Abstract 5035: Effect of FXR agonist on colitis and colorectal carcinogenesis in mice

Abstract

Abstract Background & Aims: Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and bile acids are endogenous ligand of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. FXR activation has recently reported to inhibit intestinal inflammation and tumor development. The aim of this study was to investigate whether FXR agonist prevents colitis and colorectal carcinogenesis in mice. Methods: We achieved two experiments. One experiment (Ex.1) used mouse colitis model with short term administration of FXR agonist, Nelumal A, and the other (Ex.2) employed mouse carcinogenesis model with long term administration. In Ex.1, male 5 week old A/J mice received drinking water containing 1.5% DSS for one week and were fed diets containing 100 or 400 ppm Nelumal A for 4 weeks. In Ex.2, male 5 week old A/J mice were administered once intraperitoneal injec¬]]tions of AOM (20 mg/kg body weight) and after one week, mice received drinking water containing 1.5% DSS for one week and were fed diets containing 100 or 400 ppm Nelumal A for 15 weeks. Results: In Ex.1, DSS-treated mice all had colitis and multiple colonic mucosal ulcers. Both mucosal ulcer and inflammation grade in colon were significantly reduced in 400 ppm Nelumal A-treated mice, and also tended to be reduced in 100 ppm Nelumal A-treated mice. Body weight loss and colon length had no significant difference. The results of Ex.2 showed that the number of colonic mucosal ulcer, adenoma, and adenocarcinoma and total tumor number were decreased in 400 ppm Nelumal A-treated mice, but there was no statistically significant difference. The expression levels of FXR mRNA in colonic mucosa were increased by Nelumal A treatment. Moreover, administration of Nelumal A significantly decreased the expression levels of tumor necrosis factor α, monocyte chemoattractant protein 1, and proliferating cell nuclear antigen, and increased the level of Bax in colonic epithelium. Conclusion: FXR agonist prevents chemically induced intestinal inflammation and carcinogenesis by inhibition of proinflammatory cytokine production and cell proliferation and promotion of apotosis in colonic mucosa. Citation Format: Tsuneyuki Miyazaki, Takahiro Kochi, Hiroyasu Sakai, Yohei Shirakami, Masahito Shimizu, Takuji Tanaka, Hisataka Moriwaki. Effect of FXR agonist on colitis and colorectal carcinogenesis in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5035. doi:10.1158/1538-7445.AM2015-5035