Microbes mutated in space hint at biomedical benefits to humans on Earth

Researchers are interested in studying effects on the gut microbiome and antibiotic-resistant infections.

In September 2020, UW-Madison biochemists launched a small box containing viruses and bacteria into space to investigate the ways microbes such as those residing in our guts respond to space conditions. Now, the bacteria and phages (viruses that infect bacteria) have returned to Madison with hints about how space travel may impact the gut microbiome and clues about how to treat antibiotic-resistant bacterial infections on Earth.

"Our experiment was about more than learning what happens when bacteria and phages travel in outer space. We are asking questions about how mutations acquired in space might be relevant on Earth," says biochemistry professor Vatsan Raman, who led the project. The researchers' findings are reported in the journal PLOS Biology.

Bacteria-phage relationships are essential to maintaining a healthy balance in the human gut microbiome: Gut bacteria evolve to evade infection, and in response, phages mutate to find new ways to infect bacteria. Raman's lab is harnessing this relationship to design phages that can compete with and combat bacterial infections.

"Space is such a unique environment," says Philip Huss, a postdoctoral researcher in the Raman Lab and a lead author on paper. "It has the potential to reveal possibilities for how phages can evolve that are hidden on Earth."

With scientists and astronauts spending extended periods of time in space - and the onset of recreational space travel - it's become important to understand how environments with reduced gravity (microgravity) impact the evolutionary dance between bacteria and phages. Sustained microgravity is difficult to establish on Earth. But on the International Space Station, a space-based national laboratory, it's possible to do research in the near-weightless conditions that are ideal for the Raman Lab's study.

"On Earth, we know that phages move around their environment and find a bacterial host to infect. Then they enter and kill the bacteria," explains Raman. "But in outer space, do these rules of engagement still apply? If there is no gravity, then the way that phages move around their environment will just be different. The ways they attack bacteria will be different." The UW-Madison scientists engineered phages to exhibit thousands of different mutations and sent them to space. For 25 days, ISS scientists incubated different combinations of the phages and bacteria together and in isolation. Back in Madison, the same experiments were replicated under Earth's gravity.

Huss and Chutikarn Chitboonthavisuk (a former graduate student in the Raman Lab) found key differences when they compared the phages and bacteria grown in space with those grown on Earth. In space, the phages and bacteria acquired novel mutations: Proteins on the surfaces of bacteria changed and in turn, phages mutated to bind to these altered surfaces. As a result, the mutations that allowed phages to infect bacteria in space differed from those on Earth.

The Raman Lab then engineered phages with a variety of mutations that were successful in space to test their effectiveness against bacterial pathogens on Earth, putting the novel phages to work against bacteria responsible for urinary tract infections. Currently, more than 90% of the bacteria that cause UTIs are resistant to at least one antibiotic.

"We found that the novel combinations of phage mutations were really effective at killing UTI pathogens on Earth," says Raman. "And that's pretty surprising. Why would an experiment in space inform how to design phage therapies on Earth? We don't exactly know, but one of our hypotheses is that the environmental factors stressing UTI bacteria somehow mimic the stress bacteria experience in microgravity, making their surface proteins similar."

With the experience gained through their first experiment's voyage, the researchers are now working on answering bigger questions - with experiments that must still fit in the same, small box - for a future space launch.

"First, we asked basic microbiology questions, just in space," says Huss. "Now, we're ready to study systems of multiple phages and bacteria that more closely represent the complexity of the human microbiome. What novel interactions occur in space, and what can we learn from them here on Earth?"

This study was supported by funding from the Defense Threat Reduction Agency (Grant HDTRA1-16-1-0049.