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

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, α_4, α₅, α₆ and α_ν). 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-α_ν via effects on endocytic recycling processes. Increased expression of integrin-α_v 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-α_ν 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-α_ν. We demonstrated that a specific component of the gastric refluxate, DCA, affects the epithelial barrier through modulation of integrin α_ν 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. [ABSTRACT FROM AUTHOR]