[Nature sub-journal] "Engineering bacteria" to protect the natural microbiota in the gut - controlling resistance, but still maintaining antibiotic efficacy!

This article was originally written by Translational Medicine.
Please indicate the source Author: Ashley Introduction: Antibiotics are life-saving drugs, but they can also harm the beneficial microorganisms living in the human gut
.

Following antibiotic treatment, some patients are at risk of developing inflammation or opportunistic infections such as Clostridium difficile
.

The misuse of antibiotics against gut microbes can also lead to the spread of resistance
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Recent research has engineered a bacterial strain that is safe for human consumption.
When the 'live biotherapeutics' is administered with antibiotics, it protects the microbiota in the gut but leaves the antibiotics circulating in the bloodstream.
level remains high
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To reduce the risk of antibiotic resistance in gut microbes from misuse of antibiotics, MIT engineers have developed a new method to help preserve the natural flora of the human digestive tract
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They took a bacterial strain that was safe for human consumption and engineered it to safely produce an enzyme that breaks down a class of antibiotics known as beta-lactams
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In a mouse study, researchers found that when the "live biotherapeutic" was administered with antibiotics, it protected the microbiota in the gut, but kept the levels of antibiotics circulating in the bloodstream at low levels.
higher level
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"This work shows that synthetic biology can be used to create a new class of engineered therapeutic drugs for reducing the adverse effects of antibiotics, "
said James Collins of MIT's Institute of Medical Engineering and Science (IMES)
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"An engineered live biotherapeutic for the prevention of antibiotic-induced dysbiosis" was published in Nature Biomedical Engineering
.

https:// Protecting the gut Over the past two decades, research has revealed that microbes in the human gut play important roles not only in metabolism, but also in immune function and nervous system function
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"Throughout your lifetime, these gut microbes assemble into a highly diverse community that performs important functions in your body," Cubillos-Ruiz said.
"
When
interventions such as drugs or special kinds of diets affect the composition of the microbiome, resulting in The problem arises when there is an altered state, called dysbiosis
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Some microbiota disappear, others have increased metabolic activity
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This imbalance can lead to a variety of health problems
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” A major complication that can occur is Difficile Bacterial infection, Clostridium difficile is a microorganism that normally lives in the gut but does not usually cause harm
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However, when antibiotics kill competing strains of C.
difficile, those bacteria take over and cause diarrhea and colitis
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In the United States, C.
difficile infects about 500,000 people and kills about 15,000 people each year
.

Doctors sometimes prescribe probiotics to people who take antibiotics, but those probiotics are often also sensitive to antibiotics, and they don't fully replicate the natural microbiome found in the gut
.

"Standard probiotics can't match the diversity of natural microbes," Cubillos-Ruiz said.
"
They
can't perform the same function as the native microbes you've grown throughout your life
.

" To protect the microbiome from antibiotics, the researchers decided to use modified bacteria
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They engineered a bacterial strain called Lactococcus lactis, commonly used in cheese production, to deliver an enzyme that breaks down beta-lactam antibiotics
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These drugs account for about 60 percent of the antibiotics prescribed in the United States
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When these bacteria are administered orally, they briefly populate the gut, where they secrete enzymes called beta-lactamases
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This enzyme then breaks down antibiotics that reach the gut
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When antibiotics are taken by mouth, the drug enters the blood mainly from the stomach, so the drug can still circulate in the body at high levels
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This approach can also be used with injected antibiotics, which eventually reach the gut as well
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After their work is done, the engineered bacteria are excreted through the digestive tract
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The use of engineered bacteria that degrade antibiotics presents unique safety requirements: β-lactamases confer antibiotic resistance in inclusion body cells, whose genes can be easily transmitted between different bacteria
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To get around this, the researchers used a synthetic biology approach to recode the way bacteria synthesizes enzymes
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They divided the gene for beta-lactamase into two pieces, each encoding a fragment of the enzyme
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These gene segments are located on different segments of DNA, making it extremely unlikely that two gene segments will transfer to another bacterial cell
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These β-lactamase fragments are exported outside the cell, where they are reassembled, restoring enzyme function
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Since β-lactamase can now diffuse freely in the surrounding environment, its activity becomes a "public good" for the gut bacterial community
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This prevents engineered cells from gaining an advantage over native gut microbes
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"Our biocontainment strategy enables delivery of antibiotic-degrading enzymes to the gut without the risk of horizontal gene transfer to other bacteria and without the additional competitive advantage of live biotherapeutics," Cubillos-Ruiz said
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Microbial diversity To test their method, the researchers gave mice two oral doses of the engineered bacteria, each with ampicillin
.

The engineered bacteria enter the gut and start releasing beta-lactamases
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In these mice, the researchers found that the amount of ampicillin circulating in the blood was as high as in mice that did not receive the engineered bacteria
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In the gut, mice that received the engineered bacteria maintained higher levels of microbial diversity than mice that received antibiotics alone
.

In these mice, levels of microbial diversity dropped dramatically after receiving ampicillin
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Furthermore, none of the mice that received the engineered bacteria developed opportunistic C.
difficile infections, while all mice that received only antibiotics showed high levels of C.
difficile in the gut
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"This is strong evidence that this approach protects the gut microbiota while preserving the efficacy of antibiotics because you're not changing levels in the bloodstream," Cubillos-Ruiz said
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The researchers also found that removing the evolutionary pressure for antibiotic treatment This makes the gut microbes far less likely to develop antibiotic resistance after treatment
.

In contrast, they did find many genes for antibiotic resistance in the microbes that survived the mice that received the antibiotics but not the engineered bacteria
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These genes can be passed on to harmful bacteria, exacerbating the problem of antibiotic resistance
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The researchers now plan to start developing a version of the treatment that can be tested in people at high risk for acute illness from antibiotic-induced gut dysbiosis, and they hope that eventually, it could be used to protect anyone who needs to take Antibiotics treat people with extra-intestinal infections
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"If you don't need antibiotics in the gut, then you need to protect the microbiome
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It's similar to when you take an X-ray and you put on a lead apron to protect the rest of your body from ionizing radiation," Cubillos-Ruiz said
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"None of previous interventions have provided this level of protection
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With our new technology, we can make antibiotics safer by preserving beneficial gut microbes and reducing the chance of new antibiotic-resistant variants emerging
.

" References: https://medicalxpress.
com/news/2022-04-bacteria-good-gut-microbes-antibiotics.
html Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment plans
.

For health guidance, please go to a regular hospital for treatment
.

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