Degree Type

Dissertation

Date of Award

2012

Degree Name

Doctor of Philosophy

Department

Veterinary Microbiology and Preventive Medicine

First Advisor

Michael Wannemuehler

Abstract

The gut microbiota is a complex community that consists of 1011-1012 organisms per gram of colonic contents and over 150-fold more genes than the human genome. This community has evolved with its eukaryotic host to form a mutualistic relationship. It has been known that the microbiota is involved in the production of vitamins, the breakdown of dietary substances and the maturation of the immune system. Recent work has expanded the role of the microbiota in human health. The microbiota has been implicated in the regulation of fat storage and diseases such as ulcers, diabetes, obesity, cardiovascular disease, and inflammatory bowel disease (IBD).

The work in this dissertation focuses on the role of the microbiota in IBD, a disease of unknown etiology. Several factors contribute to the development of disease, including environmental factors, host genetics, the immune response, and the gut microbiota. An environmental factor that has become increasingly recognized as a critical component in shaping the microbiota is the use of antibiotics and the potential link to IBD. The research summarized in chapter 2 reveals the effects that antibiotics have on a limited microbiota, the altered Schaedler flora (ASF). Use of a limited microbiota affords the ability to monitor effects of antibiotics on the entire community that would be missed when using a conventional microbiota. Following treatment with ampicillin, mice harboring the ASF developed more severe disease in response to a colitic insult than did mice bearing a conventional microbiota, indicating a central role for the microbiota in reducing disease severity. Those conventional mice that received ampicillin prior to colitic insult revealed that the ASF in a more complex community was less affected by the administration of antibiotics. However, conventionally-reared mice harboring a complex microbiota did exhibit low grade inflammation following colitic insult and eventually developed a physiological profile consistent with the onset of metabolic syndrome.

The research summarized in chapter 3, evaluated the immunomodulatory and anti-bacterial properties of ethanolic extracts of Prunella vulgaris and Hypericum gentianoides, which have the potential to be used as complementary and alternative treatments for gastrointestinal diseases including IBD. There is no cure for ulcerative colitis or Crohn's disease, and many of the treatments have severe side effects. This has caused some patients to seek alternative therapies to manage their disease. In chapter 3, herbal therapies were administered prophylactically to mice harboring the ASF to assess their ability to prevent or attenuate DSS-induced colitis. The results revealed that one of the herbal therapies, P. vulgaris, was actually pro-inflammatory in the ASF mice as evidenced by the increased production of pro-inflammatory cytokines/chemokines. The other botanical extract, H. gentianoides, seemed to exert both anti-inflammatory and anti-bacterial effects in this murine model of colitis indicating a possible role for H. gentianoides as a therapy for IBD.

One of the consistent observations noted in IBD patients is that their microbiota is abnormal (i.e., dysbiotic) compared to healthy controls. Whether this change in the microbiota occurs post-inflammation, or if dysbiosis initiates the inflammation, is still up for debate. Summarized in chapter 4 are the results of a temporal study that chronologically evaluated changes in the microbiota and the host's inflammatory response over the course of disease using a spontaneous model of murine colitis. The results revealed that in this model, the mucosal inflammation occurs early, before the changes in the microbiota. This indicates that the inflammation is what drives the microbial changes seen in the diseased mice. In summary, studies described herein indicate that the microbiota plays a large role in the inflammatory processes of murine models of colitis.

DOI

https://doi.org/10.31274/etd-180810-1992

Copyright Owner

Anne-Marie Caroline Overstreet

Language

en

File Format

application/pdf

File Size

244 pages

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