S1652 The Effect of the Farnesoid X Receptor (FXR) and It's Agonist - GSK488062B - On Experimental Models of Colitis and Cytokine Production from IBD Tissue

Introduction: The Farnesoid X Receptor (FXR) is a nuclear hormone receptor involved in bile acid homeostasis with a high expression in liver and intestines. In the normal intestine, FXR induces transcription of cyto-protective and innate immune genes suggesting that modulation of FXR function may be a potential therapeutic approach for the treatment of inflammatory bowel disease (IBD). The aim of this study was to assess the role of FXR expression and function in models of colitis and on cytokine production from human colon IBD biopsy tissue. Methods: Wild type and FXR knock-out (FXRKO) mice received (1) 3.5% Dextran Sodium Sulphate (DSS) for 5 days and 3 days of water; (2) were orally gavaged with luciferase tagged Citrobacter rodentium. Faecal pellets were analyzed for C. rodentium bacterial load and imaged for bioluminescence on 4 occasions. The efficacy of the FXR agonist GSK488062B was assessed in rats with 2, 4-Dinitrobenzenesulfonic Acid (DNBS) induced colitis by oral administration of 10, 30 and 100 mg/kg, bid. Signs of colitis were monitored and organs harvested at the end of the trials. The effect of GSK488062B on pro-inflammatory cytokine production and epithelial wound healing was also investigated in cultured biopsy tissue from IBD patients and in In Vitro cell culture models. Results: In the DSS colitis model, there was no difference in clinical disease activity or colonic inflammation markers between WT and FXRKO mice. However, in the C. rodentium model, there was a significant increase in clinical disease activity and whole body bioluminescent signal in the FXRKO mice compared with WT on day 3. On day 15, there was incomplete bacterial clearance in FXRKO mice, while clinical signs and colonic markers of colitis were similar in WT and FXRKO mice. In the DNBS-model, treatment with 10-100 mg/kg (po) of GSK488062B produced dose-related decreases in clinical signs of inflammation. In the ex vivo colon biopsy system, GSK488062B did not show any efficacy in reducing the cytokine profile in IBD tissue but showed a concentration-dependent increase in the rate of epithelial cell wound healing. Conclusions: The FXR agonist GSK488062B ameliorated DNBS-induced colitis and increased the rate of epithelial cell wound healing, but showed no significant effect on cytokine production from ex vivo colonic biopsy cultures of IBD patients. The FXRKO and WT mice were equally susceptibility to DSS induced colitis, whereas FXRKO mice were initially more susceptible to colonisation by bacteria. Collectively, these data suggest a role for FXR in intestinal innate immunity rather than in inflammatory diseases such as IBD.