Polyphenols synergistic drugs to ameliorate non-alcoholic fatty liver disease via signal pathway and gut microbiota: A review

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease with an increasing incidence worldwide. Single drug therapy may have toxic side effects and disrupt gut microbiota balance. Polyphenols are widely used in disease intervention due to their distinctive nutritional properties and medicinal value, which a potential gut microbiota modulator. However, there is a lack of comprehensive review to explore the efficacy and mechanism of combined therapy with drugs and polyphenols for NAFLD. Based on this, this review firstly discusses the link between NAFLD and gut microbiota, and outlines the effects of polyphenols and drugs on gut microbiota. Secondly, it examined recent advances in the treatment and intervention of NAFLD with drugs and polyphenols and the therapeutic effect of the combination of the two. Finally, we highlight the underlying mechanisms of polyphenol combined drug therapy in NAFLD. This is mainly in terms of signaling pathways (NF-κB, AMPK, Nrf2, JAK/STAT, PPAR, SREBP-1c, PI3K/Akt and TLR) and gut microbiota. Furthermore, some emerging mechanisms such as microRNA potential biomarker therapies may provide therapeutic avenues for NAFLD. Drawing inspiration from combination drug strategies, the use of active substances in combination with drugs for NAFLD intervention holds transformative and prospective potential, both improve NAFLD and restore gut microbiota balance while reducing the required drug dosage. This review systematically discusses the bidirectional interactions between gut microbiota and NAFLD, and summarizes the potential mechanisms of polyphenol synergistic drugs in the treatment of NAFLD by modulating signaling pathways and gut microbiota. Future researches should develop multi-omics technology to identify patients who benefit from polyphenols combination drugs and devising individualized treatment plans to enhance its therapeutic effect.