The liver plays a critical role in the immune surveillance against bacterial translocation or absorption of bacterial endotoxins into the portal circulation. Since the intestinal and biliary epithelia are continuous, any alterations in gut mucosal immunity (“leaky gut”) or microbiome (dysbiosis) may, therefore, lead to heightened innate immune activation (liver-gut crosstalk) resulting in hepatobiliary injury (Fig. 12.1).

One of the hypotheses for the pathogenesis of PSC is the cross-reactive immunity to an antigen leading to immune-mediated gut and biliary inflammation from the enterohepatic circulation of gut-activated T lymphocytes. During intestinal inflammation, naive lymphocytes are imprinted with gut tropism by intestinal dendritic cells localized in the intestinal mucosa via integrin ligand, mucosal vascular addressin cell addressin molecule 1 (MAdCAM-1) and gut-specific chemokine, and CCL25-dependent mechanisms. Normally, these molecules are highly restricted to the gut, where they drive selective recruitment of gut-specific T and B cells and the expression the CCL25, chemokine receptor CCR9, and the integrin combination, α4β7, which binds to MAdCAM-1. It is suggested that in a genetically predisposed individual, gut dysbiosis and intestinal inflammation with translocation of enteric pathogens beyond the mucosal barrier lead to activation of endogenous molecules termed damage-associated molecular patterns (DAMPS) [19–21]. Due to aberrant gut tropism seen in PSC, DAMP-associated activation of innate immunity and hepatic expression CCL25 and MAdCAM-1 result in the recruitment of mucosal effector lymphocytes bearing a “gut-trophic” phenotype. Additionally, the adhesion molecule and ectoenzyme vascular adhesion protein (VAP-1) are upregulated during chronic inflammation and support both lymphocyte adhesion through upregulation of several endothelial adhesion molecules, including MAdCAM-1, on sinusoidal endothelium [22, 23]. Also, it catabolizes amine substrates secreted by gut bacteria and contributes to reactive oxygen species generation. After entering the liver, effector cells use chemokine receptors such as CCR9 to respond to chemokines secreted by epithelial target cells resulting in cell-mediated immunological attack and bile duct destruction (Fig. 12.1). Hepatobiliary damage is likely enhanced by the action of toxic bile acids and heightened DAMP activation resulting in cellular production of inflammatory cytokines that act as ligands for chemokine receptors leading to downstream processes such as autophagy, apoptosis, and fibrosis [19, 24–26].

Bile acids are cholanic acid derivatives that act as detergents and are responsible for facilitating the absorption of dietary lipids, fat-soluble vitamins and for maintaining cholesterol homeostasis. The formation of bile acids is initiated in hepatocytes and mediated by cholesterol 7 α-hydroxylase (CYP7A1) [32]. Bile composed primarily of water, various ions, and solutes and is released into bile canaliculi on the apical side of hepatocytes. The bile acids flow through the canals of Hering before continuing through the biliary epithelium [32]. Despite continuous exposure to millimolar levels of hydrophobic bile salt monomers, the cholangiocytes are protected from damage due to a biliary HCO3- umbrella [33–37]. The formation of bicarbonate umbrella is mediated through transmembrane G-protein couple receptor (TGR5) [38]. Bile acids are stored in the gallbladder, and are then secreted into the duodenum where they are metabolized by enteric bacteria. Approximately, 95 % of these bile acids are absorbed in the terminal ileum and are then transported back to the liver via the portal vein for recycling [32]. These conjugated bile acids will be secreted back into the bile pool. This process is known as the enterohepatic shunt [32]. However, unconjugated bile acids are absorbed by the cholangiocytes and returned to the hepatocytes via the peribiliary vascular plexus in a process known as the cholehepatic shunt [32]. After synthesis, bile acids are conjugated with either glycine or taurine, which decreases the toxicity of bile and makes it more soluble [32]. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that results in inhibition of CYP7A1 [32]. In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 19 (FGF19), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis resulting in decreased levels of 7ahydroxy-4-cholesten-3-one (C4) and endogenous bile acids (Fig. 12.1) [32].