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

43 overlapping targets were identified between gut microbial metabolites and BPH.

• Gut microbial metabolite information was retrieved from the gutMGene database.
• Overlapping targets were identified using the SEA and STP databases.
• BPH-related targets were further filtered by integrating data from GeneCard and OMIM databases.
• A protein-protein interaction (PPI) network was constructed to screen for core targets from these 43 overlapping targets.

AKT1, IL-6, and IL-1B were identified as the core therapeutic targets for BPH.

• Core targets were selected based on PPI network analysis of the 43 overlapping targets.
• These three core targets exert therapeutic effects on BPH through interactions with 11 metabolites, 2 substrates, and 4 gut microbial species.
• The interactions were visualized through a constructed MSMT (Microbiota-Substrate-Metabolite-Target) comprehensive network.

GO analysis revealed that gut microbial metabolites influence prostatic hyperplasia by regulating inflammation, immune responses, and the activation of oxidoreductase activity.

• GO and KEGG functional enrichment analyses were performed using the DAVID database.
• Biological processes identified included regulation of inflammation and immune responses.
• Molecular function analysis highlighted activation of oxidoreductase activity as a relevant mechanism.

KEGG analysis identified five major signaling pathways involved in BPH pathogenesis related to gut microbial metabolites.

• The five pathways identified were: AGE-RAGE signaling pathway, Toll-like receptor signaling pathway, HIF-1 signaling pathway, C-type lectin receptor signaling pathway, and PI3K/Akt signaling pathway.
• These pathways were identified through systematic KEGG enrichment analysis performed via the DAVID database.
• The PI3K/Akt pathway was noted as a central regulator alongside the AGE-RAGE and HIF-1 pathways.

Molecular docking results demonstrated that butyrate may influence prostatic hyperplasia by modulating the AKT1 gene.

• Molecular docking validation was performed between the core targets and gut microbiota metabolites.
• Butyrate was identified as a key gut microbiota-derived metabolite interacting with AKT1.
• Propionate and TMAO were also identified as central regulator metabolites in the M-S-M-T network.
• Molecular docking served as validation for the network pharmacology-derived interactions.

The Bifidobacterium-tryptophan and Clostridium sporogenes-tyrosine axes were characterized as functionally significant with probiotic potential for microbiota-targeted BPH therapy.

• Four gut microbial species were found to interact with the three core targets through the MSMT network.
• Bifidobacterium and Clostridium sporogenes were among the four identified gut microbial species.
• The substrates tryptophan and tyrosine were among the 2 substrates identified in the MSMT network.
• These axes were highlighted for their probiotic potential in microbiota-targeted BPH therapy.

Modulating gut microbiota composition and function may influence the gut-prostate axis, thereby affecting the development and progression of prostatic hyperplasia.

• Growing evidence suggests the gut-prostate axis as a mechanistic link between gut microbiota and BPH.
• BPH was characterized as a chronic metabolic disorder with unclear associations to gut microbiota prior to this study.
• The gut microecosystem was described as the most abundant and complex microbial ecosystem in the human body.
• The study underscored the need for future experimental validation to decipher precise mechanistic links within the M-S-M-T network.