Degree Type

Dissertation

Date of Award

2017

Degree Name

Doctor of Philosophy

Department

Veterinary Microbiology and Preventive Medicine

Major

Immunobiology

First Advisor

Michael J. Wannemuehler

Second Advisor

Albert E. Jergens

Abstract

Inflammatory bowel disease is a group of chronic intestinal inflammatory disorders with a complex etiology, and has been associated with a microbial dysbiosis and presence of GI pathogens including adherent and invasive Escherichia coli (AIEC) and Campylobacter. A gnotobiotic murine model (altered Schaedler flora, ASF) devoid of proteobacteria was utilized to evaluate microbial and host responses after colonization with AIEC LF82, E. coli Nissle 1917, and C. jejuni alone or treated with dextran sodium sulfate (DSS). The ultimate goal of this research was to understand the effects on mucosal homeostasis after disturbance of the resident microbiota by proteobacterial pathobionts. As few studies have evaluated the stability of the microbiota over multiple generations, Chapter 3 evaluates the impact of AIEC LF82 colonization on the heritability/transmissibility of the ASF over multiple generations. Results indicated minimal changes in ASF abundance within a generation, but there was a significant shift in the microbial population when comparing early and later generations. As early-life microbial exposures have been demonstrated to influence mucosal homeostasis later in life, Chapter 4 describes changes in the sensitivity to colitis following E. coli LF82 colonization of ASF mice as an adult or neonate. We demonstrate neonatal colonization with LF82 increases the susceptibility to colitis, with increased inflammatory responses and minimal microbial changes, with neonatal colonization inducing subclinical, chronic inflammation that may predispose to more severe inflammation. In Chapter 5 of this dissertation, the benefits associated with probiotic Escherichia coli Nissle 1917 (EcN) colonization of neonatal mice to prevent or attenuate colitis as described in Chapter 4 were evaluated. Results indicated that co-colonization of neonatal mice with EcN did not impact the severity of colitis, but did reduce the host’s proinflammatory cytokine response. Finally, in Chapter 6, both conventional and gnotobiotic mice were used to demonstrate that the pathogenesis of C. jejuni is differentially influenced by the complexity of the microbiota. By investigating host-microbial relationships and their effects on intestinal homeostasis, this work provided insights into the underlying mechanisms contributing to the onset of inflammatory bowel disease, as well as what constitutes a ‘healthy’ state in the relationship with our gut microbiota.

Copyright Owner

Meghan Joyce Wymore Brand

Language

en

File Format

application/pdf

File Size

230 pages

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