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The pathognomonic feature of reflux esophagitis secondary to gastro-esophageal reflux disease is the presence of dilated intercellular spaces in the stratified squamous lining of the esophagus. Bile acid is a major constituent of gastro-esophageal refluxate. In our present study, we developed a novel in vitro transwell culture model for stratified esophageal squamous epithelium. We grew h-TERT transformed primary esophageal cell line EPC1 on polyester transwell surfaces, apically and basally supplemented with calcium enriched media, and observed that the EPC1 cells gradually stratify into a 11-layered squamous epithelium in 7 days. This epithelium also demonstrated well-formed cell junctions, essential for formation of the stratified epithelium. When the EPC1 cells on transwells were treated with a combination of bile acid and pH5, there was loss of epithelial barrier function. Electron microscopy and confocal imaging of the cell junctions showed disruption of adherens junction, tight junction and desmosomes, thus leading to dilated intercellular spaces. At the cellular level, the combination of bile acid and pH5 induced β-catenin phosphorylation and reduced SMAD-1/5/8 phosphorylation, both of which can lead to loss of cell junction proteins. In conclusion, combination of bile acid at low pH in our trasnwell culture model mimicked the effects of gastro-esophageal reflux in vivo, possibly by modulating WNT and BMP signaling pathways.