Intestinal inflammation induces alterations in enterohepatic Fgf15 signalling, changes in hepatic bile acid metabolism and a “toxic bile” composition in DSS-treated mice

Abstract

Aims: Primary sclerosing cholangitis is a chronic cholestatic liver disease affecting intra- and extrahepatic bile ducts frequently associated with inflammatory bowel disease. The pathogenetic pathway leading from intestinal inflammation to cholestatic liver disease is still poorly understood. Aims: To study alterations in enterohepatic Fgf15 signalling and associated changes in hepatic gene expression and bile composition in murine colitis. Methods: Fgf15 pathway target genes in gut and liver of DSS-treated mice (7d, 2% DSS in drinking water) and control mice were quantified by RT-PCR. Changes of bile acid transporter expression were quantified by RT-PCR and confirmed by western blotting. Fgf15 levels in serum were analyzed by ELISA. Biliary bile acid composition was differentiated by GC/MS analysis. Results: DSS-treated mice showed induction of Fxr expression in ileo-cecal region and concomitant higher concentration of Fgf15 in serum (180% vs. cntrl; p<0.05). In the liver, inhibition of bile acids synthesis by down-regulation of Cyp7a1, regulated by Fgf15 could be observed (40% vs. cntrl; p<0.05). In addition, expression of bile acid transporters such as Bsep, Ntcp, Mrp2, Mrp3 and Mrp4 were significantly down-regulated. Most importantly, bile acid composition in bile was significantly different in treated mice with lower levels of hydrophilic bile acids including α- and ß-muricholic acid and taurodeoxycholic acid (20%, 20% and 50% vs. cntrl; p<0.05). Conclusions: Our results show for the first time a functionally relevant alteration in gut-liver interaction by activated Fgf15 signalling through Fxr activation in ileo-cecal region of DSS-treated mice. As functional consequence of hepatic alterations in bile acid metabolism less cytotoxic hydrophilic bile acids are reduced and may contribute to a more toxic bilary environment by hydrophobic bile acids. The study supports the “toxic bile concept” in the pathogenesis of IBD-associated biliary disease.