Human enteric viruses shape disease phenotype through divergent innate immunomodulation

Altered enteric microorganisms in the context of genetics shape inflammatory bowel disease (IBD)phenotypes,but insight is limited to bacteria and fungi. We found that healthy human intestine resident eukaryotic viruses and bacteriophages(collectively, the virome) directly immunomodulate by eliciting atypical anti-inflammatory innate immune programs. Conversely, IBD patient viromes provoked an inflammatory response, which could be dampened by healthy virome responses. The colon tissue virome was perturbed in IBD patients, including enriched Enterovirus B that helps explain detrimental consequences of MDA5loss-of-function in IBD. 10Mice with a “humanized” healthy virome had attenuated intestinal inflammation while those with an IBD-derived virome exhibited exacerbated inflammation. Our results demonstrate that enteric virome fluctuations do not just correlate with disease but active innate recognition of healthy or IBD human enteric viromes autonomously drives disease phenotypes. Harnessing the virome may be beneficial in IBD and other diseases.