Activation of CFTR by ASBT-mediated bile salt absorption

Abstract

In cholangiocytes, bile salt (BS) uptake via the apical sodium-dependent bile acid transporter (ASBT) may evoke ductular flow by enhancing cAMP-mediated signaling to the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. We considered that ASBT-mediated BS uptake in the distal ileum might also modulate intestinal fluid secretion. Taurocholate (TC) induced a biphasic rise in the short circuit current across ileal tissue, reflecting transepithelial electrogenic ion transport. This response was sensitive to bumetanide and largely abrogated in Cftr-null mice, indicating that it predominantly reflects CFTR-mediated Cl−secretion. The residual response in Cftr-null mice could be attributed to electrogenic ASBT activity, as it matched the TC-coupled absorptive Na+flux. TC-evoked Cl−secretion required ASBT-mediated TC uptake, because it was blocked by a selective ASBT inhibitor and was restricted to the distal ileum. Suppression of neurotransmitter or prostaglandin release, blocking of the histamine H1receptor, or pretreatment with 5-hydroxytryptamine did not abrogate the TC response, suggesting that neurocrine or immune mediators of Cl−secretion are not involved. Responses to TC were retained after carbachol treatment and after permeabilization of the basolateral membrane with nystatin, indicating that BS modulate CFTR channel gating rather than the driving force for Cl−exit. TC-induced Cl−secretion was maintained in cGMP-dependent protein kinase II-deficient mice and only partially inhibited by the cAMP-dependent protein kinase inhibitor H89, suggesting a mechanism of CFTR activation different from cAMP or cGMP signaling. We conclude that active BS absorption in the ileum triggers CFTR activation and, consequently, local salt and water secretion, which may serve to prevent intestinal obstruction in the postprandial state.

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

“…Using whole-cell current recording, we found that 0.1 mmol/L of CDC did not activate CFTR and therefore conclude that stimulation of CFTR does not underlie the effect of CDC of the anion exchanger. Our data contrast with the results of Bijvelds et al, 24 who found that luminal administration of 0.5 mmol/L of taurocholate did stimulate CFTR-dependent electrogenic Cl j transport in the murine ileum. These contrasting results may be due to differences in species and tissues and the type and concentration of bile acids used.…”

Intestinal bile acid physiology and pathophysiology

“…In the small intestine, these differential species-dependent effects are not so well characterized, but they certainly differ from those in the colon. 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] .…”

“…This pertains to the actions of BAs in the large intestine, since T84 cells have a colonic epithelium phenotype. More recently, BA were described to induce ion secretion via transactivation of the cystic fibrosis transmembrane conductance regulator (CFTR) [113] . CFTR is the main chloride/bicarbonate channel in intestinal epithelial cells and is pivotal to ion secretion in the gastrointestinal tract, among other tissues.…”

“…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 simplest explanation is that ileal secretion, which is evoked in normal conditions, may be useful to aid in intestinal propulsion or to prevent the formation of micelles and the consequent epithelial damage during the absorptive process [113] . In contrast, colonic secretion occurs only in pathologic conditions and may be part of a nonspecific mechanism aimed to eliminate invading microorganisms.…”