Microbiome-metabolite signaling networks in gastrointestinal disease: systems biology, network rewiring, and precision therapeutics.

The gastrointestinal tract operates as a highly integrated, multi-layer signaling ecosystem in which microbial communities, metabolite flux, epithelial receptors, immune circuits, and neuroendocrine pathways form a coordinated regulatory network rather than isolated biological compartments. The Microbiome-Metabolite Signaling Network (MMSN) framework conceptualizes gastrointestinal homeostasis and disease as emergent properties of dynamic cross-layer interactions. This review explores the framework principally on inflammatory bowel disease and irritable bowel syndrome as representative gastrointestinal disorders, drawing on other conditions only for illustrative contrast. Within this architecture, microbiota-derived metabolites including short-chain fatty acids, bile acid derivatives, and tryptophan catabolites serve as biochemical intermediaries that relay ecological signals to host receptor systems such as GPR41/43, FXR, TGR5, the aryl hydrocarbon receptor, and innate immune sensors. These receptor-mediated inputs converge on intracellular signaling hubs, including NF-κB, STAT3, inflammasomes, and neuroimmune mediators, which act as high-centrality nodes governing epithelial integrity, cytokine gradients, metabolic coordination, and visceral sensitivity. Signaling hubs are mechanistic convergence nodes that integrate diverse upstream perturbations into coordinated inflammatory or regulatory outputs. In contrast, network fragility denotes the loss of redundancy, modularity, and buffering capacity, predisposing the system to nonlinear amplification and pathological attractor states. Gastrointestinal disorders are therefore more accurately interpreted as manifestations of network rewiring characterized by hub centralization, metabolite imbalance, and strengthened inter-module coupling rather than simple microbial compositional shifts. This review explains the clinical heterogeneity, fluctuating disease trajectories, and variable therapeutic responsiveness. A network-based translational strategy emphasizes hub stabilization, metabolite recalibration, and restoration of distributed connectivity, shifting precision therapeutics toward topology-informed intervention. Integration of microbiology, immunology, neuroscience, systems biology, and computational medicine establishes a pathway toward predictive, mechanistically grounded gastrointestinal network care.