Gut-Liver Farnesoid X Receptor-Fibroblast Growth Factor 19 Signaling in Cirrhotic Patients with Portal Hypertension
BaExperimental data suggest that the activation of farnesoid X receptor (FXR) improves gut mucosal barrier and antimicrobial defense, thus, decreasing bacterial translocation. Activation of FXR in intestinal mucosa induces transcription of fibroblast growth factor 19 (FGF19), which is secreted into the portal venous system and regulates metabolic and inflammatory pathways in hepatocytes. However, FXR-FGF19 signaling between gut and liver is poorly defined in patients with advanced chronic liver disease (ACLD; i.e. cirrhosis) and portal hypertension. Impaired intestinal FXR signaling in cirrhosis might contribute to increased gut permeability, bacterial translocation and thus, progression of portal hypertension.
The Vienna Cirrhosis Study (VICIS; NCT03267615) is a prospective registry trial that comprises data on clinical characteristics, laboratory parameters and hepatic hemodynamic measurements and is connected to a biobank that contains biological material from patients with ACLD. Patients undergo a regular follow-up schedule with clinical visits at the Vienna General Hospital. In this study we will thoroughly characterize a cohort of patients with cirrhosis and portal hypertension by hepatic venous pressure gradient (HVPG) measurements and transjugular liver biopsy, endoscopic biopsies of colonic and ileum mucosa, and assessment of intestinal permeability by oral triple sugar test.
The main aim of this translational research project is to elucidate the applicability and relevance of gut-liver signaling, focusing on the FXR-FGF19 pathway in humans with ACLD and portal hypertension. Specifically, we will assess expression and activation of FXR and FXR-related genes in gut mucosal samples and liver specimens of patients with ACLD. Intestinal permeability, antimicrobial defense and bacterial translocation will be assessed in patients with low versus high intestinal FXR/FGF19 activation. Hepatic sinusoidal dysfunction and stellate cell activation assessed in liver specimens will be correlated with intestinal FXR/FGF19 signaling.
Methods and Skills:
Clinical studies; Western blot; PCR; HPLC; haemodynamic measurements in rats
Semmler G, Simbrunner B, Scheiner B, Schwabl P, Paternostro R, Bucsics T, Stättermayer AF, Bauer D, Pinter M, Ferenci P, Trauner M, Mandorfer M, Reiberger T. Impact of farnesoid X receptor single nucleotide polymorphisms on hepatic decompensation and mortality in cirrhotic patients with portal hypertension. J Gastroenterol Hepatol : 2019; doi: 10.1111/jgh.14700. [Epub ahead of print]
Simbrunner B, Röthenbacher A, Haslacher H, Bauer D, Chromy D, Bucsics T, Schwabl P, Paternostro R, Scheiner B, Trauner M, Mandorfer M, Schwarzinger I, Reiberger T. Ascitic fluid polymorphic nuclear cell count impacts on outcome of cirrhotic patients with ascites. United European Gastroenterol J 7: 651-661, 2019