Deoxycholic acid promotes development of gastroesophageal reflux disease and Barrett's oesophagus by modulating integrin‐αv trafficking

Abstract

The fundamental mechanisms underlying erosive oesophagitis and subsequent development of Barrett's oesophagus (BO) are poorly understood. Here, we investigated the contribution of specific components of the gastric refluxate on adhesion molecules involved in epithelial barrier maintenance. Cell line models of squamous epithelium (HET‐1A) and BO (QH) were used to examine the effects of bile acids on cell adhesion to extracellular matrix proteins (Collagen, laminin, vitronectin, fibronectin) and expression of integrin ligands (α3, α4, α5, α6 and αν). Experimental findings were validated in human explant oesophageal biopsies, a rat model of gastroesophageal reflux disease (GORD) and in patient tissue microarrays. The bile acid deoxycholic acid (DCA) specifically reduced adhesion of HET‐1A cells to vitronectin and reduced cell‐surface expression of integrin‐αν via effects on endocytic recycling processes. Increased expression of integrin‐αv was observed in ulcerated tissue in a rat model of GORD and in oesophagitis and Barrett's intestinal metaplasia patient tissue compared to normal squamous epithelium. Increased expression of integrin‐αν was observed in QH BO cells compared to HET‐1A cells. QH cells were resistant to DCA‐mediated loss of adhesion and reduction in cell‐surface expression of integrin‐αν. We demonstrated that a specific component of the gastric refluxate, DCA, affects the epithelial barrier through modulation of integrin αν expression, providing a novel mechanism for bile acid‐mediated erosion of oesophageal squamous epithelium and promotion of BO. Strategies aimed at preventing bile acid‐mediated erosion should be considered in the clinical management of patients with GORD.

Deoxycholic acid disrupts the intestinal mucosal barrier and promotes intestinal tumorigenesis

“…The increased intestinal level of DCA after a high-fat diet is associated with the onset of many intestinal diseases including colorec-tal cancer. [30][31][32] However, the mechanism still remains to be elucidated. In the present study, we investigated the effects of DCA on the intestinal mucosal barrier and its role in the development of CRC.…”

Deoxycholic Acid Upregulates Serum Golgi Protein 73 through Activating NF-κB Pathway and Destroying Golgi Structure in Liver Disease

“…Its potential procarcinogenic and proinflammatory actions lead to its uniqueness among bile acids [ 27 , 28 , 29 ]. It has been reported that DCA promotes the development of Barrett’s esophagus and esophageal disease [ 15 , 30 , 31 ]. In addition, DCA has been reported to be strongly associated with the occurrence of HCC [ 32 ].…”

Correlation of Barrett's esophagus with colorectal polyps in Japanese patients: A retrospective chart review

“…Several factors might be related to an increased or decreased risk of Barrett's esophagus and colorectal neoplasms, including the bile acid level, gastrin level, genetic factors, and treatment with nonsteroidal anti‐inflammatory drugs and/or aspirin …”