Investigation of the underlying mechanism of rifampicin-induced hepatotoxicity and neurotoxicity in mice by untargeted metabolomics and gut microbiota approach.

Abstract

Rifampicin (RIF) remains a first-line antituberculosis agent. However, its usefulness is limited by its hepatotoxicity and potential neurotoxicity. The aim of this study was to investigate the association between dysbiosis of gut microbiota and dysregulation of liver and brain metabolites in mice induced by treatment with RIF. Microbiota analysis (16S rRNA gene sequencing) using fecal samples and untargeted metabolomic analysis using liver and brain tissues were performed to investigate the mechanism in RIF-induced hepatotoxicity and neurotoxicity. A total of 32 and 27 metabolites were altered in the liver and brain of mice, respectively. Based on the gut microbiota analysis, Proteobacteria and Verrucomicrobia (at the phylum level), as well as Akkermansia, Allobaculum, and Lactobacillus (at the genus level) were markedly changed in the 240 mg/kg RIF group versus the controls. The pathway analysis indicated that energy metabolism and important nutrients metabolism were disrupted, leading to inflammatory response and oxidative stress. To our knowledge, this is the first study demonstrating an alteration of gut microbiota and metabolites in the liver and brain of mice after exposure to RIF. This evidence may provide a direction for investigating the mechanism underlying the hepatotoxicity and neurotoxicity induced by treatment with RIF.