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.