Manipulation of the gut-liver axis by interruption of bile acid recirculation: an option for the treatment of sclerosing cholangitis?

Patients affected by primary sclerosing cholangitis (PSC) have a dramatically increased risk to develop end-stage liver disease and cholangiocarcinoma. Medical treatment options for PSC are currently limited and often liver transplantation remains inevitable. This demonstrates the urgent need for novel pharmacological treatment strategies that are safe and efficient.Bile acid (BA) sequestrants are resins that bind to BAs in the intestinal lumen, thereby decreasing their intestinal re-uptake and interrupting their enterohepatic circulation. Resins have a longstanding use in the treatment of BA-induced diarrhoea and cholestatic pruritus. However, only a very limited number of studies have so far investigated the therapeutic impact of BA sequestrants on the underlying cholestatic liver disease.In Gut , Fuchs et al present an experimental study investigating the effects of the BA sequestrant colesevelam on cholestatic liver disease in the Mdr2− /− mouse model of sclerosing cholangitis.1 Using this model, the authors convincingly show that colesevelam efficiently treats the clinically relevant liver phenotype including inflammation, tissue damage, fibrosis and efficiently normalised serum liver enzymes. With regard to the underlying mechanisms, the study clearly shows that colesevelam profoundly alters BA homeostasis. This is demonstrated by a marked increase of the total faecal BA output together with a nearly complete loss of the intestinal fibroblast growth factor (FGF) 15 expression and a concomitant increase of hepatic de novo BA synthesis. Interestingly, the increased synthesis apparently even overcompensates the faecal BA loss, since colesevelam-treated Mdr2− /− animals had an increased hepatic and biliary BA pool size compared with untreated controls. However, there is also a profound impact of colesevelam on BA pool …