Mechanisms of gut microbiota metabolite-mediated gut-heart Axis in heart failure: An integrative study based on network pharmacology

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  Fig. 1. Identification of gut microbiota-derived metabolite-associated targets potentially linked to HF. A Venn diagram showing the overlap between predicted targets obtained from the STP and SEA databases. The overlapping 570 targets were retained as the main predicted metabolite-associated target set for subsequent analyses. B Venn diagram showing the overlap among heart failure-related disease genes retrieved from the CTD, GeneCards, and OMIM databases. The shared genes were considered high-confidence HF-related genes. C Three-way Venn diagram showing the intersection among the STP-SEA combined target set, gutMGene-associated genes, and HF-related genes. A total of 47 overlapping genes were identified as candidate core targets potentially linking gut microbiota-derived metabolites with HF-related molecular mechanisms. D Gut-Targets-HF association network based on the 47 candidate core targets. The upper node represents gut microbiota-related information, the lower node represents heart failure, and the intermediate nodes represent candidate target genes. Edges indicate database-derived associations between gut microbiota-related targets and HF-related targets. This network was…

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  Fig. 2. Functional enrichment analysis of candidate core targets potentially linking gut microbiota-derived metabolites with HF. A GO enrichment analysis of the 47 candidate core targets. The enriched GO terms are grouped into BP, CC, and MF. The x-axis represents the GeneRatio, defined as the ratio of enriched genes to the total number of input genes. The y-axis lists enriched GO terms. Bubble size represents the number of genes enriched in each GO term, and bubble color represents the adjusted P value. The adjusted P value was calculated using multiple-testing correction, and lower adjusted P values indicate greater enrichment significance. B KEGG pathway enrichment analysis of the 47 candidate core targets. The x-axis represents the GeneRatio, and the y-axis lists enriched KEGG pathways. Bubble size represents the number of genes enriched in each pathway, and bubble color represents the adjusted P value. Major enriched pathways included MAPK signaling, PI3K-Akt signaling, Toll-like receptor signaling, TNF signaling, IL-17 signaling, NF-κB signaling, and VEGF signaling pathways, suggesting that immune-inflammatory and signal transduction pathways may be involved in the predicted…

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  Fig. 3. PPI network and hub-gene screening of candidate core targets. A Degree centrality ranking of candidate core targets in the PPI network. The x-axis represents the number of adjacent nodes, and the y-axis lists candidate target genes. Longer bars indicate higher degree centrality and stronger network connectivity. Genes with higher degree values were considered more central within the PPI network. B PPI network of candidate core targets constructed using the STRING database. Nodes represent proteins encoded by candidate target genes, and edges represent predicted or known protein-protein interactions. The network was used to evaluate the interaction relationships among candidate targets potentially involved in HF-related molecular processes. C Cytoscape visualization of the PPI network based on degree centrality. Node size and color depth reflect the degree value of each node; larger and darker nodes indicate higher connectivity. AKT1, TNF, TP53, IL6, and PPARG showed high centrality and were identified as key hub genes in the predicted interaction network.

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  Fig. 4. Microbiota-substrate-metabolite-target network associated with HF. The M-S-M-T network illustrates the predicted relationships among gut microbial taxa, substrates, gut microbiota-derived metabolites, and core HF-related targets. Nodes represent microbial taxa, substrates, metabolites, or target genes, and edges represent database-derived associations among these components. Red circular nodes represent core HF-related hub targets, including AKT1, TNF, TP53, IL6, and PPARG. Other colored nodes represent gut microbial taxa, substrates, and metabolites included in the network. The network included 74 gut microbial taxa, 29 substrates, 49 metabolites, and five hub targets. Representative metabolites prioritized in this study included IPA, ILA, linoleic acid, luteolin, and tryptamine. These metabolite-target associations are predictive and require further experimental validation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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  Fig. S1. Supplementary visualization of GO and KEGG enrichment analyses. A Bar plot of GO enrichment results for candidate core targets. Enriched terms are grouped into BP, CC, and MF. The x-axis represents the number of enriched genes, and the y-axis lists enriched GO terms. Bar color represents the adjusted P value, with lower adjusted P values indicating greater enrichment significance. B Circular visualization of representative GO enrichment results. The plot displays enriched GO terms and the distribution of candidate genes across biological process, cellular component, and molecular function categories. The inner bars indicate the number of enriched genes, and the color scale represents enrichment significance.