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Review
. 2019 Oct 21;25(39):5897-5917.
doi: 10.3748/wjg.v25.i39.5897.

Gut-liver axis signaling in portal hypertension

Benedikt Simbrunner  1 , Mattias Mandorfer  1 , Michael Trauner  1 , Thomas Reiberger  2
Affiliations
Review

Gut-liver axis signaling in portal hypertension

Benedikt Simbrunner et al. World J Gastroenterol. .

Abstract

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: Bacterial translocation; Cirrhosis; Farnesoid X receptor; Gut-liver axis; Intestinal barrier; Portal hypertension.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Farnesoid X receptor-fibroblast growth factor 19 signaling between gut and liver regulates bile acid homeostasis and impacts on mucosal barrier function. Bacterial translocation triggers fibrosis and hepatic inflammation via activation of hepatic stellate cells and liver-resident macrophages. Fibroblast growth factor (FGF) 19 binds to FGF receptor 4 on hepatocytes which subsequently suppresses the expression of CYP7A1. FGF19 is upregulated postprandially and influences farnesoid X receptor-dependent metabolic pathways involved in gluconeogenesis, protein synthesis, insulin sensitivity and lipid profile. Kupffer cells and monocyte-derived macrophages produce cytokines and chemotactic molecules in response to liver injury. Recognition of lipopolysaccharide by Toll-like receptor 4 on macrophages and Kupffer cells results in activation of the NFκ-B-regulated inflammasome and increases tumor necrosis factor-α synthesis. In the continuous presence of injury, pathogen-associated molecular patterns and/or danger-associated molecular patterns, these cells create a proinflammatory environment that finally cause hepatocyte injury and fibrosis via hepatic stellate cell stimulation that results in production of collagen and α-smooth muscle actin. FXR: Farnesoid X receptor; RXRα: Retinoid X receptor; BSEP: Bile salt export pump; FGF: Fibroblast growth factor; FGFR4: Fibroblast growth factor receptor 4; LPS: Lipopolysaccharide; α-SMA: α smooth muscle actin; TNF: Tumor necrosis factor; IL: Interleukin; HSC: Hepatic stellate cell; LSEC: Liver sinusoidal endothelial cell; TLR: Toll-like receptor; PAMPs: Pathogen-associated molecular patterns; α-SMA: α-smooth muscle actin.
Figure 2
Figure 2
An impaired mucosal epithelial barrier integrity facilitates bacterial translocation and is regulated by farnesoid X receptor-dependent mechanisms. Increased systemic inflammation in cirrhotic patients as compared to healthy subjects is considered to be associated with intestinal dysbiosis leading to translocation of pathogens- or derived pathogen-associated molecular patterns and danger-associated molecular patterns into the portal circulation, which is further facilitated by an impaired intestinal barrier. Farnesoid X receptor (FXR) activation in ileum enhances the expression of fibroblast growth factor 15 (mice) or 19 (humans) via binding to response elements in the nucleus. FXR activation leads to upregulation of tight junction proteins and decrease of bacterial translocation. FXR: Farnesoid X receptor; IgA: Immunoglobulin A; RXRα: Retinoid X receptor; FGF: Fibroblast growth factor; LPS: Lipopolysaccharide; TJ: Tight junction.
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