Bile salt stimulates intestinal epithelial cell migration through TGFβ after wounding

Background. In addition to aiding in the digestion of fats, luminal bile salts have been shown to modulate gastrointestinal epithelial growth, differentiation, and other functions. We hypothesized that bile acids could modulate the intestinal mucosal repair process of restitution. We investigated the effect of the bile salt taurodeoxycholic acid on epithelial migration and identified a role for TGFβ, a widely expressed cytokine in the intestinal villus, in this repair process. Methods. Using a well-established model of epithelial restitution, IEC-6 cells were plated on 60-mm Matrigel-coated plastic dishes and grown to confluence. The epithelium was wounded by scraping with a 6-mm-wide blade to create a smooth denuded edge and cell migration was measured 8 h later. Cells were grown in control DMEM with 5% FBS with or without 0.01-2 mM taurodeoxycholic acid (TDCA). In parallel experiments, cells were harvested for Northern analysis of TGFβ and GAPDH expression; [³H]thymidine uptake was used to measure proliferation. Anti-TGFβ antibody was added to cells grown in the presence of 0.05 mM TDCA and migration was measured at 8 h. Results. TDCA at physiologic luminal concentrations augments IEC-6 cell migration, with a maximal effect at 0.05 mM. TDCA inhibited proliferation at these concentrations. TGFβ expression increased in response to bile acid, while wounding had less of an effect on TGFβ expression. Blockade of TGFβ function with TGFβ antibody eliminated the effect of bile on cell migration. Conclusions. Bile acid at physiologic concentrations augments small intestinal epithelial cell migration. The process is dependent on TGFβ and is independent of cell division. The data further support a role for bile acids and TGFβ in differentiated intestinal cell function and in preservation of an intact mucosa.