OP016 Potential role of bile acid receptor FXR in microscopic colitis

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Abstract

Background: Microscopic colitis (MC) is a chronic inflammatory bowel disease and includes two distinct histological forms: lymphocytic colitis (LyC) and collagenous colitis (CC). The etiology of MC is probably multifactorial, secondary to an abnormal immune reaction in predisposed individuals, triggered by luminal factors (such as infection, drugs or bile acids). Bile acid (BA) malabsorption has been described in approximately 44% of MC patients, which often respond to cholestyramine, a BA-binding resin. Farnesoid X receptor (FXR) is the main BA receptor and is expressed at high levels in the intestine, especially in the terminal ileum (TI) and proximal colon. FXR-mediated mechanisms prevent the noxious effects of BA accumulation, preserving the integrity of the intestinal epithelial barrier and preventing chemically induced intestinal inflammation. Reduced FXR activation has been implicated in the pathophysiology of inflammatory bowel disease. Our aim was to explore the expression of FXR in patients with MC.

Methods: Archival formalin-fixed paraffin-embedded (FFPE) samples (from the TI, right colon-RC and left colon-LC) were obtained from patients with MC and age and gender-matched healthy controls. Immunohistochemistry was performed using a mouse anti-human FXR monoclonal antibody (Perseus Proteomics, Tokyo, Japan). Nuclear FXR expression was scored in a semi-quantitative way by one experienced gastrointestinal pathologist, who was blinded to the clinicopathological information and biopsy location.

Results: 140 FFPE samples (24 from the TI, 54 from the RC and 62 from the LC) from 34 patients with MC (26 LyC and 8 CC) and 31 controls were retrieved. There was a non-significant reduction of FXR expression in the ileum of patients with MC versus controls (moderate-high FXR expression: 76.9% vs 90.9%; p=NS). There was a significant reduction of FXR expression in patients with MC versus controls both in the right colon (moderate-high FXR expression: 23.1% vs 64.3%; p=0.003) and left colon (moderate-high FXR expression: 12.1% vs 44.8%; p=0.027). We found no difference in FXR expression between the two types of MC.

Conclusions: Patients with MC present a significantly lower expression of FXR in the colon. This could render colonic epithelial cells more susceptible to the deleterious effects of BA, contributing to disease pathogenesis and symptoms in MC. These results open the possibility of exploring FXR agonists in the treatment of steroid-refractory MC.

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