Date of Award

2019

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell Biology, Neurobiology and Anatomy

Abstract

Inflammatory Bowel Disease (IBD) remains a prominent medical concern affecting over 1.4 million people in the U.S. One of the most common forms of the disease is ulcerative colitis (UC), and UC patients will often head doctor's advice to refrain from drinking alcohol. However, whether this phenomenon of alcohol exacerbating UC symptoms occurs is still unknown, which necessitated the generation of a mouse model of UC and binge alcohol. Therefore, we examined a range of DSS concentrations (2-4%) and 2 alcohol paradigms in C57BL/6 mice. Mice receiving 2% DSS ad libitum for five days with a three-day alcohol binge had increased weight loss, colonic shortening, histopathology and clinical scores, and intestinal inflammation.During UC remission, IL-22 levels are upregulated. Following cessation of DSS, Vehicle treated mice were allowed to recover for 3 days. This resulted in increased levels of large intestine IL-22 in DSS Vehicle mice. Isolation of large intestine lamina propria cells revealed that DSS Vehicle treated mice had increased IL-22+ γδ T cells. However, these increased IL-22 levels and IL-22+ γδ T cells were abolished in DSS Ethanol mice.Alcohol's role in diminishing the IL-22 response needed for entrance into UC remission could potentially explain the UC symptom exacerbation we observed. Hence, we sought to induce IL-22 with either rIL-22 or treatment with the probiotic, Lactobacillus delbrueckii. Administration of rIL-22 attenuated alcohol induced exacerbation of UC symptoms. Furthermore, IL-22-mediated protection required STAT3 signaling, as STAT3-/- mice did not benefit from IL-22 treatment following DSS-induced colitis and alcohol. Lacto treatment also mediated protection against exacerbated UC symptoms by increasing pSTAT3.UC patients experience higher rates of intestinal infections. To model this, we utilized the enteropathogen, C. rodentium, and found DSS Ethanol + C. rod mice had decreased survival, increased weight loss, colon shortening, more severe histopathology scores, decreased colonic mucosal layer, reduced goblet cell number, decreased tight junction protein expression, increased inflammation, and increased colonization by C. rod.Our laboratory established a new model of binge alcohol exacerbating an UC flare while highlighting the protective role of IL-22, which could present a potential new therapeutic option for UC patients.

Creative Commons License

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

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