Traditional Chinese medicine (TCM) has occupied a central role in healthcare across East Asia for thousands of years, and among its most revered medicinal herbs is Bupleuri Radix (BR), derived from the roots of Bupleurum chinense DC. or Bupleurum scorzonerifolium Willd. BR is a fundamental component of numerous classical TCM formulas, including Xiao Chaihu Tang and Chaihu Shugan San, traditionally prescribed for liver qi stagnation, fever, and digestive disorders. Modern pharmacological research has validated many of these traditional applications, demonstrating BR's hepatoprotective, anti-inflammatory, immunomodulatory, and anticancer properties. However, the clinical use of BR is shadowed by persistent concerns regarding its potential hepatotoxicity, with reports of liver injury associated with BR-containing formulas raising questions about its safety profile. This review addresses this paradox by systematically examining BR's dual effects through the innovative framework of the gut-liver axis.
The gut-liver axis represents a bidirectional communication system connecting the gastrointestinal tract and the liver via the portal circulation, biliary tract, and systemic immune signaling. This axis has emerged as a critical determinant of drug metabolism, toxicity, and therapeutic efficacy, particularly for oral medications and herbal medicines that undergo extensive first-pass metabolism and microbial biotransformation. For BR, the gut-liver axis provides an essential framework for understanding how its constituents are processed by intestinal microbiota, absorbed into the portal circulation, and metabolized by the liver, while also modulating the intestinal environment that in turn influences liver health. This holistic perspective represents a significant advance over traditional reductionist approaches that examine individual compounds in isolation.
At the heart of BR's biological activity are saikosaponins, a group of triterpenoid saponins that serve as the primary bioactive markers of BR quality. The review details how saikosaponins, upon oral administration, encounter the gut microbiota, which possesses a rich array of glycosidases and other enzymes capable of transforming these relatively polar compounds into secondary metabolites with altered physicochemical properties. This microbial biotransformation typically involves deglycosylation, removing sugar moieties to generate more lipophilic products with enhanced intestinal absorption and bioavailability. The resulting metabolites, in turn, exert profound effects on the intestinal ecosystem: they regulate the composition and diversity of gut microbiota, promoting the growth of beneficial species while suppressing pathogens; they strengthen the intestinal epithelial barrier by enhancing tight junction protein expression and reducing intestinal permeability; and they alleviate intestinal inflammation through modulation of key signaling pathways. Specifically, the review highlights the NF-κB pathway as a central target for BR's anti-inflammatory actions in the gut, along with the PI3K/Akt/mTOR pathway which regulates cell survival and metabolism, and the STAT3 pathway which mediates inflammatory and immune responses.
The hepatoprotective effects of BR and its constituents are equally multifaceted. The review synthesizes evidence demonstrating that BR exerts antioxidant effects by scavenging reactive oxygen species, enhancing the activity of antioxidant enzymes such as superoxide dismutase and catalase, and reducing lipid peroxidation in liver tissue. Its anti-inflammatory actions in the liver involve suppression of pro-inflammatory cytokine production, inhibition of Kupffer cell activation, and reduction of inflammatory cell infiltration. Additionally, BR regulates hepatic metabolism, including lipid and glucose metabolism, which may contribute to its protective effects against non-alcoholic fatty liver disease and other metabolic liver disorders. These hepatoprotective mechanisms are closely intertwined with the gut-liver axis, as improvements in intestinal barrier function and reductions in gut-derived endotoxins and inflammatory mediators indirectly protect the liver from injury.
Despite these beneficial effects, the review candidly addresses the hepatotoxic potential of BR. Evidence suggests that certain saikosaponin subtypes and volatile oil components of BR may induce liver injury through mechanisms involving oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways. The dose-dependent nature of this toxicity is a critical consideration, as is the potential for idiosyncratic reactions in susceptible individuals. The gut-liver axis may also play a role in BR hepatotoxicity, as microbial metabolites of saikosaponins could potentially possess greater toxicity than the parent compounds, or alterations in gut microbiota composition could increase susceptibility to liver injury. The review emphasizes that our understanding of BR's toxicity remains incomplete, particularly regarding the toxicity of microbial metabolites and the clinical risk factors that predispose individuals to BR-induced liver injury.
Looking forward, the authors identify several critical research priorities. First, systematic studies are needed to elucidate the complex interplay between BR's multi-component actions and the gut-liver axis, moving beyond single-compound studies to examine how the full spectrum of BR constituents interacts with gut microbiota and liver metabolism. Second, the toxicity of BR's microbial metabolites requires thorough investigation, as these compounds may differ significantly from parent compounds in their pharmacological and toxicological profiles. Third, clinical studies are needed to define the risk factors for BR-induced hepatotoxicity and to establish safe dosing guidelines. By addressing these evidence gaps, future research can optimize the safe and effective application of BR, ensuring that this valuable traditional medicine continues to benefit patients while minimizing potential risks.
MedScience
Experimental study
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Innovative analysis and future prospects of Bupleuri Radix's pharmacology and toxicity based on the gut-liver axis