Elucidating the role of gut microbiota metabolites in diabetes by employing network pharmacology

BACKGROUND: Extensive research has underscored the criticality of preserving diversity and equilibrium within the gut microbiota for optimal human health. However, the precise mechanisms by which the metabolites and targets of the gut microbiota exert their effects remain largely unexplored. This study utilizes a network pharmacology methodology to elucidate the intricate interplay between the microbiota, metabolites, and targets in the context of DM, thereby facilitating a more comprehensive comprehension of this multifaceted disease. METHODS: In this study, we initially extracted metabolite information of gut microbiota metabolites from the gutMGene database. Subsequently, we employed the SEA and STP databases to discern targets that are intricately associated with these metabolites. Furthermore, we leveraged prominent databases such as Genecard, DisGeNET, and OMIM to identify targets related to diabetes. A protein-protein interaction (PPI) network was established to screen core targets. Additionally, we conducted comprehensive GO and KEGG enrichment analyses utilizing the DAVID database. Moreover, a network illustrating the relationship among microbiota-substrate-metabolite-target was established. RESULTS: We identified a total of 48 overlapping targets between gut microbiota metabolites and diabetes. Subsequently, we selected IL6, AKT1 and PPARG as core targets for the treatment of diabetes. Through the construction of the MSMT comprehensive network, we discovered that the three core targets exert therapeutic effects on diabetes through interactions with 8 metabolites, 3 substrates, and 5 gut microbiota. Additionally, GO analysis revealed that gut microbiota metabolites primarily regulate oxidative stress, inflammation and cell proliferation. KEGG analysis results indicated that IL-17, PI3K/AKT, HIF-1, and VEGF are the main signaling pathways involved in DM. CONCLUSION: Gut microbiota metabolites primarily exert their therapeutic effects on diabetes through the IL6, AKT1, and PPARG targets. The mechanisms of gut microbiota metabolites regulating DM might involve signaling pathways such as IL-17 pathways, HIF-1 pathways and VEGF pathways.