The gut-liver axis in hepatic ischemia-reperfusion injury: from microbiota dysbiosis to remote organ dysfunction

Hepatic ischemia-reperfusion injury (HIRI) is a major cause of graft dysfunction and postoperative complications after liver transplantation and hepatic resection. Increasing evidence indicates that the gut-liver axis plays a central role in modulating hepatic injury, inflammation, and tissue regeneration during HIRI.

This narrative review synthesizes current experimental and clinical evidence regarding the mechanisms linking intestinal barrier dysfunction, gut microbiota dysbiosis, microbial metabolites, and immune signaling pathways to the pathogenesis of HIRI. Recent advances in pharmacological strategies targeting the gut-liver axis were also evaluated.

Hepatic ischemia disrupts intestinal microcirculation, leading to epithelial barrier breakdown, bacterial translocation, and activation of innate immune responses through pathogen-associated molecular patterns and Toll-like receptor signaling. Microbiota-derived metabolites exert both protective and deleterious effects. Short-chain fatty acids promote anti-inflammatory responses through histone deacetylase inhibition, whereas trimethylamine N-oxide (TMAO) amplifies NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis. Disruption of the farnesoid X receptor (FXR)-fibroblast growth factor 15/19 (FGF15/19) signaling pathway further compromises intestinal barrier integrity and hepatic regeneration. Emerging therapeutic approaches, including FXR agonists, nonmitogenic FGF19 analogs, recombinant interlukin-22, postbiotics, and TMAO-targeted interventions, demonstrate promising hepatoprotective potential in preclinical studies.

The gut-liver axis is a key regulator of HIRI pathophysiology and represents a promising therapeutic target. Strategies aimed at preserving intestinal barrier integrity, modulating the gut microbiota, and restoring immunometabolic homeostasis may reduce hepatic injury and improve outcomes after liver transplantation and major hepatic surgery.