Chronic intestinal inflammation, potentially arising from a complex etiology of genetic factors, immune malfunction, and environmental triggers is the hallmark of IBD (inflammatory bowel disease), which includes Crohn’s disease and ulcerative colitis.

New research from scientists at Massachusetts General Hospital (MGH) shows that just as gut bacteria can be harmful or helpful, the intestinal viral community (virome) too can be either detrimental or beneficial for gut health.

Through in vitro studies and in vivo experiments on humanized mice, the team showed imbalances in the intestine’s virome or the inability to sense it due to mutations in cells lining the gut may promote IBD.

Kate Jeffrey, PhD, a scientist in the department of gastroenterology at MGH and an associate professor of medicine at Harvard Medical School, is senior author of the study.

Kate Jeffrey, PhD, a scientist in the department of gastroenterology at MGH and an associate professor of medicine at Harvard Medical School and who is senior author of the study said, “The fecal virome is altered in IBD, suggesting a role for viruses in the onset of these conditions. However, we were stalled at correlations.”

Jeffrey added, “Intestinal viruses are obtained at birth, shaped through life, and many are frequently found in asymptomatic individuals. Sequencing has shown clear perturbations in the virome in a range of diseases, including IBD. We wanted to move beyond correlations and test if the virome, akin to the microbiome, autonomously contributes to human health, and when perturbed if it triggers inflammation and provokes disease.”

The study was published in an article in the journal Science Immunology (“Human enteric viruses autonomously shape inflammatory bowel disease phenotype through divergent innate immunomodulation”).

Jeffrey said, “Our work provides a missing functional link that our collective virome is an important contributor to human health, but when perturbed does provoke inflammation in IBD and conceivably many other diseases.”

Jeffrey’s team isolated viruses from surgical tissue of the human colon and found that viruses from a normal intestine had anti-inflammatory effects and contributed to a healthy gut, whereas viruses isolated from inflamed intestines of patients with IBD triggered inflammation.

“Since viruses are obligate pathogens, meaning they need a host cell to replicate, we isolated viruses from patient colon tissue rather than from feces. This is where we found many viruses, including enteroviruses, previously missed in fecal analyses,” said Jeffrey.

Fatemeh Adiliaghdam, MD, is first author of the study.

The researchers exposed macrophages from human peripheral blood to viruses isolated from colon resections or ileostomy fluid from non-IBD control subjects, or from patients with ulcerative colitis or Crohn’s disease and measured inflammatory factors and cytokines in the macrophages. They found enteric viruses from non-IBD patients protect while IBD viromes promote inflammation.

The researchers also conducted experiments on mice whose normal intestinal viruses were replaced with viruses from healthy human colons or IBD patients. “We created ‘humanized’ normal virome or IBD virome mice which enabled the examination of cause and effect on the immune system and the intestine,” said Jeffrey.

Here too, the team found, whereas viruses from healthy human colons protected from inflammation, viruses from IBD patients exacerbated it. “Both scenarios were dependent on sensing by the host innate immune system demonstrating that these viruses are not ignored, rather there is a constant cross-talk between the virome and the host and indeed an altered virome can drive disease,” Jeffrey said.

The team also classified viruses unique to patients with IBD. Jeffrey said, “We categorized viruses present in human colon tissue and found an abundance of bacteriophages that infect the microbiome but strikingly also a significant elevation in enteroviruses in IBD patients. We also found copious ‘dark matter’ we cannot yet identify which is both humbling and motivating.”

Jeffrey added, “We worked with the best in the business─Scott Handley, PhD, at Washington University, St Louis─to identify these viruses using state-of-the-art computational methods.”

Earlier studies have shown that mutations in a gene that encodes an innate virus sensor (MDA5) are linked with IBD. The researchers in this study showed that colon tissue from IBD patients contain higher levels of enterovirus B which can be sensed by MDA5. In addition, they show human intestinal epithelial cells harboring mutations in MDA5 show impaired ability to maintain the integrity of the intestinal barrier upon exposure to enteric viruses from non-IBD colon tissue and greater damage when exposed to viromes from IBD patients.

“IBD remains incurable by surgical or therapeutic interventions,” said Jeffrey. Exploring strategies for IBD therapies by targeted elimination of harmful gut virus populations and replacing harmful viromes with those that promote gut health will be a priority for Jeffrey and her team in their future studies. In addition, Jeffrey believes stratifying patients with IBD and other diseases based on their unique virome would be key.

“The holy grail would be to identify individual culprit viruses that contribute to the predisposition of disease and/or inflammation flares and generate vaccines that protect. This would be a game-changer in the arena of complex immune and autoimmune diseases,” said Jeffrey.

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