A network pharmacology study to determine the integrated application of dietary plant-derived natural flavonoids and gut microbiota against nonalcoholic fatty liver disease

Background Nonalcoholic fatty liver disease (NAFLD) has been issued in a wide range of complicated progressive interruption such as steatosis, fibrosis, cirrhosis, and even hepatocellular carcinoma. However, a key therapy to unravel the progressive diseases associated with NAFLD has not been established completely among taking many of the potential compounds. In the context of the unfinished project, we comprised metabolites of gut microbiota (endogenous species) and dietary plant-derived natural flavonoids (exogenous species) known as potent antioxidant, antiinflammation, and anticancer, in search for combinatorial effects via network pharmacology analysis. Results We identified the 668 overlapping targets related to metabolites from gut microbiota between SEA and STP; and we selected 14 out of 16 flavonoids because the 2 flavonoids were violated by Lipinski’s rule. The flavonoids’ targets were 112, compared with the 668 overlapping targets to identify the significant targets. Then, we identified the final 47 intersecting targets against NAFLD. On PPI networks, both VEGFA and AKT1 had the highest degree value, which were considered as hub targets against NAFLD. In bubble chart, cAMP signaling pathway was a key mode to be functioned as inhibitive mechanism. On the networks of microbiota (or natural products)-metabolites-targets-key signaling pathway, Enterococcus sp. 45, Escherichia sp.12, Escherichia sp.33, and Bacterium MRG-PMF-1 as key microbiota; flavonoid-rich products as key natural resources; luteolin, and myricetin as key metabolites (or dietary flavonoids); CFTR, PIK3R1, and AKT1 as key targets are potential key components to treat NAFLD, by suppressing cAMP signaling pathway. Conclusion In this study, we suggested that four components (microbiota, metabolites, targets, and a key signaling pathway) and dietary plant-derived natural flavonoids can be exerted combinatorial pharmacological effects against NAFLD.