Hepatotoxicity and the role of the gut-liver axis in rats after oral administration of titanium dioxide nanoparticles

Due to its excellent physicochemical properties and wide applications in consumer goods, titanium dioxide nanoparticles (TiO₂ NPs) have been increasingly exposed to the environment and the public. However, the health effects of oral exposure of TiO₂ NPs are still controversial. This study aimed to illustrate the hepatotoxicity induced by TiO₂ NPs and the underlying mechanisms. Rats were administered with TiO₂ NPs (29 nm) orally at exposure doses of 0, 2, 10, 50 mg/kg daily for 90 days. Changes in the gut microbiota and hepatic metabolomics were analyzed to explore the role of the gut-liver axis in the hepatotoxicity induced by TiO₂ NPs.

TiO₂ NPs caused slight hepatotoxicity, including clear mitochondrial swelling, after subchronic oral exposure at 50 mg/kg. Liver metabolomics analysis showed that 29 metabolites and two metabolic pathways changed significantly in exposed rats. Glutamate, glutamine, and glutathione were the key metabolites leading the generation of energy-related metabolic disorders and imbalance of oxidation/antioxidation. 16S rDNA sequencing analysis showed that the diversity of gut microbiota in rats increased in a dose-dependent manner. The abundance of Lactobacillus_reuteri increased and the abundance of Romboutsia decreased significantly in feces of TiO₂ NPs-exposed rats, leading to changes of metabolic function of gut microbiota. Lipopolysaccharides (LPS) produced by gut microbiota increased significantly, which may be a key factor in the subsequent liver effects.

TiO₂ NPs could induce slight hepatotoxicity at dose of 50 mg/kg after long-term oral exposure. The indirect pathway of the gut-liver axis, linking liver metabolism and gut microbiota, played an important role in the underlying mechanisms.