Bacteroides uniformis mediates the alleviative effects of Rb1 on Alcohol-associated liver disease by enhancing glutamine levels and improving the urea cycle via the GCN2-eIF2α-ATF4-SLC25A2 pathway

Description

Alcohol-associated liver disease (ALD) is a leading cause of chronic liver morbidity and mortality worldwide, yet effective clinical therapeutic strategies remain scarce. Ginsenoside Rb1 (Rb1), a primary bioactive constituent of Panax ginseng, has exhibited promising hepatoprotective activity against liver injury. Here, we investigated the hepatoprotective effects and underlying mechanisms of Rb1 and its probiotic-fermented counterpart (F-Rb1) in ALD, with a focus on the gut-microbiota-liver axis. Using the Gao-Binge model (NIAAA model), we demonstrated that both Rb1 and F-Rb1 significantly attenuated alcohol-induced hepatic steatosis, inflammation, and injury, as evidenced by reduced AST, ALT, TG, TBIL and inflammatory cytokines. 16S rRNA sequencing revealed that Rb1 and F-Rb1 distinctly modulated the gut microbiota: Rb1 selectively enriched Bacteroides uniformis, whereas F-Rb1 primarily increased Prevotella copri. Metabolomics analysis and functional assays further showed that Rb1 treatment enhanced intestinal glutamine levels and restored hepatic urea cycle function by upregulating the mitochondrial ornithine transporter SLC25A2 and key enzymes (CPS1, OTC, ASS1). Mechanistically, Rb1-driven B. uniformis and its derived metabolite glutamine, which suppressed the hepatic amino acid starvation response (GCN2–eIF2α–ATF4) and upregulated SLC25A2, thereby restoring urea cycle function and reducing systemic ammonia. These effects were abrogated by antibiotic-induced microbiota depletion and recapitulated by fecal microbiota transplantation from Rb1-treated donors. Furthermore, direct administration of live B. uniformis mimicked the protective effects of Rb1, while heat-killed B. uniformis had no effect. Notably, Rb1 was metabolized by gut bacteria into rare ginsenosides (Rg3, Rg5, PPD), but these metabolites were not detected in liver tissue, supporting a gut-restricted mechanism of action. Collectively, this study uncovers a discrete mechanism by which Rb1 alleviates ALD through the B. uniformis–glutamine–GCN2-eIF2α-ATF4-SLC25A2–urea cycle axis. These findings provide new insights into microbiota-dependent actions of ginsenosides and highlight potential microbial and metabolic targets for precision therapy in ALD.

Institutions

• Jilin Agricultural University

  Jilin, Changchun

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