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Unconjugated but Not Conjugated Bile Acid Reduces Squamous Differentiation in Esophageal Cells Possibly Through Intracellular Mechanisms
Sayak Ghatak^*1, Liana Toia², Eileen Redmond², Tony E. Godfrey³, Jeffrey H. Peters^2
1Biology, University of Rochester, Rochester, NY; ²Surgery, University of Rochester Medical Center, Rochester, NY; ³Surgery, Boston University, Boston, MA

Background: Barrett's Esophagus (BE) is a precancerous lesion in which the normal squamous epithelium of the esophagus undergoes columnar metaplasia as a result of protracted duodeno-esophageal reflux. Bile acid (BA) both conjugated and unconjugated at an acidic pH, forms the chief component of reflux and has the ability to affect cellular processes by virtue of its anionic detergent action or acting as a signaling molecule. Previously, our group had shown that the esophageal squamous epithelium loses the expression of genes involved in squamous differentiation following exposure to a cocktail containing conjugated and unconjugated BA at pH5. In this study, we aimed determining which BA component, whether conjugated or unconjugated, predominantly contributed to the down-regulation of squamous differentiation.
Methods: Human telomerase-immortalized primary esophageal squamous cells (EPC1) were grown on polyester transwells and treated separately with conjugated or unconjugated BA at both pH7.4 and pH5, in 15 min pulses three times a day for six days. Trans-epithelial Electrical Resistance (TEER) was measured daily, and at the end of the treatment cells were harvested for mRNA and protein.
Results: Unconjugated BA at pH5 reduced the expression of genes involved in squamous differentiation as well as the TEER in the EPC1 in transwells culture, whereas conjugated BA did not have any significant effect. Moreover, unconjugated BA at pH5 induced the expression of FGF-19, a transcription target of BA nuclear receptor FXR.
Conclusions: Unconjugated BA at pH5 is unionized and can penetrate through cell membrane to enter EPC1 cells. On the other hand, EPC1 cell membrane is impermeable to conjugated BA due to the absence of apical BA transporters. Since the anionic detergent properties of BA increases with conjugation and ionization, these results implicate a possible intracellular signaling mechanism of action of BA to reduce the squamous differentiation in primary esophageal cells, as opposed to detergent action. Long term gastric acid suppression therapy might be putting patients at risk to BA induced altered cellular differentiation, as the therapy is known to increase bacterial deconjugation of BA.

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