Gut microbiota dysbiosis and the gut–liver–brain axis: Mechanistic insights into hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE), a severe neuropsychiatric manifestation of cirrhosis, is increasingly being understood to be intimately associated with dysbiosis of gut microbiota. The intestinal microbiota, an ever-changing consortium that performs a very critical role in the preservation of barrier function, immune homeostasis, and metabolic harmony, becomes deeply disturbed in cirrhosis. This dysregulation enhances gut permeability and enables translocation of neurotoxic metabolites like ammonia and endotoxins into systemic circulation, triggering systemic inflammation that further disrupts the blood–brain barrier and aggravates neuroinflammation beyond ammonia-mediated toxicity, accelerating hepatic decompensation and inducing neuroinflammation along the gut–liver–brain axis. This review attempts an extensive review of the changing notion regarding gut microbiota implication in HE pathogenesis. It places emphasis on mechanistic interaction among microbial dysbiosis, immune activation, and dysfunction of the central nervous system and comprehensively critiques present treatments like probiotics, prebiotics, antibiotics, and faecal microbiota transplantation (FMT). Although FMT has shown promising results in restoring microbial balance and improving neurological function, its application is limited by donor variability, procedural risks, and uncertain long-term safety. Although some clinical evidence is promising, its utility is restricted by patient-to-patient variability in microbial response, lack of beneficial biomarkers, and knowledge gaps of mechanisms. Technical innovations in metagenomics, metabolomics, and computational biology have the potential to reveal disease-specific microbial signatures and create personalized, microbiome-directed therapeutic interventions. Reestablishing microbial homeostasis is a new and potentially revolutionary treatment strategy to abrogate neuroinflammation, restore gut–liver–brain axis function, and enhance HE outcomes. This review concludes that targeting gut dysbiosis represents a paradigm shift in HE management, though personalized approaches based on a deeper mechanistic understanding are needed for future success. • Gut microbiota dysbiosis contributes to chronic liver diseases like cirrhosis, ALD, and NAFLD. • Leaky gut allows endotoxins into the liver, promoting inflammation and worsening liver disease progression. • Hepatic encephalopathy is driven by gut-derived ammonia and microbial imbalance in liver cirrhosis. • Cirrhosis alters gut microbiota, increasing pathogens and reducing beneficial bacteria like Lactobacillus. • FMT, probiotics, rifaximin, and polyphenols help restore gut balance and improve liver–brain outcomes.

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