How Engineered Bacteria Can Protect Your Gut From Antibiotics
Written by Jonas Lehar, Illustrations by Kaya Risch
In the 1900s, over 30% of all deaths in the U.S. were due to bacterial infections.
Thanks to the discovery and proliferation of antibiotic treatments, most bacterial infections today are entirely curable. However, not all bacteria are harmful, some even crucial to survival. The natural microbiota in the gut, for example, is responsible for the proper function of our metabolism, immune system, and nervous system.
Large doses of antibiotics meant for curing bacterial infections can have the unintended consequence of killing vast swathes of our natural microbiome. As said by Andrés Cubillos-Ruiz, Ph.D., a research scientist at IMES and the Wyss Institute for Biologically Inspired Engineering at Harvard University: “Some microbial groups disappear, and the metabolic activity of others increases. This imbalance can lead to various health issues.”
“Some microbial groups disappear, and the metabolic activity of others increases. This imbalance can lead to various health issues.” - Andrés Cubillos-Ruiz, Ph.D.
After one of these large bacterial wipe-outs, bacteria that might already possess a slight, innate antibiotic resistance can take over the newly freed-up space, resulting in yet another bacterial infection. One of these opportunistic pathogens is Clostridium difficile, which often shows up in hospitals after patients have been prescribed antibiotics. C. difficile is a natural constituent of the human microbiota, and its population is kept in check by the millions of other species in the gut or colon. However, it can easily take over as a persistent infection if given the opportunity. In the U.S., C. difficile is responsible for 500 000 infections and 15 000 deaths every year.
In order to protect the natural diversity of the microbiota in the gut, Cubillos-Ruiz and his team engineered Lactococcus lacti to contain an enzyme that would target beta-lactams—a class of commonly used antibiotics—and shared their findings in a new paper titled “An engineered live biotherapeutic for the prevention of antibiotic-induced dysbiosis”, published in Nature Biomedical Engineering. The enzyme would decrease antibiotic levels in the gut, preventing the aforementioned hostile takeovers of opportunistic pathogens, while maintaining a high level of antibiotics circulating in the blood.
Purposefully engineering antibiotic resistance into bacteria naturally raises the question of whether or not this is a responsible decision. beta-lactams constitute 65% of all antibiotics used worldwide, and accelerating the development of antibiotic resistance would be detrimental to global healthcare. But the researchers also found a clever solution to this problem: by breaking the enzyme into two separate fragments and encoding them in opposite ends of the genome, bacteria would be highly unlikely to pass the trait to other species through horizontal gene transfer.
Once synthesized, the two enzyme fragments can only come together and form the completed beta-lactamase outside of the cell, allowing it to be absorbed equally by all bacterial species in the gut. Furthermore, decreasing the microbiota’s overall exposure to antibiotics actually lowers the risk of any other species from naturally developing an immunity themselves. Although these experiments were done in mouse models colonized with a sample of the human microbiota, the researchers plan to develop a therapeutic that can be used in humans.
It’s great that we have antibiotics to kill some bacteria and treat infections, but we can’t forget that we also need to protect others.
Sources
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 6, 910–921 (2022). https://doi.org/10.1038/s41551-022-00871-9
Thakuria B, Lahon K. The Beta-Lactam Antibiotics as an Empirical Therapy in a Developing Country: An Update on Their Current Status and Recommendations to Counter the Resistance against Them. J Clin Diagn Res. 2013 June; 7 (6):1207-14.