Nobiletin attenuates alcohol-related liver disease by inhibting gut-liver inflammation and gut microbiota disturbance in mice.

Abstract

Purpose: Nobiletin (NOB), an extract derived from citrus fruit peels, is renowned for its anti-inflammatory and antioxidant properties. However, the specific impact of NOB on alcohol-related liver disease (ALD) and its regulatory pathways remains an underexplored area of study. This research aims not only to confirm the positive regulatory effects of NOB on ALD but also to explore its mechanism of action through the "gut-liver axis" theory.

Methods: Utilizing the Lieber-DeCarli method, C57BL/6J male mice were subjected to a four-week liquid alcohol diet to induce ALD. The mechanism of NOB alleviating ALD is explored by detecting biochemical analysis, western blot, qRT-PCR, and gut microbiota analysis.

Results: In vivo, it was observed that NOB treatment (2.5 mg/kg and 5 mg/kg) significantly alleviated alcohol-induced liver inflammation, accompanied by normalization of aberrant gene and protein expression patterns associated with inflammation. Notably, this treatment also enhanced intestinal barrier integrity, resulting in decreased intestinal LPS permeability and a subsequent reduction in ileum inflammation. Furthermore, 16 S rRNA analysis demonstrated that NOB effectively ameliorated alcohol-induced gut microbiota dysbiosis by restoring the balance between Firmicutes and Bacteroidetes and promoting the growth of beneficial bacterial families like Akkermansiaceae. In vitro, utilizing LPS-induced RAW264.7 cells, NOB's efficacy in mitigating liver inflammation was further corroborated. Specifically, the treatment was found to exert its anti-inflammatory effects through modulation of the NF-κB/TLR4 signaling pathway.

Conclusion: our study has made significant progress in understanding NOB's hepatoprotective effects on alcohol-induced ALD mice. This perspective not only clarifies NOB's therapeutic role in ALD management but also inspires future research on additional gut-liver axis indicators for a comprehensive exploration of NOB's therapeutic potential.