Integrated multi-omics of gut-liver axis to dissect the mechanism underlying hepatotoxicity induced by sub-chronic tire wear particles exposure in mice

As a novel pollutant, tire wear particles (TWPs) have been revealed as a major constituent of microplastics (MPs) and are widely present in various environmental media. Yet the current studies are limited to investigating their environmental distribution and aquatic toxicity, and the potential adverse effects of TWPs on human remain unclear. The mechanism underlying hepatotoxicity induced by long-term TWPs exposure has not yet been investigated. To address this issue, we conducted an animal experiment using forty 4-week-old female Balb/c mice, which were randomly divided into four groups (Control, L-TWPs, M-TWPs and H-TWPs). They were gavaged with PBS, 0.1 mg/day, 0.5 mg/day and 1 mg/day TWPs for 14 weeks, respectively. Results demonstrated that chronic TWPs exposure pathologically damaged liver, gut barrier, as well as induced gut microbiota dysbiosis. In addition, both the ileal and hepatic metabolomes indicated that TWPs caused riboflavin metabolism disorder. Furthermore, we found elevated abundance of Staphylococcus spp. was negatively correlated with reduced concentrations of glycerophosphoinositol, serotonin and glutathione that are responsible for maintaining intestinal barrier in ileum, while reduced Oligella spp. and Paenalcaligenes spp. were positively correlated with diminished levels of hepatic riboflavin, flavin mononucleotide and lumiflavin, all of which could maintain normal riboflavin metabolism. Consequently, TWPs-induced gut microbiota dysbiosis exacerbated intestinal barrier impairment, contributing to hepatic riboflavin metabolism disorder. In conclusion, our work provides novel evidence for deepening insight into long-term TWPs exposure-induced hepatotoxicity from the perspective of gut-liver axis.