Network-Based Functional Fragility Reveals System-Level Reorganization Of The Gut Microbiome In Inflammatory Bowel Disease

The human gut microbiome plays a critical role in host health, yet its functional organization in disease remains poorly understood. Most studies focus on taxonomic composition or pathway abundance, which fail to capture higher-order interactions governing system-level behavior. Here, we investigated microbiome functional organization in inflammatory bowel disease (IBD), including Crohns disease (CD), ulcerative colitis (UC), and healthy controls (HC), using a network-based framework across 60 metagenomic samples. Functional pathway profiles were used to construct correlation-based interaction networks, followed by analysis of network topology, functional redundancy, keystone pathway architecture, and system robustness. Disease-associated networks (CD and UC) exhibited reduced global connectivity, increased modular fragmentation, and centralization of keystone pathways, indicating a shift from distributed organization to more fragmented and fragile network structures compared to healthy controls. Notably, machine learning models demonstrated that network-derived features achieved higher classification performance (accuracy up to 0.824) compared to redundancy-based measures. These findings reveal that microbiome dysfunction in IBD is driven by large-scale reorganization of functional interaction networks rather than loss of functional capacity. This study highlights the importance of network-level analysis in understanding microbiome-associated disease and provides a systems-level framework for future research.