Bile acids play important physiological role in the solubilisation and absorption
of dietary lipids. However, under pathophysiological conditions, such as short bowel
syndrome, they can reach the colon in high concentrations inducing diarrhoea. In this
study, our aim was to characterise the cellular pathomechanism of bile-induced diarrhoea
using human samples. Colonic crypts were isolated from biopsies of patients (controls
with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients
with or without diarrhoea. In vitro measurement of the transporter activities revealed
impaired Na+/H+ exchanger (NHE) and Cl-/HCO3 - exchanger (CBE) activities in cholecystectomised/ileum-resected
patients suffering from diarrhoea, compared to control patients. Acute treatment of
colonic crypts with 0.3 mM chenodeoxycholate caused dose-dependent intracellular acidosis;
moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired.
This concentration of chenodeoxycholate did not cause morphological changes in colonic
epithelial cells, although significantly reduced the intracellular ATP level, decreased
mitochondrial transmembrane potential and caused sustained intracellular Ca2+ elevation.
We also showed that chenodeoxycholate induced Ca2+ release from the endoplasmic reticulum
and extracellular Ca2+ influx contributing to the Ca2+ elevation. Importantly, our
results suggest that the chenodeoxycholate-induced inhibition of NHE activities was
ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained
Ca2+ elevation. We suggest that bile acids inhibit the function of ion transporters
via cellular energy breakdown and Ca2+ overload in human colonic epithelial cells,
which can reduce fluid and electrolyte absorption in the colon and promote the development
of diarrhoea.
