Abstract In recent years, liver disease have become a major contributor to global morbidity and mortality, with current clinical treatments often limited by late diagnosis and rapid progression. This review aims to explore the underexplored role of gut microbiota (GM) in liver disease pathogenesis, and to highlight how Traditional Chinese Medicine (TCM) offers a novel therapeutic approach through indirect modulation of the GM. While conventional pharmacological strategies focus on direct organ-targeting interventions, TCM emphasizes a holistic, multi-target approach that aligns with the complex GM-liver axis. Specifically, we examine the interactions between GM and various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, cirrhosis, acute liver injury, autoimmune hepatitis, and hepatocellular carcinoma) and focuses on the indirect axis of "TCM-GM-liver," aiming to elucidate its scientific implications from the perspective of indirect pharmacology. Unlike current research that broadly addresses GM-derived metabolites, this review innovatively details how TCM and natural products regulate specific bacterial phyla and their representative genera to influence disease progression. In conclusion, we emphasize that GM metabolites serve as critical intermediate substances in TCM-mediated hepatoprotection. By elucidating these mechanisms, this review provides a theoretical foundation for developing microbiota-guided therapeutic strategies and advancing novel drug discovery for liver diseases. Graphical Abstract
Zhang et al. (2026) studied this question.