Mapping of Phenotype Specific Host–Microbiome Protein–Protein Interaction Networks in Colorectal Cancer Using Deep Learning

Colorectal cancer (CRC) pathogenesis is driven by complex protein–protein interactions (PPIs) between the host and the gut microbiome, yet these molecular dialogs remain largely unmapped. This study utilizes a Deep Learning framework, enhanced by protein structure embeddings, to predict approximately 8.9 billion interspecies PPIs from clinical metagenomic data. The model achieved high accuracy with an AUROC of 0.9960, identifying a high-confidence interactome representing roughly 16% of evaluated protein pairs. Phenotype-specific analysis revealed that while microbial hubs shift—transitioning from metabolic enzymes in healthy states to transport and regulatory proteins in CRC—the primary human targets remain remarkably consistent across both cohorts. These core human interactors are predominantly metalloproteins and regulators of ubiquitination, apoptosis, and zinc transport, suggesting these pathways are primary focal points for microbial manipulation regardless of disease state. Furthermore, co-occurring bacterial genera exhibit over 99% overlap in host target profiles, indicating significant functional redundancy in microbial engagement with the host. These findings suggest that CRC probably arises from network-level perturbations of stable host signaling hubs, offering a blueprint for identifying novel therapeutic targets and biomarkers.