Bacteriophages: Uncharacterized and Dynamic Regulators of the Immune System

The human gut is an extremely active immunological site interfacing with the densest microbial community known to colonize the human body, the gut microbiota. Despite tremendous advances in our comprehension of how the gut microbiota is involved in human health and interacts with the mammalian immune system, most studies are incomplete as they typically do not consider bacteriophages. These bacterial viruses are estimated to be as numerous as their bacterial hosts, with tremendous and mostly uncharacterized genetic diversity. In addition, bacteriophages are not passive members of the gut microbiota, as highlighted by the recent evidence for their active involvement in human health. Yet, how bacteriophages interact with their bacterial hosts and the immune system in the human gut remains poorly described. Here, we aim to fill this gap by providing an overview of bacteriophage communities in the gut during human development, detailing recent findings for their bacterial-mediated effects on the immune response and summarizing the latest evidence for direct interactions between them and the immune system. The dramatic increase in antibiotic-resistant bacterial pathogens has spurred a renewed interest in using bacteriophages for therapy, despite the many unknowns about bacteriophages in the human body. Going forward, more studies encompassing the communities of bacteria, bacteriophages, and the immune system in diverse health and disease settings will provide invaluable insight into this dynamic trio essential for human health.