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

Abstract

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 <i>Lachnospiraceae bacterium</i> in the gut microbiota of ALD patients and ethanol (EtOH)-fed mice, as revealed by 16S rDNA sequencing. Supplementation with <i>Lachnospiraceae bacterium</i> 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 <i>Lachnospiraceae bacterium</i> supplementation, with levels positively correlated to <i>Lachnospiraceae bacterium</i> 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 <i>Lachnospiraceae bacterium</i> mitigates alcohol-induced liver damage both <i>in vivo</i> and <i>in vitro</i> by inhibiting ferroptosis through NAG-mediated activation of the KEAP1-NRF2 pathway. <i>Lachnospiraceae bacterium</i> may serve as promising probiotics for future clinical applications.