Exploring the beneficial effect of gut microbiota metabolites on diabetic nephropathy via network pharmacology study

Diabetic nephropathy (DN) is one of the severe complications of diabetes, current treatment against DN is still limited. It is suggested that gut microbiota metabolites will be a promising alternative therapy against DN. In this study, we explore the beneficial effect of gut microbiota metabolites on DN via employing network pharmacology study. The targets of metabolites were screen from Similarity Ensemble Approach (SEA) and Swiss Target Prediction (STP). The DN targets were acquired from disease database. The intersecting targets of metabolites and DN were considered crucial targets. The Protein-Protein Interaction (PPI) networks, GO function and KEGG analysis were conducted to identify core target and key signaling pathway. A "Microbiota-Substrate-Metabolites-Targets" network was built to screen the core metabolites. Molecular docking was employed to assess the binding affinity between metabolites and targets. GO functional results indicated that the metabolites were mainly enriched in oxidative stress and inflammation. PPARG, AKT1, IL6 and JUN were the top 4 targets of gut microbiota metabolites regulating DN. Butyrate, Acetate, Indole and 3-Indolepropionic acid were the core gut microbiota metabolites that had beneficial effects on attenuating DN. Molecular docking results indicated that 3-Indolepropionic acid displayed a good binding affinity toward targets of PPARG, AKT1, IL6 and JUN. Our study revealed that the gut microbiota metabolites might exert beneficial effect on attenuating DN by regulating multi-signaling pathway and multi-targets. This work offers us a novel insight into the mechanism of DN from the perspective of beneficial benefits of gut microbiota metabolites.