Lachnospiraceae bacterium alleviates alcohol-associated liver disease by enhancing N-acetyl-glutamic acid levels and inhibiting ferroptosis through the KEAP1-NRF2 pathway

Alcohol-associated liver disease (ALD) is a prevalent global health issue primarily caused by excessive alcohol consumption. Recent studies have highlighted the gut-liver axis's protective role against ALD, mainly through gut microbiota. However, the precise mechanism remains ill-defined. Our results showed a significant reduction in Lachnospiraceae bacterium in the gut microbiota of ALD patients and ethanol (EtOH)-fed mice, as revealed by 16S rDNA sequencing. Supplementation with Lachnospiraceae bacterium strains in mice significantly reduced inflammation, hepatic neutrophil infiltration, oxidative stress, and improved gut microbiota and intestinal permeability. Multi-omics analysis identified N-Acetyl-glutamic acid (NAG) as the most significantly altered metabolite following Lachnospiraceae bacterium supplementation, with levels positively correlated to Lachnospiraceae bacterium colonization. NAG treatment exhibited significant protective effects in EtOH-exposed hepatocyte cell lines and EtOH-fed mice. Mechanistically, NAG confers hepatoprotection against ALD by activating the KEAP1-NRF2 pathway, inhibiting ferroptosis. Notably, the protective effects of NAG were reversed by the NRF2 inhibitor. In conclusion, oral supplementation with Lachnospiraceae bacterium mitigates alcohol-induced liver damage both in vivo and in vitro by inhibiting ferroptosis through NAG-mediated activation of the KEAP1-NRF2 pathway. Lachnospiraceae bacterium may serve as promising probiotics for future clinical applications.