ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Microorganisms in Vertebrate Digestive Systems
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1617496
Network Pharmacology-Based Insights into the Role of Gut Microbiota Metabolites in Insulin Resistance
Provisionally accepted
- Shandong University of Traditional Chinese Medicine, Jinan, China
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Background ： Extensive research has demonstrated that the gut microbiota plays a critical role in maintaining homeostasis and promoting overall human health. However, the pharmacological mechanisms and functional roles of gut microbiota metabolites remain insufficiently understood. This study employs a network pharmacology approach to elucidate the metabolic transformation processes of gut microbiota metabolites and their molecular mechanisms in the pathogenesis of insulin resistance (IR), aiming to uncover the complex interactions among gut microbiota, metabolites, and therapeutic targets.Methods ： Gut microbiota metabolites and their corresponding target genes were retrieved from the gutMGene database. Potential targets of the metabolites were predicted using the SEA and STP databases.Disease-related targets for insulin resistance were collected from the GeneCards, DisGeNET, and OMIM databases. Core targets were identified via a protein-protein interaction (PPI) network, followed by comprehensive GO and KEGG enrichment analyses. Finally, a network illustrating the relationship among microbiota-substrate-metabolite-target was established.Results ： Thirteen overlapping targets between the gut microbiota and insulin resistance were identified, among which IL6, JUN, and PPARG were recognized as hub genes.The MSMT (microbiota-substrate-metabolite-target) network revealed that these three hub genes exert therapeutic effects through 10 gut microbiota metabolites, 10 substrates, and 21 microbial species. KEGG pathway analysis indicated that the IL-17, Toll-like receptor, HIF-1, NOD-like receptor, TNF, and VEGF signaling pathways are the primary pathways involved in the pathogenesis of IR.Conclusion：Gut microbiota metabolites may exert therapeutic effects on insulin resistance primarily through the targets IL6, JUN, and PPARG.The regulatory mechanisms are likely associated with several key signaling pathways, including the IL-17, Toll-like receptor and HIF-1, pathways. These three pathways collectively form an interconnected inflammationmetabolismhypoxia network. Targeting key nodes within this networksuch as the IL-17 receptor, TLR4, or HIF-1 αmay offer a multidimensional therapeutic strategy for insulin resistance (IR) and its associated complications.
Keywords: Network Pharmacology, Gut Microbiota, gut microbiota metabolites, Insulin Resistance, molecular mechanism
Received: 24 Apr 2025; Accepted: 04 Jun 2025.
Copyright: © 2025 Xiao, Chen, Zong, Guan, Zhu and Bi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Siling Bi, Shandong University of Traditional Chinese Medicine, Jinan, China
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