Highlights d The human gut virome is highly individual and stable for up to 1 year d A stable and predominant fraction of viruses constitutes a persistent personal virome d Persistent bacteriophages can be linked to highly predominant gut bacterial taxa d Virulent crAss-like and Microviridae bacteriophages predominate and persist in the gut

The human gut virome is thought to significantly impact the microbiome and human health. However, most virome analyses have been performed on a limited fraction of known viruses. Using whole-virome analysis on a published keystone inflammatory bowel disease (IBD) cohort and an in-house ulcerative colitis dataset, we shed light on the composition of the human gut virome in IBD beyond this identifiable minority. We observe IBD-specific changes to the virome and increased numbers of temperate phage sequences in individuals with Crohn's disease. Unlike prior database-dependent methods, no changes in viral richness were observed. Among IBD subjects, the changes in virome composition reflected alterations in bacterial composition. Furthermore, incorporating both bacteriome and virome composition offered greater classification power between health and disease. This approach to analyzing whole virome across cohorts highlights significant IBD signals, which may be crucial for developing future biomarkers and therapeutics.

Highlights d Screening of human fecal metagenomic samples reveals 249 crAss-like phage genomes d The crAss-like phages were classified into 4 subfamilies composed of 10 candidate genera d A crAss-like phage was propagated in ex vivo human fecal fermentations d Short-tailed phage virions could be visualized by electron microscopy