Gut-liver axis

A complex interaction between the gut and the liver critically determines functioning of these organs in health and disease. The enterohepatic circulation plays an important role in this interplay via cycling of signaling (bile salts) and immune (secretory IgA) molecules. Bile salt cycling through the enterohepatic circulation encompasses secretion in the biliary compartment and return to the liver via the intestinal lumen, transport across absorptive enterocytes in the terminal ileum, and re-uptake from the portal circulation.

Well-known for their essential role in absorption of dietary lipids and lipid-soluble vitamins, the signaling role of bile salts has only recently been recognized; bile salts were identified as important regulators of global metabolism and energy homeostasis, as well as important players in intestinal barrier function, liver regeneration and hepatic inflammation. These non-traditional actions of bile salts are exerted through specific intracellular (e.g. FXR) and plasma membrane receptors (e.g. TGR5) for bile salts.

An endocrine mediator of bile salt action is fibroblast growth factor (FGF)19, an enterokine that is induced in the ileum following activation of FXR. FGF19 binds to the surface of cells expressing both FGF receptor (FGFR)4 and the transmembrane protein betaKlotho. Co-expression of these molecules is restricted to a number of tissues, including the liver and pancreas. FGF19 regulates a number of metabolic processes in the liver including bile salt synthesis and gluconeogenesis, and is furthermore engaged in liver repair. Recently, we observed that FGF19 is expressed in intrahepatic cholangiocytes and in the gallbladder, and is present in large quantities in human bile. The function of FGF19 in the biliary tree remains enigmatic and is under study.

Research Questions

  • What is the contribution of bile salt and FGF19 signaling to intestinal and hepatic dysfunction in disorders affecting the enterohepatic circulation of bile salts?
  • What is the hepatoprotective action of FGF19 in cholestasis?
  • What is the role of (biliary) FGF19 in the chronic cholangiopathy primary sclerosing cholangitis?

 

Key Publications

Zweers SJ, Booij KA, Komuta M, Roskams T, Gouma DJ, Jansen PL and Schaap FG. The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract. Hepatology 55: 575-583, 2012.

Jansen PL, van WJ, Aarts E, Berends F, Janssen I, Stoker J and Schaap FG. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig Dis 29: 48-51, 2011.

Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL and Schaap FG. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol 298: G440-G445, 2010.

Schaap FG, van der Gaag NA, Gouma DJ and Jansen PL. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis. Hepatology 49: 1228-1235, 2009.