Key pathophysiological mechanisms linking gut-liver axis alterations to HE.
| Component | Mechanism | Impact on HE pathogenesis |
|---|---|---|
| Dysbiotic microbiota | Overgrowth of urease-producing and endotoxin-generating bacteria; decreased SCFA-producing commensals | Increases ammonia and endotoxin production; impairs gut homeostasis and neurochemical balance |
| Increased gut permeability | Disruption of TJ proteins and mucosal immune dysfunction | Enables translocation of LPS and PAMPs into portal circulation, activating hepatic immune responses |
| Portal hypertension | Splanchnic vasodilation, mucosal hypoxia, and epithelial injury | Aggravates intestinal barrier breakdown and promotes systemic inflammation |
| Kupffer cell activation | Recognition of PAMPs via TLRs/NLRs triggers cytokine release | Promotes hepatic inflammation and systemic immune activation |
| Ammonia accumulation | Impaired hepatic detoxification; increased intestinal production and reduced renal clearance | Causes astrocytic swelling, glutamine accumulation, and cerebral edema |
| Microglial and astrocytic activation | Central nervous system entry of cytokines and microbial products activates neuroinflammatory cascades and oxidative stress | Contributes to synaptic dysfunction, neurotransmitter imbalance, and brain edema |
| Tryptophan catabolism alterations | Microbiota-driven modulation of kynurenine and serotonin pathways | Affects cognition, mood regulation, and microglial phenotype |
| Mitochondrial dysfunction | Disruption of oxidative phosphorylation and reactive oxygen species generation by ammonia, bilirubin, and microbial metabolites | Reduces neuronal energy availability and enhances neuronal vulnerability |
HE: hepatic encephalopathy; LPS: lipopolysaccharide; NLRs: Nod-like receptors; PAMPs: pathogen-associated molecular patterns; SCFA: short-chain fatty acid; TJ: tight junction; TLRs: Toll-like receptors.
The author Arnulfo E. Morales-Galicia gratefully acknowledges the Programa Nacional de Servicio Social en Investigación of the Dirección General de Calidad y Educación en Salud, Secretaría de Salud, México, for the valuable opportunity to carry out this internship, which substantially contributed to the development and completion of this research work.
AEMG: Visualization, Investigation, Writing—original draft, Writing—review & editing. MNRS: Visualization, Writing—review & editing. MMRM: Investigation, Writing—original draft, Writing—review & editing. NMS: Conceptualization, Writing—original draft, Writing—review & editing, Supervision. All the authors read and approved the submitted version.
Nahum Méndez-Sánchez, who is the Associate Editor and Guest Editor of Exploration of Digestive Diseases, was not involved in the decision-making or the review process of this manuscript. The other authors declare no conflicts of interest.
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