Multi-omics investigations reveal the critical role of the liver-microbiota-gut axis in tetrabromobisphenol S-induced liver fibrosis.

Tetrabromobisphenol S (TBBPS), a widely used brominated flame retardant (BFR), is increasingly detected in environmental and biological samples, raising urgent concerns. Although several in vitro studies have investigated the hepatotoxicity of TBBPS, the in vivo effects and mechanisms of chronic exposure, particularly by the liver-microbiota-gut axis, remain largely unexplored. In this study, we administered TBBPS via oral gavage to C57BL/6 J male mice and employed an integrated multi-omics strategy consisting of transcriptomics, serum non-targeted metabolomics, and 16S rDNA gene sequencing. The results showed that 1 and 5 mg/kg/day TBBPS exposure induced significant hepatic fibrosis in mice. Further TBBPS treatment markedly altered the gut microbiota composition, characterized by shifts in bile acid (BA)-metabolizing bacteria and an enrichment of pathobionts such as Desulfovibrio. This dysbiosis was closely linked to disrupted BA homeostasis, as evidenced by a decrease in serum lithocholic acid which could drive hepatic upregulation of Cyp7a1, a gene encoding the key enzyme in BA synthesis. Consequently, this perturbation of metabolic homeostasis promoted liver fibrosis by activating TGF-β. Taken together, these findings demonstrate that chronic TBBPS exposure promotes hepatic fibrosis by disrupting the BA-regulated liver-microbiota-gut axis, thereby informing risk assessment of TBBPS and advancing our understanding of BFR hepatotoxicity.