Microbe–Metabolite Differential Co-Occurrence Analysis Reveals Interaction-Based Microbial Signatures in Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by impaired innate immune responses and frequent gastrointestinal involvement, yet the reorganization of gut microbiome–metabolome interactions in CGD remains poorly understood. This study aimed to characterize disease-associated alterations in microbiome–metabolome interactions using a differential microbe–metabolite co-occurrence (DCO) framework. Paired microbiome and metabolome profiles from patients with CGD and healthy controls were used to construct group-specific co-occurrence networks and quantify differential interaction patterns between disease and health states. Microbial features prioritized by differential co-occurrence connectivity discriminated CGD from healthy controls in machine learning models and provided predictive information distinct with abundance-based markers. Functional inference suggested that disrupted interactions were involved in pathways related to regulation and metabolic adaptation. These findings demonstrate that CGD is associated with substantial rewiring of gut microbiome–metabolome interactions and support an interaction-focused, network-based multi-omics framework for characterizing disease-associated microbial alterations. The DCO framework may provide a transferable strategy for investigating microbiome-associated immune disorders and identifying interaction-level biomarkers in addition to conventional abundance-based analyses.