Bacterial Microbiome Move Over: the Gut Virome Makes Its Debut

Lara C. Pullen, PhD

November 19, 2014

A new study reveals that eukaryotic viruses are able to both shape mucosal immunity and support intestinal homeostasis in mice. Specifically, infection with murine norovirus (MNV) appears able to replace the beneficial function of bacterial colonization in the gut.

Scientists have long known that RNA viruses are commonly found in healthy infants and children, as well as in individuals recovering from acute gastroenteritis. Such viral infections have generally been assumed to be detrimental to the host. The new study turns that assumption on its head and hints that these viruses may play a role similar to that of the bacterial microbiome.

Elisabeth Kernbauer, PhD, from the New York University School of Medicine in New York City, and colleagues published the results of their murine study online November 19 in Nature. The investigators used germ-free mice that are microbiologically sterile, wild-type mice that had been treated with a cocktail of antibiotics, and mice whose gut tissue had been damaged by treatment with dextran sodium sulphate.

The new findings are the first strong evidence that viruses in the gastrointestinal tract can help maintain health and heal a damaged gut. Before this study, there had been very little investigation of the viruses that colonize the gut.

The team infected germ-free mice and antibiotic-treated mice with MNV and found that the infection triggered the repair of intestinal tissue damaged by inflammation, restored intestinal cell numbers, restored intestinal cell function, and normalized tissue architecture. The results were apparent after just 2 weeks of MNV infection.

Infection with MNV also helped restore the gut's immune system. The investigators do not yet know how the virus supports the immune system. They did find, however, increased signaling by antiviral type 1 interferon proteins, suggesting the virus was playing a key role in driving the immune response.

The investigators also documented a doubling of T-cell levels in the blood and detectable levels of antibodies in the gut and blood of antibiotic-treated mice after MNV infection. These measures were consistent with a normalization of the immune response. The authors conclude that viral infection of the gut may be helpful once antibiotic treatment has wiped out intestinal bacteria.

Treatment with MNV was also able to improve survival in antibiotic-treated mice receiving the damaging chemical dextran sodium sulphate.

"We have known for a long time that people get infected all the time with viruses and bacteria, and they don't get sick," senior investigator Ken Cadwell, PhD, also from New York University, noted in a university news release. "Now we have scientific evidence that not every viral infection is bad, but may actually be beneficial to health, just as we know that many bacterial infections are good for maintaining health."

He was referring to the growing appreciation of the gut microbiome in health and disease. Multiple microorganisms populate the gastrointestinal tract, including bacteria, archaea, fungi, and viruses. These microorganisms provide multiple health benefits, including regulation of the immune system and prevention of inflammation. Although the collection of microorganisms in the gastrointestinal tract is generally referred to as the gut microbiome, the collection of viruses that populate the gastrointestinal tract is more specifically known as the gut virome.

The new results suggest that the previously overlooked gut virome may be as important as the gut microbiome.

The investigators focused their efforts on MNV because they had previously shown that chronic MNV infection could protect mice that were susceptible to inflammatory bowel disease. The team will next turn their efforts to characterizing other gut viruses and their roles in the microbiome.

An accompanying editorial by Yao Wang and Julie K. Pfeiffer, PhD, from the University of Texas Southwestern Medical Center in Dallas, reinforces the investigators' conclusion that certain symbiotic viruses may be beneficial to the gut under certain circumstances.

"We suggest that the incredible advances in viral discovery pipelines should be leveraged to discover the commensal or mutualistic viruses that constitute the virome, in addition to traditional pathogens," conclude Dr Kernbauer and colleagues. Dr Wang and Dr Pfeiffer agree and speculate in their editorial that mammalian intestinal viruses may someday have a role in probiotics.

Dr Wang and Dr Pfeiffer also raise an additional, still unanswered, question: "[D]o mammalian intestinal viruses benefit the host in the context of the 'normal' microbiota?"

The authors and editorialists have disclosed no relevant financial relationships.

Nature. Published online November 19, 2014.

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