Microbiome refactoring associated with the onset of both irritable bowel disease (IBD) and Crohn’s Disease (CD) generates a massive expansion of the virome: prophages are induced from bacterial genomes; lytic phages replicate, and eukaryotic virus shift profiles. We have developed new computational tools to identify prophages in bacterial genomes and mined all the complete genomes to identify over 3 million prophages. We designed novel computational approaches to identify viruses accurately and specifically from both RNA- and DNA-based metagenomes from patients with IBD, CD, or healthy household controls. We combined our unique bioinformatics approaches to direct culturing of phages and viruses from stool samples to identify those viruses that reshape the microbiome in response to intestinal changes associated with disease.