Physiological concentrations of bile acids down-regulate agonist induced secretion in colonic epithelial cells.
In patients with bile acid malabsorption, high concentrations of bile acids enter the colon and stimulate Cl(-) and fluid secretion, thereby causing diarrhoea. However, deoxycholic acid (DCA), the predominant colonic bile acid, is normally present at lower concentrations where its role in regulating transport is unclear. Thus, the current study set out to investigate the effects of physiologically relevant DCA concentrations on colonic epithelial secretory function. Cl(-) secretion was measured as changes in short-circuit current across voltage-clamped T(84) cell monolayers. At high concentrations (0.5-1 mM), DCA acutely stimulated Cl(-) secretion but this effect was associated with cell injury, as evidenced by decreased transepithelial resistance (TER) and increased lactate dehydrogenase (LDH) release. In contrast, chronic (24 hrs) exposure to lower DCA concentrations (10-200 microM) inhibited responses to Ca(2+) and cAMP-dependent secretagogues without altering TER, LDH release, or secretagogue-induced increases in intracellular second messengers. Other bile acids - taurodeoxycholic acid, chenodeoxycholic acid and cholic acid - had similar antisecretory effects. DCA (50 microM) rapidly stimulated phosphorylation of the epidermal growth factor receptor (EGFr) and both ERK and p38 MAPKs (mitogen-activated protein kinases). The EGFr inhibitor, AG1478, and the protein synthesis inhibitor, cycloheximide, reversed the antisecretory effects of DCA, while the MAPK inhibitors, PD98059 and SB203580, did not. In summary, our studies suggest that, in contrast to its acute prosecretory effects at pathophysiological concentrations, lower, physiologically relevant, levels of DCA chronically down-regulate colonic epithelial secretory function. On the basis of these data, we propose a novel role for bile acids as physiological regulators of colonic secretory capacity.
Keating
Niamh
N
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
Mroz
Magdalena S
MS
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
Scharl
Michael M
MM
Division of Gastroenterology, Department of Medicine, University of California, San Diego, CA, USA.
Marsh
Christine
C
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
Ferguson
Gail
G
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
Hofmann
Alan F
AF
Division of Gastroenterology, Department of Medicine, University of California, San Diego, CA, USA.
Keely
Stephen J
SJ
Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland.
D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology*; D002460:Cell Line; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D015536:Down-Regulation; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D051381:Rats
D001647:Bile Acids and Salts