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.

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SUMMARY Human immunodeficiency virus (HIV) infection is associated with increased intestinal translocation of microbial products and enteropathy as well as alterations in gut bacterial communities. However, whether the enteric virome contributes to this infection and resulting immunodeficiency remains unknown. We characterized the enteric virome and bacterial microbiome in a cohort of Ugandan patients, including HIV-uninfected or HIV-infected subjects and those either treated with anti-retroviral therapy (ART) or untreated. Low peripheral CD4 T cell counts were associated with an expansion of enteric adenovirus sequences and this increase was independent of ART treatment. Additionally, the enteric bacterial microbiome of patients with lower CD4 T counts exhibited reduced phylogenetic diversity and richness with specific bacteria showing differential abundance, including increases in Enterobacteriaceae, which have been associated with inflammation. Thus, immunodeficiency in progressive HIV infection is associated with alterations in the enteric virome and bacterial microbiome, which may contribute to AIDS-associated enteropathy and disease progression.

A coding polymorphism (Thr300Ala) in the essential autophagy gene, autophagy related 16-like 1 (ATG16L1), confers increased risk for the development of Crohn disease, although the mechanisms by which single disease-associated polymorphisms contribute to pathogenesis have been difficult to dissect given that environmental factors likely influence disease initiation in these patients. Here we introduce a knock-in mouse model expressing the Atg16L1 T300A variant. Consistent with the human polymorphism, T300A knock-in mice do not develop spontaneous intestinal inflammation, but exhibit morphological defects in Paneth and goblet cells. Selective autophagy is reduced in multiple cell types from T300A knock-in mice compared with WT mice. The T300A polymorphism significantly increases caspase 3-and caspase 7-mediated cleavage of Atg16L1, resulting in lower levels of full-length Atg16Ll T300A protein. Moreover, Atg16L1 T300A is associated with decreased antibacterial autophagy and increased IL-1β production in primary cells and in vivo. Quantitative proteomics for protein interactors of ATG16L1 identified previously unknown nonoverlapping sets of proteins involved in ATG16L1-dependent antibacterial autophagy or IL-1β production. These findings demonstrate how the T300A polymorphism leads to cell typeand pathway-specific disruptions of selective autophagy and suggest a mechanism by which this polymorphism contributes to disease. H uman genetic studies offer an unbiased approach to identify genes and DNA variants underlying susceptibility to complex diseases. Although this approach has been successful at identifying more than 160 loci associated with Crohn disease (CD), a chronic inflammatory condition affecting the gastrointestinal tract (1, 2), ascribing function to specific risk variants has been difficult. Individuals who harbor a common threonine to alanine coding variant at position 300 in autophagy related 16-like 1 (ATG16L1) (T300A) are at increased risk of developing CD compared with individuals who possess a threonine at this position (T300T) (3, 4). The T300A variant lies within a structurally unclassified region of ATG16L1, making it challenging to identify the effect of this polymorphism.ATG16L1 is a component of the core autophagy machinery that plays a critical role in immunity and inflammation. Initial studies investigating ATG16L1 used hypomorphic Atg16L1 mouse models, which show Paneth cell abnormalities relevant to CD such as abnormal mitochondria, irregular patterns of granule morphology and lysozyme distribution, and increased expression of genes implicated in inflammation (5, 6). Although these studies have been useful in highlighting the important role of autophagy proteins in intestinal cells such as Paneth cells and goblet cells, the precise mechanisms by which ATG16L1 T300A influences pathogenesis remain unclear (7)(8)(9)(10).Previous studies have demonstrated that Atg16L1-deficient macrophages produce elevated levels of active caspase 1 and secrete higher levels of the cytokines IL-1β and IL-18 u...

Norovirus gastroenteritis is a major public health burden worldwide. Although fecal shedding is important for transmission of enteric viruses, little is known about the immune factors that restrict persistent enteric infection. We report here that while the cytokines interferon-α (IFN-α) and IFN-β prevented the systemic spread of murine norovirus (MNoV), only IFN-λ controlled persistent enteric infection. Infection-dependent induction of IFN-λ was governed by the MNoV capsid protein and correlated with diminished enteric persistence. Treatment of established infection with IFN-λ cured mice in a manner requiring non-hematopoietic cell expression of the IFN-λ receptor, Ifnlr1, and independent of adaptive immunity. These results suggest the therapeutic potential of IFN-λ for curing virus infections in the gastrointestinal tract.