Crohn’s disease (CD) is an inflammatory bowel disease characterised by chronic inflammation with a complex pathophysiology involving host, environmental, and microbial factors. The intestinal microbiota is an important regulator of inflammation within the intestine, and a disruption of the interplay between gut bacteria and host immunity is a key factor in CD development. Intestinal inflammation itself is known to cause changes to the intestinal physiology that affect the ability of various bacteria to survive. Additionally, certain environmental risk factors for CD such as antibiotics are also known for their ability to impact the intestinal microbiota. CD is associated with various changes in the intestinal microbiome including increased colonisation with a group of bacteria known as adherent-invasive Escherichia coli (AIEC). The purpose of this study is to investigate how AIEC interact with antibiotics and intestinal inflammation in vivo. Multiple classes of antibiotics were found to increase the colonisation of AIEC and to increase its persistence. These antibiotics caused a loss diversity in the intestinal microbiome, but this did not explain the increased infectivity of AIEC. Antibiotic-induced inflammation was found to produce metabolites that benefitted AIEC growth in the intestine and similar results were found with chemically-induced inflammation. These results show that AIEC can benefit from both antibiotics and other sources of inflammation through inflammation-derived metabolites, which contributes to a greater understanding of the interactions between AIEC and CD. / Thesis / Doctor of Philosophy (PhD) / Crohn’s disease is a type of inflammatory bowel disease that affects many young adults in Canada. It causes a wide range of symptoms including nausea, pain, and diarrhea. While the disease can be treated with surgery and medications, it is considered incurable and affects most individuals for life. The exact cause of Crohn’s disease is not known, but it is thought to be caused by a combination of factors including genetics, environmental exposures, and changes in the number and types of bacterial species in the intestine. Intestinal bacteria play an important role in preventing inflammation in the intestine. An unusual strain of bacteria called adherent-invasive E. coli is found more commonly in Crohn’s disease patients than in healthy individuals. This strain does not cause the disease on its own, but it may interact with other environmental factors that are also associated with Crohn’s disease, such as taking antibiotics. Antibiotic use is a risk factor for developing Crohn’s disease later in life and antibiotics have previously been shown to promote the growth of other E. coli strains in the intestine. In a mouse model of Crohn’s disease, we found that antibiotics made mice more vulnerable to infection with this E. coli strain. This increased vulnerability was because the antibiotics caused inflammation, and we also found that other sources of inflammation benefitted this E. coli strain. These findings help us understand how gut bacteria and other Crohn’s disease risk factors might interact to cause the disease.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24303 |
| Date | January 2019 |
| Creators | Oberc, Alexander |
| Contributors | Coombes, Brian, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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