Date of Award

Summer 2021

Degree Type

Thesis

Director of Thesis

Philip Brandon Busbee, Ph.D.

First Reader

Shaneika Staley

Second Reader

Shaneika Staley

Abstract

Colitis is an inflammatory bowel disorder (IBD) whose etiology is attributed to modification in the luminal microbiota and dysregulation in the immune response. Indole is a signaling molecule which is naturally produced by gut luminal microbiota. Indole-3- carbinol (I3C) is a compound commonly found in vegetables and a ligand for the aryl hydrocarbon receptor (AhR). Previous studies have detected decreased expression and activation on the AhR receptor in colitis patients, thought to possibly alter gut microbiota metabolism, subsequently promoting colitis. 1 AhR, expressed in a variety of immune and epithelial cells, contributes to gut homeostasis by affecting vital mediators such as regulatory T cell (Treg)/T helper 17 (Th17), colonic epithelial cell (CEC)- regenerating interleukin 22 (IL-22) production, and secretion of the protective mucous layer and antimicrobial peptides (AMPs) by CECs. I3C in previous experiments has been shown to help prevent colitis through induction of IL-22 via innate lymphoid type 3 cells (ILC3s). In this study, we investigated how AhR deficiency in Rorc-expressing cells (which we refer to as AR mice) affects anti-inflammatory immune response during I3C treatment of colitis, whether I3C-AhR interaction in CECs increase IL-22 production during colitis, and the effect of AhR deficiency on epigenetic modifications induced by I3C during colitis. A dextran sodium sulphate (DSS) colitis mouse model was used in this study to mimic the effects of ulcerative colitis and was introduced into drinking water and treatments of I3C treatment were given. Results showed compared to wild-type (WT) AR mice induced with colitis were unaffected by 13C treatment. In addition, the protective IL-22 production by ILC3s was lost for the AR mice. Lastly, we show that I3C treatment does induce epigenetic modifications (i.e. DNA methylation) in the promoter region of IL-22. Thus, we conclude AhR knockout in Rorc-expressing immune cells mice resist the production of IL-22 via ILC3s after I3C treatment during DSS-induced colitis, and loss of this potential protective cytokine prevents I3C-mediated beneficial alterations in the gut microbiome.

First Page

1

Last Page

16

Rights

© 2021, Michal C Williams

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