Absorption of taurocholic acid by the ileum of normal and transgenic ΔF508 cystic fibrosis mice

Abstract

Changes in intestinal transport in cystic fibrosis (CF) include both defective Cl(-) secretion and alterations in absorption. This study focused on the effects of CF on the active re-absorption of bile acids in the ileum of normal and transgenic CF mice. Taurocholic acid absorption was monitored as changes in short-circuit current (SCC) in intact and stripped ileal sheets from normal (Swiss) and transgenic CF (Cftr(tm2Cam)) mice with the DeltaF508 mutation. Taurocholic acid uptake was measured directly in everted ileal sacs and in brush-border membrane vesicles (BBMVs) using radiolabelled bile acid. Taurocholic acid caused a biphasic increase in SCC in both intact and stripped ileal sheets from Swiss mice. The initial phase of the response was associated with active bile acid absorption as it was inhibited by a low mucosal Na(+) concentration, but unaffected by Cl(-)-free conditions, serosal furosemide or mucosal diphenylamine-2-carboxylic acid (DPC). The first phase was concentration-dependent and was reduced in the presence of other actively transported bile acids. Intact ileal sheets from wild-type Cftr(tm2Cam) mice also exhibited a biphasic SCC response to taurocholic acid, but in CF tissues the initial phase was reduced and the second phase was absent. Taurocholic acid was actively taken up by everted ileal sacs from Swiss mice. This process was inhibited by a low mucosal Na(+) concentration or the presence of other actively transported bile acids. A similar taurocholic acid uptake was observed in ileal sacs from wild-type mice, but in those from CF mice transport of the bile acid was significantly reduced. However, taurocholic acid uptake was similar in BBMVs from wildtype and CF ilea. Active absorption of taurocholic acid occurs in mouse ileum and this process is reduced in transgenic mouse models of CF with the DeltaF508 mutation. However, this difference cannot be detected in an isolated preparation of brush-border membranes.

Defects in Gallbladder Emptying and Bile Acid Homeostasis in Mice With Cystic Fibrosis Transmembrane Conductance Regulator Deficiencies

“…Previous reports of very low levels of taurocholic acid uptake by the ileum of CF mice support this possibility. 26 …”

Intestinal bile acid physiology and pathophysiology

“…For instance, CDCA is a relatively poor secretagogue in the ileum [110][111][112][113] . It should be noted that ileal BA absorption is electrogenic, even in the absence of chloride/bicarbonate secretion, due to the 2:1 stoichiometry of ASBTmediated Na + :BA symport [111,114,115] . However, BAs also exert direct actions on intestinal epithelial cells.…”

“…Moreover, CFTR also plays a role in bile flow, as suggested the presence of plugging and dilatation of bile ducts in cystic fibrosis. Interestingly, BA ileal uptake is compromised in this condition, leading to BA waste and diarrhea [113,114,117] , suggesting that CFTR has a reciprocal influence on ASBT. Moreover, this provides an additional meaningful link to inhibited BA absorption in intestinal inflammation, where CFTR has been shown to be downregulated, as is ASBT itself [118,119] .…”

The effect of cystic fibrosis transmembrane conductance regulator on the function of acid/base transporters of human pancreatic duct cells

“…This may be because of increased active uptake (via bile acid transporters) of CDC in CF cells, but further experiments are required to resolve this issue. Note that the absorption of taurocholate has been reported to be either reduced 22 or increased 23 in the ileum of transgenic CF mice with the F508del CFTR mutation.…”

“…This may be due to increased active uptake (via bileacid transporters) of CDC in CF cells, but further experiments are required to resolve this issue. Note that the absorption of taurocholate has been reported to be either reduced (Hardcastle et al, 2004) or increased (Stelzner et al, 2001) in the ileum of transgenic CF mice with the F508del mutation. CDC stimulation (0.1 mM) of Cl -/HCO 3 -exchange activity was only observed in cells expressing CFTR, strongly suggesting that the presence of CFTR is necessary for this effect.…”