Identification of diverse human-bacteriophage interactions in human health

The human gut microbiome is a diverse ecosystem that encompasses multiple kingdoms of life and plays a vital role in human health. Unfortunately, due to technical limitations, most studies have focused on gut prokaryotes, overlooking gut viruses. The most common method to profile viruses is to assemble shotgun metagenomic reads and identify viral genomes de novo. While valuable, this resource-intensive and reference-independent method has limited sensitivity. Leveraging recently published catalogs of gut viral genomes, we developed a workflow that profiles human gut metagenomes in a viral-aware manner, directly from short reads. Based on simulations, the workflow is fast and accurate with respect to both prokaryotes and viruses, minimizing false positive identifications using a genome coverage-based strategy. When applied to metagenomes from healthy adults, the workflow identified ~200 viral species per sample, ~5x more than the standard assembly-based methods. Notably, we observed a 2:1 ratio between gut viruses and bacteria, with higher inter-individual variability of the gut virome. Finally, we used our method to tandemly profile gut viruses and bacteria in hundreds of samples from humans with varied age, immune status, and immunotherapy responses to identify thousands of cross-domain interactions with likely relevance to human health.