Gut microbial metabolites as therapeutics to treat of alcoholic liver disease

Abstract

Abstract Alcoholic liver disease (ALD) is resultant of excessive consumption of alcohol. ALD is the world’s third largest risk factor for diseases and disabilities and accounting for 5.9% of all deaths worldwide. ALD patients exhibit increased gut permeability, gut microbial dysbiosis, endotoxemia and hepatic steatosis. Recent studies, unequivocally demonstrated the importance of gut microbiota and their metabolites in regulating host pathophysiology. Urolithin A (UroA) is a gut microbial metabolite derived from dietary ellagic acid and ellagitannins containing foods. Previously, we showed that UroA act as an AhR agonist and activate AhR-Nrf2 pathways to induce tight junction proteins and enhance gut barrier function. In the current study, we tested the hypothesis that correcting gut barrier dysfunction, blocking inflammation and reducing hepatic steatosis simultaneously by UroA would provide better therapeutic options to treat ALD. Our studies suggested that UroA significantly induced expression of tight junction (TJ) proteins (Occludin, Cldn4 and ZO1) in AhR-Nrf2 dependent manner and protected from alcohol-induced downregulation of TJ proteins and reduced gut barrier leakage. Further, UroA attenuated ALD pathogenesis in both acute and chronic experimental mouse models by reducing alcohol induced barrier permeability, systemic endotoxin levels and inflammatory mediators. In these models, UroA treatment also significantly reduced alcohol induced liver ALT/AST levels, inflammatory mediators (TNF-α, IL-6, IL-1β) and triglyceride levels as well as prevented liver damage. In summary, these studies highlight that the mechanisms of microbial metabolite, UroA and its multi-pronged beneficial effects in attenuating ALD.