Oleanolic acid alleviates intestinal injury secondary to ischemia-reperfusion injury in severe hepatic steatosis via activation of the PPARG receptor, which promotes macrophage polarization toward the M2 phenotype.
Key Findings
Results
Rats with severe hepatic steatosis exhibited significantly greater intestinal injury and gut microbiota dysbiosis following hepatic ischemia-reperfusion injury compared to normal diet rats.
8-week-old male Sprague-Dawley rats were fed a high-fat diet to induce severe hepatic steatosis
Ischemia-reperfusion injury was induced with 80-minute ischemia
Gut microbiota composition was analyzed by 16S rDNA sequencing
Intestinal injury was assessed by hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence
Significant intestinal injury and gut microbiota dysbiosis were observed in the steatosis group compared with the normal diet group
Results
Oleanolic acid treatment markedly alleviated intestinal damage in severe hepatic steatosis rats after ischemia-reperfusion injury.
OA is described as a gut microbiota metabolite
Damage assessment included hematoxylin-eosin staining, immunohistochemistry, immunofluorescence, and cell viability assays
OA treatment reduced inflammatory cytokine levels as measured by ELISA and Western blotting
OA treatment improved intestinal function in severe hepatic steatosis rats after IRI
Results
Oleanolic acid exerts its protective effects by activating the PPARG receptor and modulating macrophage polarization toward the M2 phenotype.
Network pharmacology analysis, molecular docking, and both in vitro and in vivo experiments were used to identify the mechanism
PPARG antagonist GW9662 was used to confirm PPARG-dependent effects
In vitro intestinal injury was modeled using IEC-6 and Caco-2 co-cultures with macrophages after lipopolysaccharide treatment
OA promoted macrophage polarization toward the M2 phenotype via PPARG activation
Results
Blockade of PPARG with the antagonist GW9662 abrogated the protective effects of oleanolic acid on intestinal injury.
Rats were treated with OA or the PPARG antagonist GW9662
GW9662 treatment was used both in vivo and in vitro to confirm PPARG pathway dependency
This confirmed that OA's protective mechanism is PPARG-dependent
Results were validated across in vitro co-culture models and in vivo rat models
Background
Liver transplantation with steatotic donor livers is frequently complicated by ischemia-reperfusion injury leading to intestinal dysfunction and reduced long-term survival.
Intestinal dysfunction is identified as a consequence of IRI in the context of steatotic donor livers
Reduced long-term survival is associated with IRI following liver transplantation with steatotic livers
This clinical problem motivated the investigation of OA as a potential therapeutic strategy
Pi Y, Wang Y, Guo Q, Zheng W, Zhou H, Deng L, et al.. (2026). Oleanolic acid alleviates intestinal injury after hepatic ischemia-reperfusion under steatosis via PPARG-dependent M2 macrophage polarization.. International immunopharmacology. https://doi.org/10.1016/j.intimp.2026.116162