Date of Award
Doctor of Philosophy
Theses & dissertations (Interdisciplinary)
Michael J. Wannemuehler
Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract (GI) that develops in part as a result of an aberrant immune response to enteric bacteria in the GI tract. The initial provocation and subsequent inflammatory trigger(s) that contribute to the pathogenesis of IBD have yet to be fully elucidated. A multiple-hit model of IBD was developed using defined flora (DF) mice as a model to address the aberrations in the immune response that develop following colonization with a bacterial provocateur prior to an environmental/inflammatory trigger. These studies demonstrated that Helicobacter bilis colonization of immune competent, DF mice induced antigen-specific Th1 and Th17 immune responses to antigens derived from their resident flora, thus, predisposing the host to colitis following exposure to an otherwise innocuous inflammatory insult.;It was hypothesized that the nature of the provocateur (i.e., virulence potential) influences the manner in which the host reacts to its microflora, thus, modulating the susceptibility to subsequent colitic insults (i.e., triggers). Depending on the severity of a subsequent inflammatory insult, these studies demonstrated that introduction of a non-pathogenic, commensal strain of Escherichia coli could also serve as a mucosal provocateur and that its impact on the colonic mucosal homeostasis (e.g., gene expression, aberrant immunity) is a critical factor that predisposes to the onset of IBD. Furthermore, the interaction between luminal bacteria and host epithelial cells are likely central to the induction of colitis since bacterial colonization of the mucosal epithelium provoked innate responses that contributed to the induction of mucosal inflammation that correlated with the in vivo severity of mucosal inflammation observed.;Collectively, these results have demonstrated the importance of the enteric flora in the development of IBD in an immune competent animal. Future research efforts should focus on determining the mechanism(s) underpinning the initial host-bacterial interactions that contribute to a dysregulation of immunological tolerance to the resident flora, resulting in aberrant immune responses that predispose to IBD.
Digital Repository @ Iowa State University, http://lib.dr.iastate.edu/
Abigail Lynn Henderson
Henderson, Abigail Lynn, "Provocateurs and triggers: induction of antigen-specific responses to the colonic resident microbiota and susceptibility to colitis" (2008). Retrospective Theses and Dissertations. 15683.