Total glucosides of paeony in cirrhosis: mechanisms of action via the gut–liver axis – a review

Background & aim Liver cirrhosis, the end-stage of chronic liver diseases, imposes a high global burden. Gut–liver axis dysregulation—microbiota imbalance, barrier failure, endotoxin translocation, bile acid disturbance, suppressed FXR signaling, and NLRP3 activation—drives cirrhosis progression. Total glucosides of paeony (TGP), a Paeonia lactiflora extract rich in paeoniflorin (>90%), possesses anti-inflammatory and immunomodulatory properties. However, a systematic review of TGP’s mechanisms via the gut–liver axis is lacking. This review aims to systematically summarize and critically evaluate the molecular mechanisms by which TGP modulates the gut–liver axis to treat cirrhosis, covering its effects on microbiota restoration, barrier repair, bile acid normalization, FXR reactivation, and dual inhibition of NF-κB and NLRP3 inflammatory pathways, thereby providing a comprehensive mechanistic framework for its therapeutic application. Main findings Preclinical evidence shows TGP is associated with improved microbiota balance (increased Lactobacillus, Akkermansia, Lachnospira), Through short-chain fatty acids, the expression of tight junction proteins (ZO-1, Occludin, Claudin-3) may be upregulated, and the levels of endotoxin and bacterial translocation in the portal vein may be reduced. TGP normalizes primary-to-secondary bile acid conversion (CA/CDCA to DCA/LCA), thereby activating intestinal and hepatic farnesoid X receptor (FXR). Its main component, paeoniflorin, enhances FXR through PKCα/MAPK inhibition and SIRT1 upregulation. Activated FXR dually suppresses NF-κB (directly and via Nrf2/HO-1) and inhibits NLRP3 Ser295 phosphorylation, while reducing bile acid synthesis, achieving coordinated anti-inflammatory and barrier-protective effects. Conclusion TGP may intervene in the vicious cycle of liver cirrhosis through a hierarchical cascading reaction - barrier repair, bile acid restoration, FXR activation, and dual NF-κB/NLRP3 inhibition. Despite predominantly preclinical data, TGP’s multi-target profile offers promising therapeutic potential; future large-scale clinical trials and formulation refinement are needed to enable TGP to meet the demand for the transition from preclinical evidence to clinical application, benefiting patients with liver cirrhosis.