How the gut-liver axis shapes hepatic encephalopathy: mechanistic and therapeutic perspectives

Hepatic encephalopathy (HE) is a debilitating neuropsychiatric complication of liver dysfunction that spans a continuum from subtle cognitive impairment to deep coma. While historically attributed to hyperammonemia, current insights reveal a multifactorial pathogenesis involving systemic inflammation, astrocyte dysfunction, blood-brain barrier (BBB) disruption, and altered neurotransmission. Central to this complex network is the gut-liver axis—a bidirectional system that links the gut microbiota, intestinal barrier integrity, bile acid metabolism, and hepatic immune responses. In cirrhosis, dysbiosis and increased intestinal permeability facilitate the translocation of microbial products—such as endotoxins and ammonia—that trigger hepatic and systemic immune activation, amplifying neurotoxicity through the gut-liver-brain axis. Experimental and clinical evidence has shown that ammonia and bilirubin synergistically promote neuroinflammation, mitochondrial dysfunction, and glial activation. Multiomics data further support the role of the microbiota as an active modulator of liver-brain homeostasis. Microbiota-targeted therapies—including rifaximin, probiotics, synbiotics, and fecal microbiota transplantation (FMT)—demonstrate efficacy in reducing HE recurrence, improving cognition, and restoring microbial balance. Novel receptor-based strategies targeting the farnesoid X receptor (FXR), Takeda G-protein-coupled receptor 5 (TGR5), and aryl hydrocarbon receptor (AhR) show promise for modulating bile acid pathways and mitigating neuroinflammation. Emerging approaches also focus on dietary interventions, the reinforcement of epithelial barrier function, and artificial intelligence (AI)-driven tools for personalized monitoring. Despite these advances, challenges persist regarding FMT standardization, long-term safety, and the integration of digital diagnostics into routine care.