Gut microbiota protects from triptolide-induced hepatotoxicity: Key role of propionate and its downstream signalling events

As a potential drug for treating inflammatory, autoimmune diseases and cancers, triptolide (TP) is greatly limited in clinical practice due to its severe toxicity, particularly for liver injury. Recently, metabolic homeostasis was vitally linked to drug-induced liver injury and gut microbiota was established to play an important role. In this study, we aimed to investigate the functions of gut microbiota on TP-induced hepatotoxicity using metabolomics in mice. Here, predepletion of gut microbiota by antibiotic treatment strikingly aggravated liver injury and caused mortality after treated with a relatively safe dosage of TP at 0.5 mg/kg, which could be reversed by gut microbial transplantation. The loss of gut microbiota prior to TP treatment dramatically elevated long chain fatty acids and bile acids in plasma and liver. Further study suggested that gut microbiota-derived propionate contributed to the protective effect of gut microbiota against TP evidenced by ameliorative inflammatory level (Tnfa, Il6 and Cox2), ATP, malondialdehyde and hepatic histology. Supplementing with propionate significantly decreased the mRNA levels of genes involved in fatty acid biosynthesis (Srebp1c, Fasn and Elovl6), resulting in the decreased long chain fatty acids in liver. Moreover, TP restricted the growth of Firmicutes and led to the deficiency of short chain fatty acids in cecum content. In conclusion, our study warns the risk for TP and its preparations when antibiotics are co-administrated. Intervening by foods, prebiotics and probiotics toward gut microbiota or supplementing with propionate may be a clinical strategy to improve toxicity induced by TP.