P059 INDOLEAMINE 2,3-DIOXYGENASE 1 EXPRESSION PROMOTES EPITHELIAL SECRETORY CELL DIFFERENTIATION VIA ARYL HYDROCARBON RECEPTOR

Abstract

In mouse models of IBD, the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) has been shown to limit disease severity. Our studies indicate that intestinal epithelial cells are an important source of IDO1 expression in these conditions; however the mechanism remains unknown. We have identified IDO1 expression in goblet cells as well as colocalization with secreted mucin. As mucin is both a physical barrier against bacterial invasion and an energy substrate for luminal microbes, we hypothesized that epithelial IDO1 may limit colitis severity is through enhancement of mucus barrier function. We generated a novel transgenic mouse model which overexpresses EGFP-tagged IDO1 specifically in the intestinal epithelium (IDO1-TG). Primary epithelial spheroid cultures were utilized to assess growth and gene expression by RT-qPCR and immunofluorescence in vitro. Histology revealed an increase in goblet and Paneth cells in IDO1-TG small intestine tissue. Analysis of gene expression in enteroids revealed higher levels of stem cell markers Lgr5 and Lrig1 in IDO1-TG compared to wildtype (WT). Additionally, the secretory lineage transcription factor Atoh1 and downstream effector Gfi1 were significantly upregulated in IDO1-TG, leading to enhanced secretory lineage markers for Paneth cells, goblet cells, and enteroendocrine cells, and a reduction in absorptive cell markers. Enteroids genetically deficient of Ido1 showed the opposite trend. Inhibition of IDO1 did not reduce expression of secretory cell markers, but incubation with a specific inhibitor of the aryl hydrocarbon receptor restored baseline expression levels. Taken together, these data indicate expression of IDO1 in the intestinal epithelium promotes secretory cell differentiation and mucus production, whereby identifying a novel mechanism by which non-enzymatic activity of IDO1 modulates intestinal homeostasis.View Large Image Figure ViewerDownload Hi-res image Download (PPT)