Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

Inflammatory bowel diseases (IBD) affect a large number of individuals around the world. This group of diseases is largely composed of two types: Crohn's disease (CD) and ulcerative colitis (UC). Upon development of IBD, patients experience cyclical episodes of inflammation, known as flares. Flare induction appears to arise from multiple factors, which can also vary on a person-to-person basis. Alcohol has been shown to trigger IBD flares and onset, though the underlying mechanism has not been established.Defining factors of the IBD intestinal environment include an altered microbiome, bacterial infiltration of the intestinal epithelium, and increased leakage of proinflammatory bacterial byproducts. In particular there are noted increases in the pro-inflammatory Enterobacteriaceae bacteria and decreases in bacteria that promote intestinal health. Many of these bacterial changes in IBD parallel those seen in alcohol consumption, therefore we hypothesized that alcohol enhances the symptoms associated with colitis by altering intestinal bacterial populations.Using a patient database, we identified that individuals admitted for IBD with a concurrent documented history of alcohol use and admission for IBD had increased intestinal infections, increased diagnostic procedures, and increased antibiotic usage. Using a mouse model of colitis and ethanol administration developed in our lab, we identified that the combination of alcohol in the setting of colitis exacerbates overgrowth of the pro-inflammatory Enterobacteriaceae and limiting growth of healthy bacteria like Lactobacillus. This was found to be related to increased expression of intestinal nitric oxide synthase 2 (Nos2), which can facilitate growth of Enterobacteriaceae. Inhibition of nitrate production and nitrate utilization limited Enterobacteriaceae growth in colitis, but when alcohol was administered after colitis, the rise in Enterobacteriaceae was only slightly depressed. The combination of ethanol and colitis also led to alterations in the liver inflammatory response. In summary, the results of these studies have implications for limiting the exacerbation of colitis flares and possibly the induction of colitis flare through the promotion of a healthy intestinal microbiome and limitation of alcohol consumption.

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Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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