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Human Intestinal Virome Can Provoke Inflammatory Bowel Disease or Protect Against It

Key findings

  • This study compared the function of the intestinal virome in patients with inflammatory bowel disease (IBD) and healthy controls
  • In human macrophages or intestinal epithelial cells, viruses from colon tissue or ileostomy fluid in healthy volunteers were beneficial, promoting anti-inflammatory reactions, while those from an IBD intestine robustly promoted inflammation
  • Viruses significantly elevated in IBD colon tissue included the Caudovirales order of bacteriophages and enterovirus B; the latter is newly identified here as a pathogenic factor in IBD
  • Transplantation of healthy human gut viromes protected against inflammation and damage in a mouse model of ulcerative colitis, whereas viromes from people with IBD worsened tissue damage
  • Targeted elimination of pathogenic viruses and transplantation of viromes isolated from healthy individuals are two potential strategies for suppressing inflammation in IBD and perhaps other diseases

Imbalance of the fecal virome (community of viruses) has been reported in patients with ulcerative colitis (UC), Crohn's disease (CD), and other types of inflammatory bowel disease (IBD). It's unclear, though, whether fluctuations in the virome have a mechanistic role in those conditions.

Kate L. Jeffrey, PhD, a scientist in the Center for the Study of Inflammatory Bowel Disease in the Division of Gastroenterology at Massachusetts General Hospital and associate professor of Medicine at Harvard Medical School, Fatemeh Adiliaghdam, MD, MPH, a postdoctoral research fellow and researcher in Dr. Jeffrey's lab, and colleagues have provided the first major evidence that a healthy intestinal virome can help build gut immunity in humans—a contrast to the misconception that all viruses are harmful.

Just as exciting, viromes from patients with IBD provoked inflammation in the laboratory and in mice. The research team's report in Science Immunology discusses the implications of these findings for virus-based IBD therapies.

Divergent Immunomodulation

Since viruses need a host cell to replicate, the researchers studied colon tissue rather than feces. They isolated viruses from resected tissue samples from healthy volunteers and patients with UC or CD and delivered them to human macrophages or intestinal epithelial cells.

In both types of experiments, viruses from a healthy intestine dampened the classical antiviral response and promoted anti-inflammatory reactions. Conversely, viruses from an inflamed UC or CD intestine robustly promoted a state of inflammation.

Similar results were observed when the researchers isolated viruses from ileostomy fluid of healthy volunteers and IBD patients.

Pathogenic Viruses

Viruses significantly elevated in IBD colon tissue included the Caudovirales order of bacteriophages and enterovirus B, particularly echovirus serotypes. Fecal virome analyses have missed eukaryotic enteroviruses as a potential pathogenic factor in IBD.

Animal Experiments

To confirm the in vitro findings, the researchers diminished the intestinal virome in mice and introduced either normal, UC-associated, or CD-associated human colon tissue viromes. Mice humanized with a normal virome were protected from intestinal inflammation, whereas the IBD viromes provoked inflammation and intestinal damage.

Similarly, in a mouse model of ulcerative colitis, transplantation of healthy human gut viromes protected against inflammation and damage, whereas those from people with IBD worsened tissue damage.

Recognition of a virome by the host immune system was an absolute requirement for it to produce immunity or contribute to disease. Thus, the intestinal virome has autonomous immunoregulatory potential, akin to the microbiome.

Future Directions

Harnessing the intestinal virome is a potential approach to suppressing inflammation in IBD. The Mass General team plans to explore two strategies: targeted elimination of pathogenic viruses (e.g., using vaccines or antiviral medications) and transplantation of viromes isolated from healthy individuals, particularly from colon tissue.

Viruses might already play a role in the success of fecal transplantation in treating infections such as Clostridium difficile, the authors speculate.

Fluctuations in the virome have also been reported in colorectal cancer, type 1 diabetes, nonalcoholic fatty liver disease, HIV infection, and other diseases, so therapeutic modulation of the virome might have broad implications.

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