Intestinal epithelium intrinsic RARα signaling regulates gut barrier integrity via IL-18

Abstract

Abstract Intestinal epithelium, overlying mucus layer and anti-microbial peptides together form a physico-chemical barrier crucial for homeostasis with the gut microbiota. Intestinal epithelial cells (IECs) are at the frontline of host-microbe interactions in the gut, yet how they modulate barrier function in response to dietary cues is poorly understood. Vitamin A and its key metabolite retinoic acid (RA), are crucial regulators of gut immune homeostasis. In this study, we employ a mouse model that expresses a dominant negative retinoic acid receptor exclusively in IECs (dnRARVillin-Cre) to establish a novel role for RA signaling in regulating the mucus barrier. The absence of RA signaling in colonic epithelium resulted in significant increase in mucus layer thickness indicating that RA regulates goblet cell function. Concomitant with this, we observed that in dnRARVillin-Cre mice there are more goblet cells and an enhanced spatial separation between host and the gut microbiota. Further, we showed that dnRARVillin-Cre mice have a diminished sensitivity to chemically induced colitis in comparison to wild-type mice. Quantitative RNA and protein analysis uncovered that gene transcription and protein activation and secretion of key pro-inflammatory cytokine IL-18 was severely impaired in epithelium of dnRARVillin-Cre mice. IL-18 has previously been shown to act as a negative regulator of goblet cell function in the intestinal epithelium. We now show that intestinal epithelium intrinsic RA signaling can modulate IL-18 levels to regulate the mucus barrier. Our results have thus disclosed a novel link between a diet derive metabolite and intestinal epithelial cell function that can be harnessed to modulate mucosal immunity.