Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 21, 2019; 25(39): 5897-5917
Published online Oct 21, 2019. doi: 10.3748/wjg.v25.i39.5897
Gut-liver axis signaling in portal hypertension
Benedikt Simbrunner, Mattias Mandorfer, Michael Trauner, Thomas Reiberger
Benedikt Simbrunner, Mattias Mandorfer, Michael Trauner, Thomas Reiberger, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
Benedikt Simbrunner, Mattias Mandorfer, Thomas Reiberger, Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
Author contributions: All authors equally contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and final approval of the final version.
Conflict-of-interest statement: No financial support has been received for this review. Benedikt Simbrunner has received travel support from AbbVie and Gilead; Mattias Mandorfer has served as a speaker and/or consultant and/or advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, W.L. Gore & Associates and Janssen; Michael Trauner received speaker fees from BMS, Falk Foundation, Gilead and MSD; advisory board fees from Albireo, Falk Pharma GmbH, Genfit, Gilead, Intercept, MSD, Novartis, Phenex and Regulus. He further received travel grants from Abbvie, Falk, Gilead and Intercept and unrestricted research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda. Thomas Reiberger received grant support from Abbvie, Boehringer-Ingelheim, Gilead, MSD, Philips Healthcare, Gore; speaking honoraria from Abbvie, Gilead, Gore, Intercept, Roche, MSD; consulting/advisory board fee from Abbvie, Bayer, Boehringer-Ingelheim, Gilead, MSD, Siemens; and travel support from Boehringer-Ingelheim, Gilead and Roche.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Thomas Reiberger, MD, Associate Professor, Doctor, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1180, Austria.
Telephone: +43-1-4040065890 Fax: +43-1-4040047350
Received: June 4, 2019
Peer-review started: June 4, 2019
First decision: July 21, 2019
Revised: August 15, 2019
Accepted: September 27, 2019
Article in press: September 27, 2019
Published online: October 21, 2019

Portal hypertension (PHT) in advanced chronic liver disease (ACLD) results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition (structural component) and intrahepatic vasoconstriction (functional component). PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding. Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns (PAMPs) that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways. Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability: The intestinal barrier function is affected by impaired microcirculation, neoangiogenesis, and abnormal vascular and mucosal permeability. The close bidirectional relationship between the gut and the liver has been termed “gut-liver axis”. Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function, intestinal barrier integrity, as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects. The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments, however, further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed. In this review, we summarize the clinical impact of PHT on the course of liver disease, discuss the underlying pathophysiological link of PHT to gut-liver axis signaling, and provide insight into molecular mechanisms that may represent novel therapeutic targets.

Keywords: Cirrhosis, Portal hypertension, Gut-liver axis, Bacterial translocation, Intestinal barrier, Farnesoid X receptor

Core tip: In advanced chronic liver disease, portal hypertension (PHT) results from increased intrahepatic resistance and leads to splanchnic vasodilation and patholocgical neoangiogenesis. Gut dysbiosis, increased intestinal permeability, translocation of bacteria and pathogen-associated molecular patterns promote liver disease progression via immune system activation and subsequent induction of a proinflammatory state. The close relationship between gut and liver and their bidirectional interaction has been termed gut-liver axis. This review describes the impact of PHT on the gut-liver axis by providing insight into pathophysiology and summarizing important clinical observations and potential therapeutic strategies.