Abstract 396: The bile acid receptor FXR suppress colitis-induced colon cancer

Abstract

Abstract Colorectal cancer (CRC) is the third most common cancer and a major cause of cancer related death. Colitis-associated colorectal carcinoma (CAC) is a type of CRC that develops in patients with inflammatory bowel disease (IBD), and is associated with chronic, idiopathic intestinal inflammation. While the underlying cause(s) are poorly understood, environmental factors including high fat diets and aberrant intestinal immune responses contribute to disease progression. Bile acid (BA) overproduction is implicated in diarrhea associated with IBD and CAC. As early sensors of dietary status, BAs are critical mediators of gut inflammation and immunity, in part through their ability to affect the activity of the Farnesoid X Receptor (FXR). FXR is considered the master regulator of BA homeostasis, also a key modulator of the pro- and anti-inflammatory responses in the intestinal epithelium, whose function severely compromised in both CAC patients and in AOM/DSS mouse model. Here, we show that inflammation-induced epithelial abnormalities altered the BAs profile, given the role of the crypt-villus architecture in establishing a BA gradient necessary for homeostasis. In addition, AOM/DSS treatment enhanced immune cell infiltration, as well as induced the formation of massive tumors in the colon. Given that intestinally-restricted FXR agonist FexD can reduced tumorigenesis in APCmin/+ mice, we also treated AOM/DSS mice with FexD. Notably, FexD activated FXR signaling pathway and restored BA homeostasis. Further, it reduced fecal bleeding, intestinal permeability, and decreased serum levels of the late carcinogenesis markers CEA and CA19. Treatment of FexD also resulted in a smaller spleen and reduced pro-inflammatory cytokine levels such as IL17 and IL6. The present study highlights the role of FXR in inflammation induced colon cancer, opening new therapeutic avenues for the treatment of CAC. Citation Format: Ting Fu, Ronald Evans. The bile acid receptor FXR suppress colitis-induced colon cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 396.