Triptophenolide aggravates triptolide-induced liver injury through disrupting the biological function of intestine

Tripterygium wilfordii, Hook f. (TW) has been traditionally used in Chinese medicine to treat conditions like rheumatoid arthritis, nephritis, and lupus erythematosus. However, the toxic reactions to the liver pose a huge obstacle to TW's clinical applications. The toxicological mechanisms of TW remain unclear. Male C57BL/6 mice were administered with TW ingredient triptolide (TP) and triptophenolide (TPH) alone or in combination to investigate their individual and synergistic effects on the liver. Elisa tested for LPS in the plasma correlated with liver injury. Metabolomics and 16S rRNA analysis were used to investigate pathological markers associated with intestine function disorder which may contribute to liver injury. The correlation analysis between the differential metabolites and the changing flora was carried out to find the fundamental metabolic molecules, and the results of the correlation analysis were verified by the addition of metabolites in vivo. The concurrent use of TPH and TP cause intestinal bleeding and microbial dysbiosis, then augment level of LPS in the plasma to prompting more severe liver damage induced by TP. Metabolomic analysis and changes in microflora composition proved that the toxic metabolite PCS was significantly related to intestinal barrier damage, and the addition of PCS promoted hepatotoxicity in combination administration. By augmenting PCS, TPH compromises the gut barrier, escalates circulating LPS, and activates the hepatic TLR4/MyD88 pathway, thereby exacerbating TP-induced hepatic injury.