The scale of the problem motivating the review is considerable. According to the Global Burden of Disease 2021 database cited by the authors, the global incidence of liver cirrhosis reached 58.4 million cases in 2021, with deaths attributable to cirrhosis totaling 1,425,142. Overall incidence rose by 58.21 percent between 1990 and 2021, and cirrhosis currently ranks as the eleventh most common cause of death worldwide, accounting with liver cancer for roughly 3.5 percent of all deaths. A recent systematic review and meta-analysis estimated the pooled global prevalence of advanced liver fibrosis at 3.3 percent and of cirrhosis at 1.3 percent in the general population, with an upward trend after 2016. The etiological landscape has also shifted: while viral hepatitis and alcohol-related liver disease historically dominated, non-alcoholic fatty liver disease—now termed metabolic dysfunction-associated steatotic liver disease (MASLD)—has emerged as the leading global cause of incident cirrhosis, with a pooled cirrhosis prevalence of 3.26 percent in general practice settings and as high as 14.51 percent among inpatients or patients referred for liver biopsy.

The review’s central premise rests on the gut–liver axis, the bidirectional communication network linking the intestine and liver through the portal vein, the biliary system, and the systemic circulation. Under physiological conditions, the portal vein carries nutrients, microbial metabolites, and bacterial products from the gut to the liver, while the liver secretes bile acids and antimicrobial molecules into the intestinal lumen, shaping the microbiota and maintaining ecological balance. In cirrhosis, this circuit breaks down. Gut dysbiosis—marked by reductions in commensal bacteria such as Bifidobacteria and Lactobacilli and expansion of potentially pathogenic Enterobacteriaceae and Veillonellaceae—impairs intestinal barrier integrity and increases gut permeability. Microbial products, particularly lipopolysaccharide (LPS), then translocate into the portal circulation, where they activate Kupffer cells via Toll-like receptor 4 signaling and trigger release of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. This cascade activates hepatic stellate cells, the principal effectors of fibrogenesis, driving collagen deposition and progressive architectural distortion of the liver.

Bile acid dysregulation deepens the cycle. Bile acids begin as primary forms—cholic acid and chenodeoxycholic acid—synthesized from cholesterol in the liver and secreted into the intestine, where anaerobic bacteria expressing bile salt hydrolases convert them into the secondary bile acids deoxycholic acid and lithocholic acid. About 95 percent of bile acids are reabsorbed in the terminal ileum and returned to the liver, completing the enterohepatic circulation. In cirrhosis, alterations in bile acid-metabolizing bacterial groups such as Lachnospiraceae and Ruminococcaceae reduce the conversion of primary to secondary bile acids and shrink the diversity of the bile acid pool. Because secondary bile acids are potent agonists of FXR, their decline leaves the FXR signaling pathway inadequately activated. FXR is essential for maintaining the intestinal epithelial barrier and the gut-vascular barrier, and it suppresses de novo bile acid synthesis by inhibiting cholesterol 7α-hydroxylase (CYP7A1). When FXR activity falls, bacterial translocation increases and bile acid synthesis becomes uncontrolled, allowing toxic bile acids to accumulate and further damage the liver.

The NLRP3 inflammasome adds a third layer to the pathological circuit. This multiprotein complex assembles upon recognition of pathogen-associated and danger-associated molecular patterns, promoting caspase-1-mediated maturation of the inflammatory cytokines IL-1β and IL-18. In the cirrhotic liver, toxic bile acids can directly activate the NLRP3 pathway, while in the intestine the inflammasome responds to bacteria and their metabolites. Sustained inflammation impairs the mucosal barrier, triggering bacterial translocation into the portal circulation and further hepatic inflammatory activation. Chronic low-grade inflammation pushes hepatic stellate cells from a quiescent to an activated state, producing excessive extracellular matrix and collagen deposition. As fibrosis progresses, compression of the biliary tree causes cholestasis, prolonging exposure to toxic bile acids and perpetuating the cycle. Notably, animal studies have shown that NLRP3 gene knockout can partially reverse the metabolic disturbances associated with dysbiosis and alleviate liver fibrosis, underscoring the inflammasome’s driving role.

Against this backdrop, the review details how TGP—a multicomponent extract in which paeoniflorin accounts for more than 90 percent of total glucosides, alongside albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin—may act at each node. At the microbiota level, preclinical studies report that TGP enriches beneficial genera including Lactobacillus, Akkermansia, Lachnospira, Dubosiella, and Bacteroides while suppressing potentially pathogenic taxa such as Ligilactobacillus and Mucispirillum. Lactobacillus is a recognized producer of short-chain fatty acids such as butyrate and acetate, which serve as energy sources for intestinal epithelial cells, upregulate tight junction protein expression, and promote regulatory T cell differentiation. Akkermansia, a mucin-degrading bacterium, has been shown to enhance tight junction protein expression and improve barrier integrity. The authors note that similar microbiota-reshaping effects have been observed in mouse models of fatty liver disease and ulcerative colitis, suggesting the action is generalizable across disease contexts rather than specific to cirrhosis models.

Barrier repair follows from microbial restoration. TGP has been reported to upregulate the tight junction proteins ZO-1, Occludin, and Claudin-3, to reduce release of zonulin and pro-inflammatory cytokines including IL-1β, TGF-β, and TNF-α, and to decrease intestinal permeability. In a neonatal rat model of necrotizing enterocolitis, TGP treatment increased tight junction protein expression and improved barrier function; in a mouse model of ulcerative colitis, it enhanced barrier integrity by upregulating colonic ZO-1, Occludin, and claudin proteins while alleviating chemically induced intestinal inflammation. By restoring the barrier, TGP would in principle reduce the translocation of viable bacteria and endotoxins into the portal system, intervening at the key link in the vicious cycle that runs from dysbiosis through barrier impairment and bacterial translocation to hepatic inflammation.

The mechanistic core of the proposed framework lies in FXR. According to the review, TGP restores the conversion of primary bile acids to secondary bile acids by increasing Lactobacillus abundance, raising colonic concentrations of DCA and LCA and thereby supporting FXR activation. TGP may also enhance FXR through microbiota-independent routes: inhibition of PKCα and MAPK pathway activation suppresses ERα activity, which otherwise binds the estrogen response element in the FXR promoter and represses its transcription; and upregulation of SIRT1 promotes deacetylation of FXR, favoring formation of transcriptionally active FXR/RXRα heterodimers. Chen and colleagues demonstrated in 2021 that paeoniflorin protects against ANIT-induced cholestatic liver injury by activating the SIRT1-FXR pathway. Activated FXR then exerts three protective functions: direct inhibition of NF-κB transcriptional activity, indirect suppression of NF-κB through the Nrf2/HO-1 pathway, and reduction of bile acid synthesis via CYP7A1 inhibition. FXR also directly suppresses phosphorylation of NLRP3 at serine 295, blocking inflammasome activation, while additional mechanisms—SIRT1-mediated inhibition of PKM2-driven aerobic glycolysis and blockade of mitochondrial reactive oxygen species accumulation—may further restrain NLRP3 assembly.

The authors are candid about the limits of their synthesis. The mechanistic model is assembled from studies conducted in different experimental systems rather than causal verification within a single one, and most mechanism studies rely on single cell lines or acute injury models such as carbon tetrachloride-induced fibrosis, bile duct ligation, or LPS/D-galactosamine-induced acute liver injury, which do not fully capture the metabolic, immune, and microbial complexity of human cirrhosis. Pharmacokinetic data are severely lacking: TGP’s oral bioavailability is approximately 3 to 4 percent owing to extensive gut microbial metabolism and efflux, and the portal hypertension, intestinal congestion, and compromised liver function characteristic of cirrhosis may profoundly alter drug absorption and metabolism. The differential contributions of individual TGP components remain unclear, long-term safety data are insufficient, and no clinical trial registration currently exists for TGP in cirrhosis—existing registered trials focus on autoimmune hepatitis, psoriasis, and vitiligo. The authors also note there is no evidence that TGP directly regulates NLRP3 phosphorylation; that link is inferred from FXR biology.

Looking forward, the review outlines a translational agenda: exploratory trials in patients with compensated cirrhosis measuring intestinal permeability, serum endotoxin, inflammatory markers, and liver function; germ-free animal models and fecal microbiota transplantation experiments to separate microbiota-dependent from microbiota-independent effects; multi-omics approaches to identify key active metabolites; targeted delivery formulations such as enteric-coated or nano-encapsulated TGP to improve bioavailability; and combinations with existing agents such as obeticholic acid, probiotics, or rifaximin. The authors argue that TGP’s established clinical safety record in rheumatoid arthritis provides a foundation for long-term use, and that its multi-target profile—spanning microbiota, barrier, bile acids, FXR, and inflammatory effectors—may offer more physiological regulation than single-target drugs. For now, however, the framework remains a preclinical hypothesis awaiting the clinical validation, mechanistic deepening, and formulation optimization the authors identify as the decisive next steps.

Subject of Research: Mechanisms by which total glucosides of paeony may modulate the gut–liver axis in liver cirrhosis

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

Article References: Chen, S., & Zheng, Q. (2026). Total glucosides of paeony in cirrhosis: mechanisms of action via the gut–liver axis – a review. Frontiers in Gastroenterology, 5, 1981682. https://doi.org/10.3389/fgstr.2026.1981682

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1981682

Keywords: liver cirrhosis, gut–liver axis, total glucosides of paeony, paeoniflorin, farnesoid X receptor, NLRP3 inflammasome, NF-κB, gut microbiota, bile acids, intestinal barrier, preclinical research, Paeonia lactiflora