In scientists’ quest to understand how gut microbes affect human health, bacteria take center stage. But bacteriophages, the viruses that attack the bacteria, are often overlooked, says microbiologist Luisa De Sordi of the Institut Pasteur in France. “We keep an equilibrium of bacteria in our gut. This equilibrium has to be controlled. There is still a lot to learn about the balance between bacteriophages and bacteria.”

Now, De Sordi and colleagues report that the diverse bacterial community of the mouse gut encourages a bacteriophage to adapt to new bacterial hosts, affecting both the phage’s genetic diversity and its infectivity. The findings, published in Cell Host & Microbe, offer insight into the evolutionary forces that maintain a healthy gut microbiome.

The scientists presented a bacteriophage known as P10 with one strain of E. coli that the researchers knew, based on an in vitro study, the phage could kill; they also presented P10 another strain that they knew the phage couldn’t recognize. Over the course of 24 days, the team regularly sampled the P10 phages to test their ability to attack the two strains of bacteria. But the researchers did so in three different environments: the test tube, the mouse gut containing only the two E. coli strains, and the mouse gut harboring its natural bacterial community.

By the end of the study, 20 percent of the mice with diverse gut bacteria contained phages that had evolved to attack the resistant E. coli strain, while also retaining the capacity to attack the original host strain. Genome sequencing of the viral population revealed that the same mutated gene was present in all phages that infected the resistant strain. The researchers then confirmed the gene’s role by inserting it into the original phage. Meanwhile, none of the P10 phages in the other two environments had evolved this new ability.

Why might a diverse community of bacteria encourage phage evolution? The researchers hypothesized that the phage may have first evolved to attack one or more other bacteria in the mouse’s microbiome, which brought about genomic changes in the phage that then better positioned it to evolve to attack the resistant E. coli strain. Looking to test their theory, they identified another strain of E. coli that was largely resistant to the original P10 phage but highly susceptible to the evolved phage. In a test tube, they found that the phage only adapted to infect the first resistant strain when this other E. coli strain was in the mix.

This strain served as a sort of stepping stone on the path to adapting to the original resistant strain, says microbiologist Graham Hatfull of the University of Pittsburgh, who was not involved in the study. “You might not be able to jump from one river bank to another, but with stepping stones, it becomes relatively easier.”

Previous studies have explored the interactions between bacteria and phages in test tubes or through computer models. “Switching host range or expanding host range—those things have been known to happen for some time,” says Hatfull. “But [this study has] gone beyond the test tube and shown what really happens in a natural environment.”

“What we show here is that not all of the dynamics can be predicted from in vitro studies,” says De Sordi. But, she adds that this research is a first step. “We would really like to go after the full complex of viruses in the gut.”

Microbial ecologist Corinne Maurice of McGill University, who was not connected to the study, called the work exciting, noting that gut bacteria’s prominent role in mammalian health suggests that “understanding how their main predators affect them is, therefore, important for our health.”