Engineered Live Biotherapeutic Could Eliminate Gut Impacts of Antibiotics

An engineered live biotherapeutic may be able to offset the negative gut impacts of antibiotics and help limit resistance against pathogens like Clostridioides difficile, according to a new report.

The study, which was published in the journal Nature Biomedical Engineering, found that the oral therapeutic minimized antibiotic-associated gut dysbiosis in a mouse model, but did not affect the antibiotic’s concentration in the serum.

Corresponding author James J. Collins, PhD, of the Massachusetts Institute of Technology, and colleagues, noted that antibiotics come with a significant medical tension. On the one hand, they are an essential tool to treat bacterial infections; however, they can lead to gut dysbiosis when they eventually reach the gut. The result is an increased risk of secondary infections, including C difficile. Most of the time, the investigators said, antibiotics are an unnecessary intruder in the gut.

“Since antibiotic presence in the gut is only required when treating gastrointestinal infections, antibiotics should be excluded from the distal gut in all other usage indications to spare the native microbiota,” they wrote.

The question Collins and colleagues faced was how exactly to achieve that goal. The use of probiotics is a common strategy to offset the harmful gut effects of antibiotics, but the investigators said there is insufficient data regarding whether and how that strategy works.

“[T]here are no clearly described mechanisms by which standard probiotic formulations might prevent the loss of native species or replace the multifaceted functions of the endogenous microbiota,” they wrote.

Instead, the authors posited a different approach. They turned to food-associated bacteria to deliver biological effectors to the intestine. Their engineered live biotherapeutic product (eLBP) is designed to be taken at the same time as parenteral β-lactam antibiotics. It leverages β-lactamases, an enzyme produced by bacteria to inactivate β-lactam antibiotics. Whileβ-lactamases can be a negative force in the wrong contexts, Collins and colleagues figured they could also be used strategically to eliminate antibiotics from unwanted locations such as the gut.

“We hypothesized that transient gut occupancy by an eLBP population secreting a β-lactamase as a ‘public good’ could prevent the collapse of the gut microbial communities when challenged with a β-lactam antibiotic,” they wrote.

In the article, they explain what happened when they administered the eLBP in a mouse model of parenteral ampicillin treatment. “The engineered β-lactamase-expression system does not confer β-lactam resistance to the producer cell, and is encoded via a genetically unlinked two-gene biosynthesis strategy that is not susceptible to dissemination by horizontal gene transfer,” they explained.

The authors found that their therapy successfully minimized gut dysbiosis, but did not affect levels of ampicillin in serum. Furthermore, it prevented antimicrobial resistance in the gut microbiome, precluding the loss of resistance against C difficile.

Collins and colleagues said the idea of utilizing β-lactamases to fight gut dysbiosis has been proposed before. However, they said their product has two key advances. They said their product’s defined bacterial formulation would make it easier to manufacture at scale, and it also would be more likely to be efficacious throughout the intestine due to its continuous metabolic activity.

“We envision that simple oral administration of our eLBP before parenteral antibiotic administration may significantly reduce the morbidity and mortality associated with antibiotic-related complications of gut dysbiosis,” they concluded.