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

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tions involved in the development of intestinal inflammation. Here we investigated whether high fat diet-induced obesity alters the course of trinitrobenzene sulfonic acid (TNBS) induced colitis and evaluated the extent of mesenteric fat depot involvement. Methods: Male C57BL/ 6 mice were divided into four groups (n=8). Groups 1 and 2 were kept on regular diet and groups 3 and 4 on high fat diet (HFD) for six weeks. After six weeks groups 2 and 4 received intracolonic TNBS (100 mg/kg), while groups 1 and 2 received vehicle. Protein and RNA were isolated from mesenteric fat depots and intestine. Myeloperoxidase (MPO) activity was measured on adipose tissue protein lysates. H & E stained mesenteric fat tissue sections were examined. Results: Light microscopic analysis in TNBS-exposed mice showed higher levels of inflammatory cell infiltrates in the intestine and adipose tissue and increased colonic histological damage in HFD-treated obese mice compared to all other groups. MPO activity was elevated in fat and intestine from TNBS treated animals under both dietary conditions (p<0.05), but significantly higher in the tissues isolated from high fat-fed animals (p<0.01). Furthermore, obesity also increased mRNA expression of the proinflammatory cytokines IL1β, TNFα, MCP-1 and KC, (p<0.001 for adipose and p<0.05 for intestine) while it reversed the TNBS-induced increases in IL-2 and IFNγ (two cytokines involved in T-cell maturation, p<0.05) in both adipose and intestinal tissues. Conclusions: Our data suggest a strong correlation between preexisting obesity and the degree of acute experimental colitis. Overall, our results may reflect conditions that are important for the pathophysiology of inflammatory bowel disease (IBD). Supported by a Research Fellowship from CCFA to JK and NIH grant DK47343 to CP.