Gut-liver axis signaling in portal hypertension

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 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.