Phages in the Gut can Exacerbate Collateral Damage from Antibiotics

Your gut microbiome teems with bacteria-eating viruses that have longed baffled scientists. Using a new mouse model that can eliminate and revive these virus communities, Virginia Tech biologists discovered that the viruses can exacerbate collateral damage from antibiotics.

Some things just go together in your belly: peanut butter and jelly, salt and pepper, bacteria and bacteria-eating viruses.

For the bacterial species that inhabit your gut, there's a frenzy of viruses called bacteriophages that naturally infect them. Although they co-evolved with bacteria, phages get far less glory. They're harder to classify and so deeply entangled with the bacteria they target that scientists struggle to understand what functions they serve.

But what if there was a way to compare the exact same gut microbiome conditions with and without phages?

Virgina Tech biologist Bryan Hsu's team found a way to do just that.

Hsu and graduate student Hollyn Franklin built a model that allows them to diminish phage communities from a mouse gut microbiome - and then bring them back - without affecting the bacteria. On a test run of their model, researchers found evidence that phages may increase gut bacteria's sensitivity to antibiotics. Their results were published April 28 in the journal Cell Host and Microbe.

It's for Research, Mom

What could inhibit a bacteria's viruses but not the bacteria itself? In her early search through the literature, Franklin found a chemical compound called acriflavine that fit the bill. It's a component of a widely available medication used in Brazil to treat urinary tract infections (UTI).

Fortuitously, a member of Hsu's lab and paper co-author, Rogerio Bataglioli, is a native Brazilian. He shipped a massive order of acriflavine to his parent's house. But he forgot to tell his parents it was coming, Hsu said.

"His mom called, and asked, 'Is everything OK? Because 20 boxes of UTI treatment just arrived under your name.'"

After that got sorted, Franklin began administering acriflavine to lab mice. Over a period of 12 days, there was a dramatic reduction in the concentration of viral particles. And they didn't bounce back when she stopped administering the drug.

But when Franklin reintroduced a tiny sample of the mouse's own gut microbiome, extracted before treatment, the natural phage populations sprang back to life.

"It goes away when we wanted it to, and came back when we wanted it to," said Hsu. "Which means we have a bacteriophage conditional mouse model."

Or, more fun: BaCon mouse model.

Exacerbating Antibiotic Damage

To see if the mouse model had some significance for health, Hsu's research team went straight to one of the hottest topics in the field: the collateral damage that antibiotics have on a patient's resident microbial population.

Antibiotics save millions of lives every year, but the drug rages indiscriminately through bad, benign, and beneficial bacteria alike, disrupting our gut microbiome and leaving us vulnerable to new pathogens.

Could phages be playing a role in the destructive wake of an antibiotic treatment? Hsu and Franklin used their BaCon mouse model to ask this question and administered antibiotics to mice with and without phage populations.

Their results suggest that phages increase the sensitivity of bacteria to antibiotics.

"It's hard to make definitive conclusions, but these results are telling us that phages have some significance for how we respond to antibiotics," Hsu said.

The next questions, according to Franklin, will explore if phages caused these effects or are simply correlated with them, and what role phages play in diseases - which would open new doors in microbiome studies.

Answers may be served with a side of BaCon mouse.

Funding for this work was provided by the Virginia Tech Institute for Critical Technology and Applied Science, the National Institute of General Medical Sciences of the National Institutes of Health.

Research collaborators include:

• Frank Aylward, associate professor of biological sciences
• Anh Ha, postdoctoral research associate
• Rita Makhlouf, graduate student, biological sciences
• Zachary Baker, graduate student, biological sciences
• Sydney Murphy ´24, former undergraduate researcher in the Hsu Lab
• Hannah Jirsa ´23, former undergraduate researcher in the Hsu Lab
• Joshua Heuler, graduate student, biological sciences
• Teresa Southard, associate professor of anatomic pathology