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. 2026 Mar 29;58(1):2650232. doi: 10.1080/07853890.2026.2650232

Figure 1.

This diagram illustrates the inflammatory gut-liver-brain axis in hepatic encephalopathy. Portal hypertension and impaired liver function cause gut dysbiosis and barrier failure, leading to bacterial translocation and cirrhosis-associated immune dysfunction with immune cell hyperactivation and exhaustion. Systemic inflammation ensues with elevated cytokines. At the blood-brain barrier, TNF-α upregulates the Rhcg transporter, facilitating ammonia entry into the brain. Neuroinflammation occurs via neutrophil extracellular traps, matrix metalloproteinase-9 release, and microglial activation, culminating in cerebral energy crisis and cognitive impairment. Therapeutic interventions target the gut (lactulose, rifaximin, fecal microbiota transplantation) and systemic inflammation (albumin, interleukin inhibitors).

The inflammatory gut-liver-brain axis in hepatic encephalopathy. This integrative figure illustrates the complex interplay between gut-derived factors, systemic inflammation, and neuroinflammation in the pathogenesis of hepatic encephalopathy (HE), as well as therapeutic interventions targeting each level of this axis. ① Gut Pathology: Portal hypertension in cirrhosis and impaired liver function lead to mucosal congestion, reduced blood flow, and hypoxia. These hemodynamic alterations, combined with gut dysbiosis (↓ beneficial taxa, ↑ Enterobacteriaceae), compromise intestinal barrier integrity through downregulation of tight junction proteins. This results in increased intestinal permeability and enhanced bacterial translocation. ② Bacterial Translocation and Systemic Inflammation: Live bacteria and pathogen-associated molecular patterns (PAMPs, e.g. LPS) translocate into the portal and systemic circulation. This drives cirrhosis-associated immune dysfunction (CAID), characterized by a dual defect: (a) hyperactivation of Kupffer cells and monocytes with excessive cytokine release, and (b) immune exhaustion evidenced by reduced HLA-DR expression on monocytes. Systemic levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) are elevated. ③ Therapeutic Interventions: Interventions are positioned at their primary sites of action: (a) Gut-targeted therapies include lactulose, rifaximin, fecal microbiota transplantation (FMT), dietary interventions, and probiotics/prebiotics, which aim to restore eubiosis, reduce ammonia production, and enhance barrier function. (b) Systemically, albumin and interleukin inhibitors target circulating inflammatory mediators. (c) Conventional ammonia-lowering therapies complement these approaches. ④ Blood–Brain Barrier (BBB) Interaction: Systemic cytokines, particularly TNF-α, upregulate the ammonia transporter Rhcg on brain endothelial cells, facilitating ammonia entry into the central nervous system. This represents a key molecular mechanism by which systemic inflammation synergistically amplifies ammonia neurotoxicity. ⑤ Neuroinflammation and Cerebral Consequences: Within the CNS, infiltrating neutrophils release neutrophil extracellular traps (NETs) and matrix metalloproteinase-9 (MMP-9), degrading the basement membrane and compromising BBB integrity. Microglia are activated by cytokines and PAMPs, releasing further inflammatory mediators. This neuroinflammatory milieu, combined with ammonia-induced astrocyte swelling, leads to an energy crisis characterized by impaired mitochondrial ATP production, neuronal dysfunction, and synaptic deficits, ultimately manifesting as cognitive impairment. This figure integrates the key pathogenic mechanisms discussed in Sections 2.1.2 and 2.2.1, and the therapeutic interventions detailed in Section 3.