Bile salt stimulates intestinal epithelial cell migration through TGF betaafter wounding

Background. In addition to aiding in the digestion of fats, luminal bile sa lts have been shown to modulate gastrointestinal epithelial growth, differe ntiation, and other functions. We hypothesized that bile acids could modula te the intestinal mucosal repair process of restitution. We investigated th e effect of the bile salt taurodeoxycholic acid on epithelial migration and identified a role for TGF beta, a widely expressed cytokine in the intesti nal villus, in this repair process. Methods. Using a well-established model of epithelial restitution, IEC-6 ce lls were plated on 60-mm Matrigel-coated plastic dishes and grown to conflu ence. The epithelium was wounded by scraping with a 6-mm-wide blade to crea te a smooth denuded edge and cell migration was measured 8 h later. Cells w ere grown in control DMEM with 5% FBS with or without 0.01-2 mM taurodeoxyc holic acid (TDCA). In parallel experiments, cells were harvested for Northe rn analysis of TGF beta and GAPDH expression; [H-3]thymidine uptake was use d to measure proliferation. Anti-TGF beta 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 mig ration, with a maximal effect at 0.05 mM. TDCA inhibited proliferation at t hese concentrations. TGF beta expression increased in response to bile acid , while wounding had less of an effect on TGF beta expression. Blockade of TGF beta function with TGF beta antibody eliminated the effect of bile on c ell migration. Conclusions. Bile acid at physiologic concentrations augments small intesti nal epithelial cell migration. The process is dependent on TGF beta and is independent of cell division. The data further support a role for bile acid s and TGF beta in differentiated intestinal cell function and in preservati on of an intact mucosa. (C) 2001 Academic Press.