Investigating the impact of gut microbiota-derived metabolites on benign prostatic hyperplasia using network pharmacology approaches.

backgroundThe gut microecosystem represents the most abundant and complex microbial ecosystem in the human body. Maintaining homeostasis of gut microbiota and their metabolites is essential for human health. As a chronic metabolic disorder, the association between benign prostatic hyperplasia (BPH) and gut microbiota remains unclear. Growing evidence suggests that modulating the composition and function of gut microbiota may influence the gut-prostate axis, thereby affecting the development and progression of prostatic hyperplasia. In this study, we employed network pharmacology to systematically elucidate the complex interactions among gut microbiota, microbial metabolites, and BPH-related therapeutic targets.

methodsIn this study, we first retrieved information on gut microbial metabolites from the gutMGene database. Subsequently, we identified overlapping targets of these metabolites using the SEA and STP databases. To further clarify targets related to BPH, we integrated data from authoritative databases such as Genecard and OMIM. Based on this information, we constructed a protein-protein interaction (PPI) network to screen for core targets. In addition, we performed systematic GO and KEGG functional enrichment analyses of these targets using the DAVID database. we constructed a network model to illustrate the interactions among microbiota, substrates, metabolites, and targets.Finally, molecular docking validation was performed between the core targets and gut microbiota metabolites.

resultsWe identified 43 overlapping targets between gut microbial metabolites and BPH. Subsequently, we selected AKT1, IL-6, and IL-1B as core therapeutic targets for BPH. By constructing an MSMT comprehensive network, we found that these three core targets exert therapeutic effects on BPH through interactions with 11 metabolites, 2 substrates, and 4 gut microbial species. Furthermore, GO analysis revealed that gut microbial metabolites influence prostatic hyperplasia by regulating inflammation, immune responses, and the activation of oxidoreductase activity. KEGG analysis indicated that the AGE-RAGE signaling pathway, Toll-like receptor signaling pathway, HIF-1 signaling pathway, C-type lectin receptor signaling pathway, and PI3K/Akt signaling pathway are the major pathways involved in BPH.The molecular docking results demonstrated that butyrate may influence prostatic hyperplasia by modulating the AKT1 gene. DISCUSSION: This study employs a network pharmacology approach to elucidate the intricate "Microbiota-Substrate-Metabolite-Target" (M-S-M-T) network in Benign Prostatic Hyperplasia (BPH), identifying key hub genes (AKT1, IL-6, IL-1B), signaling pathways (PI3K/Akt, AGE-RAGE, HIF-1), and gut microbiota-derived metabolites (butyrate, propionate, TMAO) as central regulators. It further characterizes the functional significance of the Bifidobacterium-tryptophan and Clostridium sporogenes-tyrosine axes, highlighting their probiotic potential for microbiota-targeted BPH therapy. While demonstrating the therapeutic promise of modulating the gut microbiome, the study underscores the need for future experimental validation to decipher the precise mechanistic links within the M-S-M-T network and its role in BPH pathogenesis

conclusionIL-6, AKT1, and IL-1B serve as the primary targets through which gut microbiota metabolites exert their therapeutic effects on benign prostatic hyperplasia.