Bile acid-stimulated expression of the farnesoid X receptor enhances the immune response in Barrett esophagus

A (Astrid) Capello, Leon Moons, Anouk Winkel, PD (Peter) Siersema, H (Herman) van Dekken, Ernst Kuipers, JG (Johannes) Kusters

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Abstract

OBJECTIVES: Barrett's esophagus (BE) is a premalignant condition of the esophagus. It is a consequence of mucosal injury from chronic gastroesophageal reflux in which bile acids are an important toxic component. The farnesoid X receptor (FXR) is a nuclear receptor involved in the regulation of bile acid synthesis, transport, and absorption. FXR activation is also involved in the induction of the innate immune response. This suggests that FXR is involved in the pathogenesis and the inflammation seen in BE. METHODS: mRNA levels of FXR and the FXR-regulated genes, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and chemokines interleukin (IL)-8 and macrophage inflammatory protein 3 alpha (MIP3 alpha), were determined by real time-polymerase chain reaction (RT-PCR). Protein expression was determined by immunohistochemistry. RESULTS: FXR was not expressed in squamous epithelium of healthy subjects (N = 7), but was present in both squamous and columnar epithelium of BE patients. Compared to the squamous epithelium of BE patients, their columnar epithelium displayed a 2.3-fold (P = 0.02) increase in FXR mRNA. Also, IBABP (2.2-fold; P = 0.0029), SHP (2.7-fold; P = 0.007), IL-8 (1.5-fold; P = 0.04), and MIP3 alpha (1.7-fold; P = 0.019) transcription levels were increased. Exposure of esophageal cell line TE7 to deoxycholic acid (DCA) resulted in a similar induction. The induction was abolished by the FXR antagonist guggulsterone. CONCLUSIONS: Expression levels of the bile acid receptor FXR, the bile acid metabolism genes IBABP and SHP, and the chemokines IL-8 and MIP3 alpha are increased in Barrett's epithelium. The in vitro induction of FXR by DCA suggests that bile acids can actively induce the inflammatory response in BE by recruiting immune cells.
Original languageUndefined/Unknown
Pages (from-to)1510-1516
Number of pages7
JournalAmerican Journal of Gastroenterology
Volume103
Issue number6
DOIs
Publication statusPublished - 2008

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