ARYL HYDROCARBON RECEPTOR REGULATES GENES IN COLONIC EPITHELIAL CELLS TO MITIGATE COLITIS SEVERITY IN THE DSS-INDUCED MURINE MODEL

Abstract

Abstract Current treatment of ulcerative colitis (UC) leaves a clear unmet need to target the colonic epithelial cells (CECs). In our previous study we found that aryl hydrocarbon receptor (AhR) expression on CECs has a vital role during indole-3-carbinol (I3C)-mediated protection against colitis. However, the precise mechanism behind this remains unclear. We investigated how intestinal regulatory components were altered in the absence or presence of AhR in CECs during I3C treatment under colitis (mouse model) or colitis-like conditions (colonic organoid). We generated conditional AhR-CEC knockout mice (AV) and induced colitis using the dextran sodium sulfate (DSS) model. Our results showed that the AV mice lost the protective effects of I3C against colitis. AV mice had higher disease scores and increased inflammation compared to controls. I3C treated AV mice that had DSS induced colitis were not able to regulate the colitis-associated parameters, even though flow cytometry analysis revealed AV mice were still capable of increasing protective interleukin-22 (IL-22) production in the colon. These results prompted us to study the CEC-specific mechanism involved in I3C-mediated protection against colitis. Whole transcriptome analysis of RNA isolated from enriched CECs of experimental mice was performed and results showed significant altered expression of several microRNAs, mucins (muc2 and muc13), and tight junction proteins (Cld3 and Cld4) in AV mice when compared to controls. RT-PCR data and direct effects of I3C on CECs (immunostaining) using organoids validated these results. This data concluded that AhR-dependent signaling orchestrates I3C-mediated protection of colitis. NIH 5P20GM103641