of BFT in human colonoids, and before expanding into CF samples.

Together, we took a comprehensive computational approach to exploring the developing intestinal microbiome in infants with CF and reveal several novel findings that have created opportunities for future experiments with the goal of motivating novel therapeutic development to improve the quality of life of these patients.

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