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Date of Award

Spring 5-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

The intestinal commensal microbiota has been implicated in the development of numerous human disorders. However, whether the microbiota is directly involved in the disease process and the key bacterial taxa that might initiate or propagate disease, has been difficult to discern. In this thesis we study immune activation against commensal bacteria to investigate bacterial role in disease. In patients with Inflammatory bowel disease (IBD), we observed significantly higher mucosal immunoglobulin (Ig) responses against fecal commensal bacteria as compared to healthy individuals. These responses correlated with increasing Crohn’s disease (CD) and Ulcerative colitis (UC) disease activity. Furthermore we identified bacterial taxa that are uniquely immunogenic in CD or UC and others that might be specifically involved in active vs. inactive disease. In contrast to IBD which is a bonafide intestinal inflammatory disorder, we also studied Irritable bowel syndrome (IBS) which is primarily considered a somatization disorder with potential involvement of the commensal microbiota, an altered gut-brain axis and altered motility. Surprisingly we observed a role for bacterial driven inflammation as there was significantly increased immunoglobulin targeted bacteria in diarrhea-predominant IBS (IBSd) patients as compared to controls or Celiac Sprue patients, excluding a generic inflammation driven phenomenon. To model IBS in mice, we utilized a restraint stress paradigm that led to increased diarrheal features, visceral hypersensitivity and increased bacterial-targeted immune activation also observed in IBSd. We show that stress induced microbial dysbiosis drives these features that can be observed a week after stress and that dysbiosis is in fact sufficient in the absence of concurrent stress. Notably, increased immune activation in IBSd also correlates with microbial dysbiosis and somatization severity, a metric to assess undue physiologic stress. Thus, in this work we highlight the role of dysbiotic commensal bacteria in driving exaggerated immune responses and potentially contributing to disease pathogenesis in IBD and IBS patients.

Language

English (en)

Chair and Committee

Chyi-Song Hsieh

Committee Members

Matthew Ciorba, Rodney Newberry, Andrew Kau, Gautam Dantas,

Comments

Permanent URL:https://doi.org/10.7936/xnpt-8952

Available for download on Monday, May 15, 2119

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