A microbiome-bile acid axis mediates protection from chronic liver disease in females

Sex-based differences in chronic liver disease (CLD) incidence and progression are well documented, yet the mechanistic basis of this sexual disparity remains elusive. Here, leveraging a large-scale metabolomics database comprising 9,254 individuals, we identify the endogenous bile acid, isoursodeoxycholic acid (isoUDCA), as a candidate mediator of female-associated hepatoprotection. We trace the origin of isoUDCA to a bacterial consortium, which is selectively enriched by estrogen through shaping a specialized intestinal microenvironment. Mechanistically, isoUDCA promotes the nuclear accumulation of SREBP2. This upregulates the intracellular transporter STARD4 and its functionally coupled downstream enzyme CYP7B1, thereby facilitating intracellular cholesterol handling and metabolic conversion. Collectively, our findings support a microbiome-bile acid-liver axis that may contribute to sex differences in CLD susceptibility and support further evaluation of isoUDCA as a potential therapeutic intervention.