A living defender of microflora
Antibiotic therapy destroys not only pathogenic bacteria that cause infection, but also trillions of "good" bacteria that make up the microbiome, leading to dysbiosis – a change in the bacterial composition of the intestine. In 35% of patients, this is accompanied by diarrhea, and it may take months of supplementation and diet correction to eliminate it. In some patients, the microbiome does not recover, which threatens the development of a number of autoimmune, metabolic and neurological diseases.
This is due to the fact that a person and bacteria in his intestines have formed a symbiotic (mutually beneficial) relationship, actually turning into a "superorganism" in which a person as a host corrects the composition of the microbiome with the help of the intestinal environment, food and other habits. In turn, microorganisms produce a variety of compounds that affect the digestion of food, the use of energy and the functioning of the immune system. Despite the importance of the microbiome for human health, there is still no effective treatment for dysbiosis caused by taking antibiotics.
A research team from the Wyss Institute of Bioengineering at Harvard University and the Massachusetts Institute of Technology has designed a live biotherapeutic product (eLBP), which, when administered together with beta-lactam antibiotics (penicillin derivatives), protects the intestinal microbiome from antibiotics.
When developing the biopreparation, the researchers used Lactococcus lactis bacteria harmless to humans, which secrete the enzyme β-lactamase, which destroys β-lactams.
Typically, β-lactamase is encoded by a single gene, which can be transmitted between bacteria using horizontal gene transfer. The enzyme itself is located inside the bacterial cell wall. This not only protects the bacteria from certain antibiotics that attack the outer shells, but also allows their resistance to spread to other bacteria in the microbial population of the intestine. Researchers have developed regulation blocks in the β-lactamase expression system. In fact, they split a specific gene encoding β-lactamase into two genetically unrelated halves and placed them in different parts of bacterial DNA in such a way that the fragments were secreted from the producing cell and bound to each other with high affinity, forming a functional enzyme in the external environment.
Then the researchers showed the effectiveness of eLBP in mice treated with the antibiotic ampicillin orally: the biopreparation minimized changes in the microbiota in the intestines of each animal. Sequencing a part of the bacterial genome of 16S rDNA, which is a genetic barcode for identifying bacterial species and families, they found that eLBP significantly weakens the breakdown of microbial populations and allows them to fully restore their original diversity and composition three days after the end of antibiotic treatment. Mice from the control group who received only ampicillin showed a much greater loss of bacterial diversity, which was not restored throughout the experiment.
It is important to note that during its stay in the digestive tract, eLBP protected the microbiome without changing the concentration of ampicillin circulating in the blood, and also slowed down the spread of various antibiotic resistance genes in the microbial community, which usually occurs against the background of antibiotic therapy.
The main consequence of dysbiosis is the seizure of the liberated intestinal territory by "bad" bacteria, such as Clostridioides difficile. These are opportunistic bacteria that exist in small quantities in the intestines of many people and, when it becomes possible to divide uncontrollably, cause inflammation and diarrhea. The group simulated infection by infecting ampicillin-treated mice with C.difficile spores. eLBP successfully prevented colonization of the intestine by them.
Currently, the authors are developing an effective, short and inexpensive clinical trial. They also intend to investigate the use of eLBP as a therapy for diseases based on intestinal dysbiosis.
Article by A.Cubillos-Ruiz et al. An engineered live biotherapeutic for the prevention of antibiotic-induced dysbiosis is published in the journal Nature Biomedical Engineering.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Wyss Institute: Protecting the human intestinal microbiome with synthetic biology.