Non-alcoholic fatty liver disease (NAFLD) is considered to be a significant health threat globally, and has attracted growing concern in the research field of liver diseases. NAFLD comprises multifarious fatty degenerative disorders in the liver, including simple steatosis, steatohepatitis and fibrosis. The fundamental pathophysiology of NAFLD is complex and multifactor-driven. In addition to viruses, metabolic syndrome and alcohol, evidence has recently indicated that the microbiome is related to the development and progression of NAFLD. In this review, we summarize the possible microbiota-based therapeutic approaches and highlight the importance of establishing the diagnosis of NAFLD through the different spectra of the disease via the gut–liver axis.

Background Non-alcoholic fatty liver disease (NAFLD) is a serious public health issue globally, currently, the treatment of NAFLD lies still in the labyrinth. In the inchoate stage, the combinatorial application of food regimen and favorable gut microbiota (GM) are considered as an alternative therapeutic. Accordingly, we integrated secondary metabolites (SMs) from GM and Avena sativa (AS) known as potent dietary grain to identify the combinatorial efficacy through network pharmacology. Methods We browsed the SMs of AS via Natural Product Activity & Species Source (NPASS) database and SMs of GM were retrieved by gutMGene database. Then, specific intersecting targets were identified from targets related to SMs of AS and GM. The final targets were selected on NAFLD-related targets, which was considered as crucial targets. The protein–protein interaction (PPI) networks and bubble chart analysis to identify a hub target and a key signaling pathway were conducted, respectively. In parallel, we analyzed the relationship of GM or AS─a key signaling pathway─targets─SMs (GASTM) by merging the five components via RPackage. We identified key SMs on a key signaling pathway via molecular docking assay (MDA). Finally, the identified key SMs were verified the physicochemical properties and toxicity in silico platform. Results The final 16 targets were regarded as critical proteins against NAFLD, and Vascular Endothelial Growth Factor A (VEGFA) was a key target in PPI network analysis. The PI3K-Akt signaling pathway was the uppermost mechanism associated with VEGFA as an antagonistic mode. GASTM networks represented 122 nodes (60 GM, AS, PI3K-Akt signaling pathway, 4 targets, and 56 SMs) and 154 edges. The VEGFA-myricetin, or quercetin, GSK3B-myricetin, IL2-diosgenin complexes formed the most stable conformation, the three ligands were derived from GM. Conversely, NR4A1-vestitol formed stable conformation with the highest affinity, and the vestitol was obtained from AS. The given four SMs were no hurdles to develop into drugs devoid of its toxicity. Conclusion In conclusion, we show that combinatorial application of AS and GM might be exerted to the potent synergistic effects against NAFLD, dampening PI3K-Akt signaling pathway. This work provides the importance of dietary strategy and beneficial GM on NAFLD, a data mining basis for further explicating the SMs and pharmacological mechanisms of combinatorial application (AS and GM) against NAFLD.

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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.