Gut-liver axis signaling in portal hypertension

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.

Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality

“…14,15 Abnormal translocation of bacteria and pathogen-associated molecular patterns from the intestinal lumen into the portal and systemic circulation is considered J o u r n a l P r e -p r o o f central role of the gut-liver-axis. 17 While acute decompensation may be triggered by significant SI, the exact chronological relationship between bacterial translocation, SI, and decompensation currently remains elusive. 16 A better understanding of the pathophysiological factors driving the transition across ACLD stages is necessary to redefine therapeutic strategies.…”

<p>Increases in Autoantibody Level Associated with Degenerative Changes in the Intestinal Mucosa in Liver Cirrhosis</p>

“…[6][7][8] Changes in physiological processes in the liver can cause the development of intestinal dysfunction with microbiota A B disturbance, which stimulates the secretion of proinflammatory cytokines, and can lead to increased enterocyte penetration. 9 On the other hand, the intestinal barrier disturbance exposes the liver to toxic factors. 10 Studies devoted to the investigation of chronic inflammatory processes in the intestines in patients with cirrhosis show that portal hypertension is the basis of the pathogenesis of enteropathies and colonopathies.…”

Liver Cirrhosis and Sarcopenia from the Viewpoint of Dysbiosis

“…In recent years, the association between dysbiosis and alcoholic hepatitis associated with excessive drinking has been receiving more attention [ 110 ]. In alcoholic liver injury, intestinal permeability is increased (i.e., leaky gut), and pathogen-associated molecular patterns (PAMPs) represented by endotoxin (lipopolysaccharide (LPS)) derived from bacteria reach the liver through the portal vein and cause liver damage by activating Kupffer cells [ 110 ]. Endotoxin is mainly present in the cell wall of Gram-negative bacteria.…”