Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Palm, Noah
Abstract
Gut commensals with the capacity to translocate across the intestinal barrier can drive the development of diverse immune-mediated diseases. However, the key factors that dictate bacterial translocation remain unclear. Recent studies have revealed that gut microbiota strains can adapt and evolve throughout the lifetime of the host, raising the possibility that changes in individual commensals themselves over time may impact their propensity to elicit inflammatory disease. Here we show that within-host evolution of the model gut pathobiont Enterococcus gallinarum facilitates bacterial translocation and initiation of chronic inflammation. Using a combination of in vivo experimental evolution and comparative genomics, we found that E. gallinarum diverges into independent lineages adapted to colonize either luminal or mucosal niches in the gut. Compared to ancestral and luminal E. gallinarum, mucosally-adapted strains evade detection and clearance by the immune system, exhibit increased translocation to and survival within the mesenteric lymph nodes and liver, and initiate inflammatory responses in the intestine and liver. Mechanistically, these changes in bacterial behavior are associated with non-synonymous mutations or indels in defined regulatory genes in E. gallinarum, altered microbial gene expression programs, and remodeled cell wall structures. By extending to other commensal species, we found that Lactobacillus reuteri also exhibited broadly similar patterns of divergent evolution and enhanced immune evasion in a monocolonization-based model of within-host evolution. Overall, these studies define within-host evolution as a critical regulator of commensal pathogenicity that provides a unique source of stochasticity in the development and progression of microbiota-driven disease.
Recommended Citation
Yang, Yi, "A Novel Microbial Source of Stochasticity in Microbiota-Driven Diseases" (2023). Yale Graduate School of Arts and Sciences Dissertations. 938.
https://elischolar.library.yale.edu/gsas_dissertations/938
