Gut-Liver Translocation of Bacteroides Uniformis Alleviates Advanced Metabolic Dysfunction-Associated Steatotic Liver Disease by Suppressing Hepatocyte Ferroptosis via Propionic Acid Secretion.

Interactions between hepatic metabolism and the gut microbiota play a crucial role in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD), highlighting the gut-liver axis as a promising therapeutic target. However, little is known about how gut dysbiosis influences the composition of liver-resident microbiota, and how this alteration contributes to disease progression. In this study, 16S rRNA sequencing of liver samples from patients with advanced MASLD reveals a marked reduction in the abundance of Bacteroides uniformis (B. uniformis), a trend also observed in fecal samples. These findings are replicated in a mouse model, where B. uniformis levels are decreased in both hepatic and gut microbial communities. Notably, gavage of B. uniformis increases its abundance in the liver and attenuates multiple features of advanced MASLD. Further investigation identifies propionic acid (PA) as a key mediator responsible for the protective effects of B. uniformis. Mechanistically, both B. uniformis and PA administration suppress lipid peroxidation and ferroptotic stress in hepatocytes through activating mammalian target of rapamycin phosphorylation and upregulating glutathione peroxidase 4 expression. Taken together, our results uncover a distinctive liver-resident microbiota in advanced MASLD and underscore the therapeutic potential of promoting gut-liver translocation of B. uniformis to curb disease progression.