Abstract
Background: The interaction network between the human host proteins and the proteins of the gut bacteria is essential for the establishment of human health, and its dysregulation directly contributes to disease development. Despite its great importance, experimental data on protein-protein interactions (PPIs) between these species are sparse due to experimental limitations. Methods: This study presents a deep learning-based framework for predicting PPIs between human and gut bacterial proteins using structural data. The framework leverages graph-based protein representations and variational autoencoders (VAEs) to extract structural embeddings from protein graphs, which are then fused through a Bi-directional Cross-Attention module to predict interactions. The model addresses common challenges in PPI datasets, such as class imbalance, using focal loss to emphasize harder-to-classify samples. Results: The results demonstrated that this framework exhibits robust performance, with high precision and recall across validation and test datasets, underscoring its generalizability. By incorporating proteoforms in the analysis, the model accounts for the structural complexity within proteomes, making predictions biologically relevant. Conclusions: These findings offer a scalable tool for investigating the interactions between the host and the gut microbiota, potentially yielding new treatment targets and diagnostics for disorders linked to the microbiome.