Alpha-tocopheryl quinone attenuates liver fibrosis through enriching Christensenella minuta and modulating bile acids metabolism via gut-liver axis

Liver fibrosis, characterized by the progressive accumulation of excessive extracellular matrix (ECM), remains a major global health issue with limited treatment options. The gut-liver axis, particularly the dynamics of gut microbiota and bile acids (BAs), plays a pivotal role in modulating hepatic fibrogenesis. Alpha-tocopheryl quinone (TQ), a vitamin E metabolite, exhibits antioxidative and anti-inflammatory properties; however, its impact on liver fibrosis remains unexplored. A murine fibrosis model was induced using carbon tetrachloride (CCl4), coupled with gut microbiota depletion via antibiotic cocktail (Abx) and fecal microbiota transplantation (FMT) from cirrhotic donors, to evaluate TQ's therapeutic effects. Biochemical and histological analyses assessed liver injury and fibrosis, while 16S rRNA sequencing determined gut microbiota composition. BAs profiles were quantified using LC-MS/MS. Glycine-β-muricholic acid (Gly-MCA), a gut-restricted farnesoid X receptor (FXR) antagonist, was employed for investigating mechanistic pathways. TQ treatment significantly alleviated liver damage and fibrosis in CCl4-treated mice, with a notable reshaping of the gut microbiota, particularly an increased abundance of Christensenella minuta (C. minuta). Mechanistically, TQ activated the intestinal FXR/FGF15 pathway, resulted in reduced hepatic BAs synthesis and enhanced fecal excretion. Abx and FMT experiments confirmed the microbiota-dependent antifibrotic effects of TQ, with C. minuta identified as a key mediator. Co-treatment with Gly-MCA abrogated the protective effects of C. minuta, highlighting the critical role of intestinal FXR signaling. TQ attenuates liver fibrosis via modulation of gut microbiota, particularly enriching C. minuta abundance, and regulating BAs metabolism via activation of the intestinal FXR/FGF15 axis. These results establish TQ as a promising therapeutic targeting the gut-liver axis, with C. minuta identified as a pivotal mediator in BAs metabolism and fibrotic resolution. This study lays the groundwork for microbiota-centered therapeutic strategies against hepatic fibrosis.