Dilireba Aimaier, WanQuan Bai, Yun Zhang, Xiang Li, Chen Ma, Jian Gu, Le Zhang

College of Pharmacy and Food, Southwest Minzu University, Chengdu, Sichuan, 610225, People’s Republic of China

Correspondence: Le Zhang, Email zhangle_only@163.com

Background: Polygonum multiflorum (PM), known as a traditional Chinese herb renowned for its tonic properties, has been used medicinally for millennia. However, it has drawn attention significantly due to the potential to induce idiosyncratic drug-induced liver injury (IDILI) in recent years. Previous studies identified the TNF-α, the pro-inflammatory cytokine, as a key factor contributing to susceptibility to PM induced-IDILI (PM-IDILI). However, the effects by which TNF-α mediates PM-IDILI remain poorly understood.
Methods: This study sought to elucidate the role of TNF-α in PM-IDILI using a TNF-α-sensitized C57BL/6J mouse model, integrating analyses of the gut microbiota and metabolomics We employed biochemical analysis, inflammatory markers, inflammatory liver histopathological, sequencing of 16S rRNA gene, as well as untargeted metabolomics based on LC-MS to systematically evaluate the extent of liver injury and characterize alterations in gut microbiota and liver metabolites following PM administration in TNF-α pre-treated mice.
Results: The results demonstrated that PM treatment in TNF-α-sensitized mice significantly elevated levels of indicators as AST (3.6-fold compared to the control group, P < 0.05) and ALT (3.9-fold compared to the control group, P < 0.01), increased plasma levels of IL-6 and IL-1β (P < 0.05 or P < 0.01), induced infiltration of inflammatory cell substantially in the liver. TNF-α-mediated PM disrupted the intestinal microbiota structure, characterized by reduced abundance of Akkermansia and increased abundance of Lachnospiraceae_NK4A136_group, Bacteroides, Alloprevotella, and Blautia. Furthermore, hepatic metabolomics analysis revealed that significant perturbations in TNF-α + PM treated mice, particularly affecting glutathione metabolism, purine metabolism, and arachidonic acid metabolism pathways.
Conclusion: These findings suggest that TNF-α sensitization predisposes mice to PM-IDILI, potentially by disrupting gut microbial homeostasis and altering host hepatic metabolism. This research provides critical theoretical and experimental evidence relevant to the safe and effective clinical application of PM.

Keywords: Polygonum multiflorum, TNF-α, idiosyncratic drug-induced liver injury, gut microbiota, metabolomics, susceptibility