Engineered Bacteria Could Help Prevent Antibiotic-Driven Damage to Gut Microbiome

Illustration of an antibiotic-resistant bacteria (white) on the colon epithelium. The antibiotic-resistant bacteria will go on to transfer its antibiotic resistance genes horizontally to the bacteria surrounding it. Microbiome illustration.
Source: NANOCLUSTERING/SCIENCE PHOTO LIBRARY/Getty Images

Scientists at MIT have created a genetically engineered strain of Lactococcus lactis bacteria that can break down beta-lactam antibiotics, such as ampicillin and amoxicillin, in the gut that can harm beneficial bacteria in the gut microbiome.

As observed in a mouse model, the advantage of this strategy is that levels of the antibiotic remain high in the blood so they can treat the infection they are needed for, but the non-pathogenic gut bacteria can be protected.

Antibiotics are life-saving drugs, but their overuse in recent years has caused a range of problems. Excessive antibiotic use is now discouraged because of rising problems with antimicrobial resistance in bacterial strains, which have resulted in multi-drug resistant infections in some cases.

These drugs can also have a negative effect on the gut microbiome. “Disruption of the ecological balance in gut microbial communities, termed dysbiosis, has been associated with a wide range of immunological and metabolic disorders such as allergies, autoimmunity and obesity,” write James Collins, a professor in MIT’s Institute for Medical Engineering and Science, and colleagues in the article describing the research published in Nature Biomedical Engineering.

Collins and team have discovered a way to allow treatment with antibiotics, which is still required for many infections, but also to protect the gut microbiome.

They used synthetic biology techniques to re-engineer a safe bacterium, Lactococcus lactis, to allow it to degrade beta lactam antibiotics, which can otherwise cause a lot of harm to so-called ‘friendly’ gut bacteria. The engineered bacteria produce a heterodimeric β-lactamase enzyme allowing antibiotic breakdown, but do not encourage antibiotic resistance to develop.

When tested in a mouse model, the biotherapeutic bacteria reduced damage to the gut microbiome and did not impact the concentration of ampicillin in serum. No evidence of antibiotic resistance genes in the gut microbiome was observed following treatment and colonization resistance against Clostridioides difficile was maintained.

“This work shows that synthetic biology can be harnessed to create a new class of engineered therapeutics for reducing the adverse effects of antibiotics,” said Collins in a press statement.

Probiotic treatments of one form or another have been around for some time, but their lack of specificity can mean they lack effectiveness and can cause problems such as the spread of resistance genes.

“Our biocontainment strategy enables the delivery of antibiotic-degrading enzymes to the gut without the risk of horizontal gene transfer to other bacteria or the acquisition of an added competitive advantage by the live biotherapeutic,” said Andres Cubillos-Ruiz, a research scientist at MIT and the Wyss Institute for Biologically Inspired Engineering at Harvard University who is also the first author of the paper.

The research team now plan to develop their work further and move towards testing the bacterial therapy in humans at risk of gut dysbiosis from antibiotic use.

“If the antibiotic action is not needed in the gut, then you need to protect the microbiota. This is similar to when you get an X-ray, you wear a lead apron to protect the rest of your body from the ionizing radiation,” Cubillos-Ruiz says. “No previous intervention could offer this level of protection. 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.”

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