Deep Learning Transforms Phage-Host Interaction Discovery from Metagenomic Data

Microbial communities are essential for sustaining ecosystem functions in diverse environments, including the human gut. Phages interact dynamically with their prokaryotic hosts and play a crucial role in shaping the structure and function of microbial communities. Previous approaches for inferring phage-host interactions (PHIs) from metagenomic data are constrained by low sensitivity and the inability to accurately capture ecological relationships. To overcome these limitations, we developed PHILM ( P hage- H ost Interaction L earning from M etagenomic profiles), a deep learning framework that predicts PHIs directly from the taxonomic profiles of metagenomic data. We validated PHILM on both synthetic datasets generated by ecological models and real-world data, finding that it consistently outperformed the co-abundance-based approach for inferring PHIs. When applied to a large-scale metagenomic dataset comprising 7,016 stool samples from healthy individuals, PHILM identified 90% more genus-level PHIs than the traditional assembly-based approach. In a longitudinal dataset tracking PHI dynamics, PHILM’s latent representations recapitulated microbial succession patterns originally described using taxonomic abundances. Furthermore, we demonstrated that PHILM’s latent representations served as more discriminative features than taxonomic abundance-based features for disease classifications. In summary, PHILM represents a novel computational framework for predicting phage-host interactions from metagenomic data, offering valuable insights for both microbiome science and translational medicine.