Proceedings of The Physiological Society

University College Dublin (2009) Proc Physiol Soc 15, PC184

Poster Communications

Ursodeoxycholic acid exerts antisecretory actions on colonic epitheial cells

O. Kelly1,2, F. E. Murray2, S. J. Keely1

1. Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland. 2. Gastroenterology, RCSI/Beaumont Hospital, Dublin, Ireland.


Background: The primary bile acid, chenodeoxycholic acid (CDCA) stimulates colonic fluid and electrolyte secretion. Increased colonic delivery of CDCA contributes to diarrhea in conditions of bile acid malabsorption. However, CDCA is metabolised by colonic bacteria to ursodeoxycholic acid (UDCA) and lithocholic acid (LCA) and little is known of their effects on colonic secretory function. Aims: To investigate the effects of UDCA on colonic epithelial secretory function. Methods: Cl- secretion was measured as changes in short circuit current (Isc) across voltage-clamped monolayers of T84 colonic epithelial cells.Results were expressesd as mean +/- SEM for a series of n experiments. Statistical analyses were made by one wat ANOVA using Newman Keuls multiple comparison test. P values <0.05 wereconsidered to be significant Results: At high concentrations (500 µM- 1mM) CDCA rapidly stimulated Cl- secretion across T84 cells. In contrast, UDCA (50 µM - 1 mM) was devoid of prosecretory activity. However, pretreatment of T84 cells with UDCA (500 µM) significantly attenuated subsequent secretory responses to the Ca2+-dependent agonist, carbachol (CCh; 100 µM) and the cAMP-dependent agonist, forskolin (10 µM) to 11.9 ± 4.2% (n=9; p<0.001) and 43.0 ± 13.0% ( n=6; p< 0.05) of controls, respectively. The effects of UDCA were concentration-dependent with antisecretory actions being apparent at concentrations as low as 50 µM. However, UDCA (1 mM) did not alter transepithelial resistance implying it did not exert toxic effects. In further experiments we measured Na/K-ATPase pump activity in apically permeabilised monolayers and found that UDCA inhibited Na/K-ATPase pump activity to 16.2 ± 3.9% of that in control cells (n=4; p<0.001). In experiments designed to isolate basolateral K+ conductance, UDCA inhibited activity to 13.7 ± 2.4% of controls (n=5, p<0.001). Similar to UDCA, LCA was also without effect on basal Cl- secretion in T84 cells. However, pretreatment of cells with LCA (50 - 200 µM) significantly potentiated responses to CCh. LCA (100 µM) increased CCh-induced responses to 146.67 ± 8.7% of those in controls (n = 8; p < 0.001). However, at concentrations > 500µM, LCA exerted antisecretory actions similar to UDCA. Conclusion: Bacterial metabolism of CDCA alters its ability to regulate colonic epithelial secretion. While UDCA exerts mainly antisecretory effects, LCA enhances secretion at relatively low concentrations but is antisecretory at high concentrations. Our data also suggest that altering bile acid metabolism by pharmacological means or through antibiotic/probiotic manipulation of the enteric flora may prove useful in treating intestinal transport disorders associated with dysregulated epithelial transport.

Where applicable, experiments conform with Society ethical requirements