Human enteric viruses autonomously shape inflammatory bowel disease phenotype through divergent innate immunomodulation

Author:

Adiliaghdam Fatemeh1ORCID,Amatullah Hajera1,Digumarthi Sreehaas1,Saunders Tahnee L.1ORCID,Rahman Raza-Ur1ORCID,Wong Lai Ping23,Sadreyev Ruslan24,Droit Lindsay5,Paquette Jean6ORCID,Goyette Philippe6,Rioux John D.67ORCID,Hodin Richard8,Mihindukulasuriya Kathie A.5ORCID,Handley Scott A.5ORCID,Jeffrey Kate L.19ORCID

Affiliation:

1. Department of Medicine, Division of Gastroenterology and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

2. Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

3. Department of Genetics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

4. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

6. Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.

7. Université de Montréal, Montreal, Quebec H3C 3J7, Canada.

8. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

9. Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn’s disease colon resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing–dependent fashion. Furthermore, there were detrimental consequences for IBD patient–derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine,Immunology

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