Abstract
BackgroundBarrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease. The aim of this study was to assess the expression of bile acid receptors in the esophagus (normal, esophagitis, Barrett's esophagus and adenocarcinoma) and to investigate their possible function.Resultsthe expression of the bile acid receptors FXR and VDR in esophageal biopsies from patients with a normal mucosa, esophagitis, Barrett's esophagus or adenocarcinoma (n = 6 per group) and in cell lines derived from Barrett's esophagus and esophageal adenocarcinoma, was assessed by real time Q-PCR and immunohistochemistry. The effect of guggulsterone, an antagonist of bile acid receptors, on apoptosis of Barrett's esophagus-derived cells was assessed morphologically, by flow cytometry and by measuring caspase 3 activity.The expression of FXR was increased in esophagitis, Barrett's esophagus and adenocarcinoma compared to normal mucosa by a mean of 44, 84 and 16, respectively. Immunohistochemistry showed a weak expression in normal esophagus, a strong focal reactivity in Barrett's esophagus, and was negative in adenocarcinoma. VDR expression did not significantly differ between groups. In cell cultures, the expression of FXR was high in Barrett's esophagus-derived cells and almost undetectable in adenocarcinoma-derived cells, whereas VDR expression in these cell lines was not significantly different. In vitro treatment with guggulsterone was associated with a significant increase in the percentage of apoptotic cells and of the caspase 3 activity.Conclusionthe bile acid receptor FXR is significantly overexpressed in Barrett's esophagus compared to normal mucosa, esophagitis and esophageal adenocarcinoma. The induction of apoptosis by guggulsterone in a Barrett's esophagus-derived cell line suggests that FXR may contribute to the regulation of apoptosis.
Highlights
Barrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease
In an experimental rat model, the creation of a duodenoesophageal anastomosis led to esophagitis, intestinal metaplasia and eventually esophageal AC [6], and biliary diversion did not lead to regression of Barrett's esophagus (BE), but prevented AC [7]
Expression of farnesoid X receptor (FXR) and vitamin D receptor (VDR) in tissue biopsies There was an increase in the relative expression of FXR in the sequence from normal esophagus (1 ± 0.83) to esophagitis (44 ± 15, p = 7·10-5) and to BE in which this receptor resulted most elevated (84 ± 36, p = 8·10-4)
Summary
Barrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease. The aim of this study was to assess the expression of bile acid receptors in the esophagus (normal, esophagitis, Barrett's esophagus and adenocarcinoma) and to investigate their possible function. Barrett's esophagus (BE), defined by the detection of intestinal metaplasia in the esophagus at histological examination [1], is the most important risk factor for esophageal adenocarcinoma (AC) [2]. In subjects with BE the annual incidence of esophageal AC is approximately 0.4–2.1% [3]. Prevailing theories link this type of cancer to gastroesophageal reflux disease (GERD). The contribution of bile acid receptors to the apoptotic processes in BE and esophageal AC is unknown
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