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

Abstract

Background: 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.

Aim of review: 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.

Key scientific concepts of review: 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.

Keywords: Gut-liver conduction; Individualized treatment; Mechanism; Non-alcoholic fatty liver disease.

Graphical abstract

Fig. 1

Influence of intrinsic and extrinsic factors on the development of NAFLD. Non-alcoholic fatty liver diseases mainly include primary factors and secondary factors. The primary factors mainly include genetic factors and insulin resistance; the secondary factors mainly include virus, drugs, industrial poison, lack of exercise, overeating, smoking and drinking. These pathogenic factors affect human health through the gut-liver axis. NAFLD generally has three stages of development, hepatitis, cirrhosis and hepatic cancer. In addition, it may also cause coronary heart disease, hypertension, hyperlipidemia, diabetes, uremia, and brain disorders.

Fig. 2

Changes of inflammatory factors and gut microbiota in the development and treatment of NAFLD. The combination of polyphenols and drugs modulates the abundance of gut microbiota as well as inhibits the production of pathogens in the body. A comparison of the gut of healthy and NAFLD showed that the latter produced a large number of pathogenic bacteria and inflammatory factors, reduced anti-inflammatory factors, and impaired intestinal barrier function. For example, TNF-α, IFN-γ, IL-8, IL-6, IL-1β and IL-17 were increased, IL-4 and IL-10 were decreased, and the gut microbiota was imbalanced. Combination therapy improves and alleviates NAFLD by modulating the gut microbiota to maintain gut-liver axis homeostasis, including increasing the abundance of beneficial bacteria, maintaining the strength of the intestinal barrier, and regulating the gut microbiota and macrophage infiltration and polarization.

Fig. 3

Schematic diagram illustrating the dispersed combination of dietary polyphenols and drugs. The gut-liver axis can promote the body’s immune and metabolic functions through gut microbes, and fruits and vegetables rich in dietary polyphenols, which are beneficial to promote the body’s metabolism. There are many drugs for the treatment of NAFLD, but drug therapy has dose-dependence and toxic side effects, so polyphenols combined with drugs can be used to reduce the dosage, so as to achieve the effect of improving and intervening in NAFLD.

Fig. 4

Schematic diagram of the mechanism of insulin resistance in the development of NAFLD. The development of insulin resistance in adipose tissue results in local lipolysis of adipose tissue, leading to the entry of free fatty acid into the blood and then into the liver; the entry of FFA into hepatocytes stimulates the synthesis of steroid regulatory element binding protein-1c and its downstream genes, increasing lipid synthesis in hepatocytes. When steatosis occurs in the liver, the intermediate products of metabolism, lysophosphatidic acid, phosphatidic acid and diacylglycerol, will activate protein kinase C, kappa-B kinase and Jun-amino-terminal kinase, and weaken insulin receptor substrate tyrosine phosphorylation to inhibit insulin signaling, which in turn leads to islet β-cell injury promoting NAFLD.

Fig. 5

Potential therapeutic mechanisms and pathways of polyphenols and drugs in combination with NAFLD. The gut-liver axis is involved in regulating the occurrence and improvement of NAFLD, mainly including signal pathways, gut microbiota and potential biological targets. These factors are associated with lipid accumulation, insulin resistance, oxidative stress, and inflammatory factors. The signal pathways include inhibition of the activation of the NF-κB pathway, inhibition of the inflammatory response, up-regulation of PPAR-α to increase β-FAO, activation of AMPK and down-regulation of SREBP-1c to inhibit adipogenesis, stimulation of the Nrf2 pathway to enhance antioxidant defence, lipid autophagocytosis and autophagy, and potential biomarker therapy.