Bile acid metabolic disorders and their role in hepatic encephalopathy of cirrhosis

Figure 4 Bile acid receptor signaling in the gut-liver-brain axis. Bile acids act as signaling molecules to regulate the gut-liver-brain axis through nuclear receptors (farnesoid X receptor and pregnane X receptor) and membrane receptors (Takeda G protein-coupled receptor 5 and sphingosine-1-phosphate receptor 2). Farnesoid X receptor and pregnane X receptor maintain Bile acid homeostasis, enhance intestinal and blood-brain barrier (BBB) integrity, and suppress inflammation. Takeda G protein-coupled receptor 5 exerts anti-neuroinflammatory effects by inhibiting microglial activation and NACHT, LRR and PYD domains-containing protein 3 inflammasome. In contrast, sphingosine-1-phosphate receptor 2 disrupts the BBB, promotes chemokine ligand 2 release, and triggers neuroinflammation. These receptors jointly mediate intestinal barrier damage, liver fibrosis, BBB dysfunction, and central neuroinflammation, thereby driving the pathogenesis of hepatic encephalopathy. BA: Bile acid; S1PR2: Sphingosine-1-phosphate receptor 2; TGR5: Takeda G protein-coupled receptor 5; PXR: Pregnane X receptor; FXR: Farnesoid X receptor; SHP: Small heterodimer partner; BBB: Blood-brain barrier; CCL2: Chemokine ligand 2; P-gp: P-glycoprotein; IL-1β: Interleukin-1β; NF-κB: Nuclear factor κB; iNOS: Inducible nitric oxide synthase; COX2: Cyclooxygenase-2; TNF-α: Tumor necrosis factor-α; NLRP3: NACHT, LRR and PYD domains-containing protein 3; AP-1: Activator protein-1. Created in BioRender.