Esophageal barrier function and tight junction expression in healthy subjects and patients with gastroesophageal reflux disease: functionality of esophageal mucosa exposed to bile salt and trypsin in vitro

Abstract

BACKGROUND AND AIMS. Gastroesophageal reflux disease (GERD) is associated with impaired epithelial barrier function. However, the influence of acid and/or bile acids on human esophageal epithelial barrier function and the tight junction (TJ) proteins has not been fully elucidated. The aim of the study is to investigate the esophageal barrier function and TJ expression in healthy subjects and patients with GERD. The functionality of esophageal mucosa exposed to bile salt deoxycholic acid (DCA) and trypsin has been studied in vitro. MATERIAL AND METHODS. Endoscopic biopsies from healthy controls and patients with GERD-related symptom with endoscopic erosive signs, as well as esophageal mucosa taken from patients undergoing esophagectomy were evaluated in Ussing chambers and by western blot and immunohistochemistry. RESULTS. The esophageal epithelium from GERD patients had lower electrical resistance and higher epithelial currents than controls. Claudin-1 and -4 were significantly decreased in GERD patients. The bile salt DCA in the low concentration of 1.5 mM and trypsin increased the resistance and claudin-1 expression, while the higher concentration of 2.5 mM DCA and trypsin decreased the resistance and the claudin-3, -4 and E-cadherin expressions. CONCLUSION. In addition to acidic reflux, duodenal reflux components, such as bile salts and trypsin, have the potential to disrupt the esophageal barrier function, partly by modulating the TJ proteins. However, the expression of TJ is dependent on both the refluxed material as well as the concentration of the bile salt.

Gastrointestinal mucosal barrier function and diseases

“…Although no change in occludin or ZO-1 expression has been reported in GERD patients, the expression of CLDN1 and CLDN2 mRNA and protein has been reported to be increased [34] and unchanged [35] in GERD, and the expression of CLDN1 and CLDN4 has been reported to be decreased in GERD [33]. The reason for these inconsistent results may be due to the fact that total CLDN protein was measured rather than a specific subpopulation of CLDNs.…”

“…In an analysis of esophageal biopsy specimens using an Ussing chamber, the resistance of esophageal mucosa was lower in patients with GERD than in healthy controls, indicating a loss of barrier function in GERD [31][32][33]. Although no change in occludin or ZO-1 expression has been reported in GERD patients, the expression of CLDN1 and CLDN2 mRNA and protein has been reported to be increased [34] and unchanged [35] in GERD, and the expression of CLDN1 and CLDN4 has been reported to be decreased in GERD [33].…”

Evaluation of Esophageal Mucosal Integrity in Patients with Gastroesophageal Reflux Disease

“…Epithelial thickness, particularly basal cell layer thickness, was also confirmed in GERD [17]. Other studies have reported that tight junction proteins, such as claudin-1, are altered in patients with GERD [18]. These results indicate that impaired esophageal barrier function plays a role in causing GERD symptoms.…”

“…Recently, impaired mucosal integrity was confirmed in several studies [16, 18, 19, 25, 26, 33, 36, 37]. If endoscopy-guided measurements of mucosal integrity are applied more widely, they may be of great benefit in clinical practice.…”

Inhibition of p38 MAPK activation attenuates esophageal mucosal damage in a chronic model of reflux esophagitis

“…19,20 The esophageal epithelium from GERD patients had lower electrical resistance and higher epithelial currents than controls. 21 During gastro-esophageal reflux, luminal acid caused injury of the esophageal epithelium by altering the apical junction complexes and caused an early increase in paracellular permeability and dilated intercellular space. 22 The acid then penetrated the intercellular spaces to initiate a cascade that results in cell necrosis, inflammation, and erosion.…”