Ellagic Acid Protects\nagainst Alcohol-Related Liver\nDisease by Modulating the Hepatic Circadian Rhythm Signaling through\nthe Gut Microbiota–NPAS2 Axis

Alcohol-related liver disease (ALD) encompasses a spectrum\nof hepatic\ndisorders resulting from alcohol abuse, which constitutes the predominant\netiology of morbidity and mortality associated with hepatic pathologies\nglobally. Excessive alcohol consumption disrupts the integrity of\nthe intestinal barrier and perturbs the balance of gut microbiota,\nthereby facilitating the progression of ALD. Ellagic acid (EA) has\nbeen extensively reported to be an effective intervention for alleviating\nliver symptoms. However, the target molecules of EA in improving ALD\nand its underlying mechanism remain elusive. First, our study indicates\nthat EA ameliorated ALD through the hepatic circadian rhythm signaling\nby up-regulating neuronal PAS domain protein 2 (NPAS2). Furthermore,\nanalysis of the intestinal microbiome showed that EA significantly\nenhanced the abundance of beneficial bacteria, which was positively\ncorrelated with NPAS2 expression and negatively correlated with liver\ninjury. Finally, antibiotic treatment and fecal microbiota transplantation\n(FMT) experiments established a causal relationship between the reshaped\nmicrobiota and NPAS2 in the amelioration of ALD. In summary, our study\ndemonstrates novel evidence that EA attenuated ALD by modulating the\nhepatic circadian rhythm signaling pathway via the gut microbiota–NPAS2\naxis, providing valuable insights for EA and microbiome-targeted interventions\nagainst ALD.