Diversity and Ecology of Caudoviricetes Phages with Genome Terminal Repeats in Fecal Metagenomes from Four Dutch Cohorts

The human gut harbors numerous viruses infecting the human host, microbes, and other inhabitants of the gastrointestinal tract. Most of these viruses remain undiscovered, and their influence on human health is unknown. Here, we characterize viral genomes in gut metagenomic data from 1950 individuals from four population and patient cohorts. We focus on a subset of viruses that is highly abundant in the gut, remains largely uncharacterized, and allows confident complete genome identification—phages that belong to the class Caudoviricetes and possess genome terminal repeats. We detect 1899 species-level units belonging to this subset, 19% of which do not have complete representative genomes in major public gut virome databases. These units display diverse genomic features, are predicted to infect a wide range of microbial hosts, and on average account for <1% of metagenomic reads. Analysis of longitudinal data from 338 individuals shows that the composition of this fraction of the virome remained relatively stable over a period of 4 years. We also demonstrate that 54 species-level units are highly prevalent (detected in >5% of individuals in a cohort). Finally, we find 34 associations between highly prevalent phages and human phenotypes, 24 of which can be explained by the relative abundance of potential hosts.