SUMMARY Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease- and cohort-specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.

The intestinal microflora, typically equated with bacteria, influences diseases such as obesity and inflammatory bowel disease (IBD). Here we show that the mammalian gut contains a rich fungal community that interacts with the immune system through the innate immune receptor Dectin-1. Mice lacking Dectin-1 exhibited increased susceptibility t chemically-induced colitis, which was the result of altered responses to indigenous fungi. In humans we identified a polymorphism in the gene for Dectin-1 (CLEC7A) that is strongly linked to a severe form of ulcerative colitis. Together our findings reveal a novel eukaryotic fungal community in the gut (the “mycobiome”) that coexists with bacteria and substantially expands the repertoire of organisms interacting with the intestinal immune system to influence health and disease.

Ulcerative colitis (UC) is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. We performed two distinct UC genome-wide association (GWA) studies, and analyzed these jointly with a previously published scan1, comprising, in aggregate, 2,693 patients with UC and 6,791 controls. A total of 59 SNPs from 14 independent loci attained P < 10−5. Seven of these loci exceeded genome-wide significance (P < 5 × 10−8). After testing an independent cohort of 2009 patients with UC and 1580 controls, 14 loci were significantly associated, including novel UC associations with FCGR2A, 5p15, 2p16, CARD9 and ORMDL3. In our study we confirmed association with 14 previously identified UC susceptibility loci, while an analysis of acknowledged Crohn's disease (CD) loci showed that roughly half of known CD associations are shared with UC. These data implicate approximately 30 loci for UC, providing novel insights into disease pathogenesis.

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