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Abstract

We acknowledge Bijvelds et al for their comments and recognition of the gallbladder shunt as an explanation for the abnormalities in bile acid metabolism observed in the cystic fibrosis (CF) mouse model that we investigated, and also as an important factor to consider in CF-related fat malabsorption. Regarding bile acid handling in the intestine, we did not find that fecal bile acid output was significantly increased, but we did find a reduced ileal bile acid absorption, in agreement with previous reports.1Fondacaro J.D. et al.Pediatr Res. 1982; 16: 494-498Crossref PubMed Scopus (55) Google Scholar, 2O'Brien S. et al.Gut. 1993; 34: 1137-1141Crossref PubMed Scopus (79) Google Scholar The decrease in apical sodium-dependent bile acid transporter (ASBT) expression that we authenticated by reverse transcriptase polymerase chain reaction and Western blot is not incompatible with a detection of the protein by immunostaining, which is a nonquantitative method.3Bijvelds M. et al.Am J Physiol Gastrointest Liver Physiol. 2005; 288: G646-G653Crossref PubMed Scopus (47) Google Scholar As outlined in the comments, we concluded that the normal level of fecal bile acid excretion in Cftr−/− mice was a result of a low duodenal influx that was offset by a low absorption rate. Although the duodenal bile acid influx was not directly measured, hepatobiliary scintigraphy clearly showed that gallbladder filling was prolonged, whereas release of bile into the intestine was markedly delayed. A deficit in both the presence and transport of bile acids in the intestine of Cftr−/− mice was further demonstrated by the marked decrease in the ileal expression of Fgf15, Shp, Ibabp, and Ostα/β, all known to be positively regulated by bile acids. Although there is evidence to indicate that bile acids may also increase ileal ASBT levels,4Stravitz R.T. et al.Gastroenterology. 1997; 113: 1599-1608Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar the regulation of ASBT by bile acids indeed has been a subject of conflicting results, and we cannot exclude that other factors contributed to decrease its expression. The fact that, despite very low levels of intestinal ASBT, Cftr−/− mice had normal levels of bile acids in the portal blood remains fully supportive of the gallbladder shunt model. The gallbladder is vascularized by vessels that drain blood into the portal vein just like the intestine. Therefore, decreased intestinal absorption was compensated by increased short-circuit cycling in these animals, and ultimately the amount of bile acids circulating in the portal blood and entering the liver did not significantly differ between the knockout and wild-type animals, the visible consequence of the short-circuit cycling being the lack of secondary bile acids. We agree that the liver phenotype in Cftr−/− mice is influenced by the genetic background as well as the environment, and we previously reported the importance of diet.5Cottart C.H. et al.Pediatr Res. 2007; 62: 528-532Crossref PubMed Scopus (24) Google Scholar However, this is also the case in CF patients and applicability of our model to CF human disease is supported by the fact that similar findings including enlarged gallbladders with emptying defect, delayed appearance of bile acids in the duodenum, decreased proportions of secondary bile acids, and decreased bile acid uptake by CF ileal mucosa, have all been previously reported in CF patients.1Fondacaro J.D. et al.Pediatr Res. 1982; 16: 494-498Crossref PubMed Scopus (55) Google Scholar, 6Weizman Z. et al.Gut. 1986; 27: 1043-1048Crossref PubMed Scopus (36) Google Scholar, 7Santamaria F. et al.J Pediatr Gastroenterol Nutr. 1990; 10: 303-306Crossref PubMed Scopus (17) Google Scholar, 8O'Connor P.J. et al.Hepatology. 1996; 23: 281-287Crossref PubMed Google Scholar, 9Strandvik B. et al.J Hepatol. 1996; 25: 43-48Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 10Smith J.L. et al.Hepatology. 2004; 39: 1673-1682Crossref PubMed Scopus (47) Google Scholar Finally, we agree that this new paradigm should promote further studies both in CF patients and in CF mouse models to elucidate the mechanisms of abnormal bile acid homeostasis and liver disease in CF. Bile Acid Handling in Cystic Fibrosis: Marked Phenotypic Differences Between Mouse ModelsGastroenterologyVol. 143Issue 6PreviewDebray et al reported an intriguing study centered on the observation of delayed gallbladder emptying in cystic fibrosis (CF) mice, that is, mice with a genetically induced defect in CF transmembrane conductance regulator (CFTR) function.1 The authors propose that in CF mice, defective gallbladder emptying provokes cholecystohepatic shunting, namely, the (re)absorption of bile acids (BAs) from the gallbladder and transfer back to the canaliculi. It is hypothesized that, as a result, CF mice secrete less BA into the intestine, and that enterohepatic cycling of BAs is reduced. Full-Text PDF