Colitis is an inflammatory bowel disorder (IBD) characterized by chronic inflammation of the large intestine or colon. This disease, affecting over 1 million people and costing over a billion dollars/year in the US alone, has a complex etiology and to date, there are few and effective treatment options to patients. In the current study, we demonstrate that in TNBS-induced colitis, a natural indole product found in numerous cruciferous vegetables (Indole-3-carbinol, or I3C) and ligand for the aryl hydrocarbon receptor (AhR) is effective at preventing symptoms of colitis. Most notably, I3C was able to prevent colitis-associated dysbiosis and increase colonic butyrate. Specifically, I3C prevented increases in colitis-associated gram-negative bacteria (e.g. Bacteroides acidifaciens), while also increasing butyrate producing Roseburia. IL-22 was found to be significantly increased after I3C treatment, and neutralization of this cytokine prevented I3C from reducing disease severity and altering the gut microbiome and metabolome. In the current proposal, the central hypothesis is I3C mediates its beneficial effects through regulation of cross talk immune cells and colonic epithelial cells (CECs) by activation of AhR and depends on IL-22 production to mediate its protective effects during colitis.
The aims of this study will be as follows: 1.) Dependency of AhR in I3C-mediated protective effects will be investigated using conditional KO of AhR on immune cells (T cells and innate lymphoid type 3 cells/ILC3s) or CECs, both of which express AhR. These studies will determine if I3C-mediated effects are dependent on AhR expression in immune cells and/or CECs in preventing colitis and altering disease-associated microbial dysbiosis and the metabolomic profile,. Focus on the impact AhR plays in regulating I3C-mediated modulation of IL-22 will be performed to identify AhR-specific dioxin response elements (DREs) on IL-22 and IL-22 promoting genes. 2.) Additionally, studies will be conducted to determine the cell source of IL-22 production and investigate epigenetic modifications( microRNA/miRNA and DNA methlyation) affecting IL-22, which could be mediated by I3C treatment during colitis.
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