New Treatment Approach May Prevent Antibiotic-Induced Dysbiosis

An engineered live biotherapeutic product may help limit antibiotic resistance versus pathogens such as Clostridioides difficile.

Use of an engineered live biotherapeutic product (eLBP) may help limit antibiotic resistance versus pathogens such as Clostridioides difficile infection (CDI), according to a study published in Nature Biomedical Engineering.

The team of investigators found that the oral therapeutic reduced antibiotic-associated gut dysbiosis in a mouse model; however, it did not have an impact on the antibiotic’s concentration in the serum.

They noted that antibiotic use causes significant medical tension because they are an essential treatment for bacterial infections, but can cause gut dysbiosis after reaching the gut. This can bring an increased risk of secondary infections, including CDI, with the researchers noting that in most cases, 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.

Although probiotics are commonly used to offset the harmful impact that antibiotics have on the gut, the research team indicated insufficient data exist on how well this approach 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.

As a result, the investigators used food-associated bacteria to deliver biological effectors to the intestine. The eLBP was designed to be taken simultaneously with parenteral β-lactam antibiotics. β-lactamases are an enzyme produced by bacteria to inactivate β-lactam antibiotics.

Although β-lactamases can have a negative impact, the researchers believed it could also strategically 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.

After administering the eLBP in a mouse model of parenteral ampicillin treatment, the researchers found that the engineered β-lactamase-expression system did not confer β-lactam resistance to the producer cell, which they noted, “is encoded via a genetically unlinked two-gene biosynthesis strategy that is not susceptible to dissemination by horizontal gene transfer.”

The investigators found that the eLBP therapy successfully minimized gut dysbiosis, but did not impact levels of ampicillin in serum. Further, it stopped antimicrobial resistance in the gut microbiome, precluding the loss of resistance against CDI.

The researchers said the idea of using β-lactamases to fight gut dysbiosis was previously suggested, however, they said eLBP has 2 key advances. One of which is the product’s defined bacterial formulation makes it easier to manufacture at scale, and the other is that it would be more likely to be effective throughout the intestine because of 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.

Reference

Cubillos-Ruiz, A., Alcantar, M.A., Donghia, N.M. et al. An engineered live biotherapeutic for the prevention of antibiotic-induced dysbiosis. Nat. Biomed. Eng (2022). https://doi.org/10.1038/s41551-022-00871-9.