Bile acids regulate colonic epithelial defensin secretion: implications for pathogenesis and therapy of inflammatory bowel disease

Abstract

Increased secretion of colonic epithelial human β defensins (HβDs) has been proposed to contribute to the pathenogenesis of ulcerative colitis (UC). Although alterations in the colonic bile acid pool also occur in UC, the roles of bile acids in regulating HβD production are not yet known. Here, we investigated the effects 2 common colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial HβD release. HβD release from monolayers of T84 colonic epithelial cells or muscle-stripped sections of human colon mounted in Ussing chambers were measured by ELISA after treatment with DCA (10 - 150 µM) or UDCA (50 - 100 µM). Use of human tissue was approved by the Beaumont Hospital Ethics Committee. DCA significantly increased HβD-1 and HβD-2 secretion in T84 cells from 190 ± 28 pg/ml to 413 ± 34 pg/ml and 27 ± 5 pg/ml to 291 ± 2 pg/ml (n = 4; p < 0.01), respectively. Furthermore, UDCA attenuated DCA-stimulated HβD-1 and HBD-2 release to 82 ± 10 pg/ml and 95 ± 17 pg/ml, respectively (n = 4; p < 0.05). Similar effects were seen in ex vivo sections of distal human colon. Similar to DCA, (INT-777, 10 µM) a specific agonist of the bile acid receptor, TGR-5, stimulated both HβDs release from T84 cells and these responses were significantly reduced by UDCA treatment. Finally, a specific inhibitor of NF-κB, BMS-34451 (25 μM) attenuated DCA (150 µM)-induced HβD-2, but not HβD-1, secretion to 27 ± 8 pg/ml (n = 6; p < 0.01). Taken together our data suggest that, activation of TGR5, promotes epithelial HβDs. In contrast, UDCA inhibits HβD secretion and may therefore exert antinflammatory effects. Thus, alterations in colonic bile acid pool may influence UC pathogenesis through alterations in HBD production.