A signature-protein-based approach for accurate and efficient profiling of the human gut virome.

The human gut virome represents a critical yet underexplored component that regulates bacterial communities and maintains gut health. However, virome analysis remains challenging due to the vast diversity and genomic variability. Existing profiling methods often struggle with accuracy and efficiency, hindering novel viral species detection and large-scale analyses. Here, we present signature-protein-based virome profiling (SinProVirP), a signature-protein-based genus-level virome profiling tool. By analyzing 275,202 phage genomes to establish a database of 109,221 signature proteins across 6,780 viral clusters (VCs), SinProVirP achieves genus-level phage quantification with accuracy comparable to the benchmark method while reducing computational demands by over 80%. Crucially, SinProVirP outperforms existing tools in detecting novel viruses, achieving over 80% recall. Applied to inflammatory bowel disease (IBD) cohorts, SinProVirP revealed disease-specific virome dysbiosis, identified high-confidence phage-host interactions, and improved the performance of bacteria-only disease classification models. SinProVirP enables robust cross-cohort virome analysis and improves our understanding of the virome's role in health.