The gut microbiota mediates triptolide-induced liver injury via the gut-liver axis

Abstract

Abstract Triptolide (TP) is a toxic component of Tripterygium wilfordii Hook. f. that exhibits liver and gastrointestinal toxicity. However, TP-induced liver injury varies between individuals via an unknown mechanism, which limits the safe clinical application of TP. Herein, we aimed to study the mechanism underlying the regulation of TP-induced liver injury via the gut-liver axis using a multi-omics technique. C57BL/6 mice were administered with TP at 800 µg/kg. We also constructed a mouse model based on the male C57BL/6 gut microbiota with quadruple antibiotics. 16S rRNA gene sequencing, hematoxylin and eosin staining, and biochemical analyses were used to analyze the intestinal microbiota composition in stool samples and TP-induced hepatotoxicity and enterotoxicity. Proteomics and targeted metabonomics were performed to analyze key proteins related to intestinal injury and differential liver metabolic markers. Gut microbiota Lactobacillus and Bacteroides were related to TP hepatotoxicity, while the Lactobacillus rhamnosus or Bacteroides fragilis colonization alleviated TP-induced liver and ileum damage after gut microbiota disorder. Multi-omics analyses showed that the TP caused changes in genes related to intestinal and liver immune responses. Gut microbiota disorder amplified related immune responses, causing changes in intestinal immune barrier-related proteins REG3B and REG3G and changes to liver metabolites via the gut-liver axis. Thus, the gut microbiota (via the gut–liver axis) plays an important role in liver injury induced by TP, allowing a better interpretation of TP-induced hepatotoxicity.