Date of Award
Spring 6-8-2024
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
George O'Toole
Abstract
In the quest to understand the complex interplay between the gut microbiota and cystic fibrosis (CF), a disease characterized by chronic upper respiratory complications and an exacerbated proinflammatory response, our lab engaged in a collaborative study with Dartmouth-Hitchcock Medical Center (DHMC) to characterize the gut microbiota of pediatric CF patients. Initial analyses established a connection between gut microbial composition and respiratory health, particularly highlighting a scarcity of Bacteroides species compared to healthy controls. In following investigations, we utilized random forest models to understand how stool microbiota may influence clinical outcomes of these pediatric CF patients, including: age, upper respiratory infections, and proinflammatory biomarkers like NLR. We identified specific bacterial genera including Faecalibacterium, Butyricoccus, and Bacteroides as significant indicators of upper respiratory infection frequencies within the first two years of life.
A deeper dive into the functional role of Bacteroides revealed their capacity to suppress IL-8 production, attenuating inflammation in CFTR−/− intestinal epithelial cells. This anti-inflammatory action was further evidenced in a CF mouse model, where Bacteroides supplementation yielded a local increase in propionate levels and a significant reduction in systemic pro-inflammatory cytokines, showcasing the potential of gut microbiota manipulation in managing CF-related inflammation.
A pivotal element of our study was the examination of microbiota biogeography within the gut, assessing how spatial distribution across various gut regions, particularly the colon's luminal and mucosal surfaces, influences microbial diversity and immune gene expression. Our findings indicate that while Bacteroides supplementation post-antibiotic treatment successfully colonizes the gastrointestinal tract, it primarily establishes in the luminal colon and by itself does not drive huge differences in alpha or beta diversity, as measured by 16s RNA amplicon sequencing. Gavage with Bacteroides further showed the highest response by the host in the small intestine, where the most regulated pathways are those regulating the adaptive immune system.
This thesis underscores the therapeutic promise of tailored gut microbiota management, highlighting how microbial biogeography informs the modulation of systemic inflammation in CF. The nuanced understanding of these spatial microbial patterns, and their interplay with host immune responses, charts a course for innovative, microbe-centered interventions, leveraging the gut-lung axis to ameliorate the burdens of this chronic disease.
Recommended Citation
Valls, Rebecca A., "Establishment of Bacteroides in the gut and its role in the cystic fibrosis gut-lung axis" (2024). Dartmouth College Ph.D Dissertations. 284.
https://digitalcommons.dartmouth.edu/dissertations/284
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