MIT researchers engineered a strain of bacteria, noted as L. lactis spTEM1 in the image, that can help protect the natural flora of the human digestive tract from antibiotics and prevent opportunistic infections, such as C. difficile, from developing. Credit: Courtesy of the researchers, edited by MIT News
MIT researchers have modified a strain of bacteria normally used in cheese production to protect beneficial gut microbes from antibiotics, while still allowing a high level to circulate in the bloodstream for their intended purpose. The new approach works on about 60 percent of the antibiotics commonly prescribed in the United States.
Over the past two decades, increased research into gut microbes has revealed the important roles they play in the nervous system, metabolism and immune function. But, gut microbes are sensitive so medications, and even specific diets, can negatively affect the composition of the microbiota—creating an altered state called dysbiosis.
“Some microbial groups disappear, and the metabolic activity of others increases. This unbalance can lead to various health issues,” said Andres Cubillos-Ruiz, a research scientist at MIT’s Institute for Medical Engineering and Science (IMES) and the lead author of a new paper on the subject.
One major complication that can occur is infection of Clostridioides difficile, a bacterium that commonly lives in the gut but doesn’t usually cause harm. When antibiotics kill off the strains that compete with C. difficile, however, these bacteria can take over and cause diarrhea and colitis. C. difficile infects about 500,000 people every year in the United States, and causes around 15,000 deaths.
To protect microbiota from antibiotics and the body from C. difficile, Cubillos-Ruiz and his team engineered a strain of Lactococcus lactis bacteria, which is normally used in cheese production, to deliver an enzyme that breaks down beta-lactam antibiotics, including the commonly prescribed ampicillin and amoxicillin. When these bacteria are delivered orally, they populate the intestines, where they secrete the enzyme, which is called beta-lactamase. This enzyme then breaks down antibiotics that reach the intestinal tract.
For their study, published in Nature Biomedical Engineering, the research team gave mice two oral doses of Lactococcus lactis for every injection of ampicillin. Compared with mice that received only antibiotics, the mice that received the engineered bacteria maintained a much higher level of gut microbial diversity. In the antibiotics-only mice, the researchers noted a drastic drop in diversity after ampicillin injection.
Additionally, none of the mice that received the engineered bacteria developed C. difficile infections, while all of the mice who received only antibiotics showed high levels of the dangerous bacteria in the gut.
“This work shows that synthetic biology can be harnessed to create a new class of engineered therapeutics for reducing the adverse effects of antibiotics,” says James Collins, professor at IMES and senior author of the study.
Importantly, the researchers found that the amount of ampicillin circulating the bloodstream was the same for both sets of mice. This means that while Lactococcus lactis did prevent the antibiotic from causing harm to gut microbes, the engineered bacteria did not prevent the antibiotic from accomplishing what it was meant to—successfully fight the infection.
The researchers also found that eliminating the evolutionary pressure of antibiotic treatment made it much less likely for the gut microbes to develop antibiotic resistance after treatment. In contrast, they did find many genes for antibiotic resistance in the microbes that survived in mice who did not receive the engineered bacteria.
“No previous intervention could offer this level of protection,” said Cubillos-Ruiz. “With our new technology we can make antibiotics safer by preserving beneficial gut microbes and by reducing the chances of emergence of new antibiotic-resistant variants.”
The team is now working on a version of the treatment that could be tested in people at high risk of developing acute diseases that stem from antibiotic-induced gut dysbiosis, and they hope that eventually, it could be used to protect anyone who needs to take antibiotics for infections outside the gut.