Scientists are paving the way to reducing the harmful side effects of antibiotics on gut bacteria

Antibiotics help us treat bacterial infections and save millions of lives each year. But they can also harm the helpful microbes residing in our gut, weakening one of our body’s first lines of defense against pathogens and compromising the multiple beneficial effects of our microbiota on our health. Common side effects of this collateral damage from antibiotics are gastrointestinal problems and Clostridioides difficile infections. They also include long-term health problems, such as the development of allergic, metabolic, immunological or inflammatory diseases.

Researchers from the Typas group at EMBL Heidelberg, the Maier laboratory of the excellence group “Controlling Microbes to Fight Infections” at the University of Tübingen and collaborators analyzed the effects of 144 antibiotics on our most common intestinal microbes. The study published in the journal Nature greatly improves our understanding of the effects of antibiotics on gut microbes. It also suggests a new approach to mitigate the adverse effects of antibiotic therapy on the gut microbiome.

The human gut is home to a complex community of different microbial species as well as numerous viruses, collectively referred to as the gut microbiome. Together, they allow us to use nutrients more efficiently and prevent disease-causing bacteria from taking up residence in our gut. However, when we treat a bacterial infection with antibiotics, there is a risk of damaging the gut microbiome.

“Many antibiotics inhibit the growth of various pathogenic bacteria. This broad spectrum of activity is useful when treating infections, but it increases the risk that microbes in our gut are also targeted,” explained Lisa Maier, group leader. DFG Emmy Noether at the University. from Tubingen. Maier is an alumnus of the Typas lab and one of the study’s two lead authors.

If certain intestinal bacteria are more affected than others, antibiotic therapy can lead to an imbalance in the composition of our microbiota, commonly known as dysbiosis. Diarrhea is a common short-term effect, while allergic conditions such as asthma or food allergies and obesity are possible long-term consequences. The fact that antibiotics are also active against gut microbes has long been known, but their effects on the wide variety of microbes we carry in our gut had not yet been systematically studied, mainly due to technical challenges.

“So far, our knowledge of the effects of different antibiotics on individual members of our gut microbial communities has been patchy. Our study fills major gaps in our understanding of which type of antibiotic affects which types of bacteria and how “, said Nassos Typas, Senior Scientist and Group Leader at EMBL Heidelberg.

Building on a previous study by the Typas, Bork, Patil and Zeller groups at EMBL, the scientists observed how each of the 144 antibiotics affected the growth and survival of up to 27 bacterial strains commonly inhabiting our guts. The researchers determined the concentrations at which a given antibiotic would affect these bacterial strains for more than 800 antibiotic-strain combinations, expanding existing data sets of antibiotic spectra in gut bacterial species by 75%.

Importantly, the experiments revealed that tetracyclines and macrolides – two families of commonly used antibiotics – not only prevented the bacteria from growing, but also led to their death. About half of the intestinal strains tested did not survive treatment with these types of antibiotics.

“We did not expect to see this effect with tetracyclines and macrolides, as these classes of antibiotics were thought to only have bacteriostatic effects, meaning they stop bacterial growth, but do not kill bacteria. bacteria,” said postdoctoral fellow Camille Goemans. member of the Typas group who shares first paternity with Maier. “Our experiments show that this hypothesis is not true for about half of the gut microbes we studied. Doxycycline, erythromycin, and azithromycin, three commonly used antibiotics, killed several abundant gut microbial species, whereas others simply inhibited.”

Selective killing of specific microbes by tetracyclines and macrolides could lead to the unintended loss of these microbes from the gut microbiota much faster than microbes whose growth is only inhibited, as the authors showed with synthetic microbial communities. This could explain the strong changes in the microbiota witnessed by some patients treated with these antibiotics.

There is, however, a way to reduce the damage. “We have shown before that drugs interact differently in different bacterial species. We therefore explored whether a second drug could mask the harmful effects of antibiotics on abundant gut microbes, but allow antibiotics to retain their activity against pathogens. It would provide something like an antidote. , which would reduce the collateral damage of antibiotics on gut bacteria,” Typas explained.

Scientists combined the antibiotics erythromycin or doxycycline with an array of nearly 1,200 pharmaceuticals, to identify drugs that would rescue two abundant gut bacterial species from the antibiotic. Indeed, researchers have identified several non-antibiotic drugs that could save these gut microbes and other related species. Importantly, the combination of one antibiotic with a second protective drug did not compromise the effectiveness of antibiotics against pathogenic bacteria.

Follow-up experiments indicated that this approach might also work in the context of a natural microbiome. With the help of collaborators, the scientists showed that combining erythromycin with an antidote attenuated the loss of certain intestinal bacterial species that are abundant in the mouse gut. Similarly, the antidotes protected human gut microbes from erythromycin in complex bacterial communities derived from stool samples.

“Our approach that combines antibiotics with a protective antidote could open new opportunities to reduce the harmful side effects of antibiotics on our gut microbiomes,” Maier concluded. “No single antidote will be able to protect all the bacteria in our gut, especially since these differ so much from individual to individual. But this concept opens the door to developing new personalized strategies to maintain our gut microbes. in good health.”

Further research will be needed to identify the optimal combinations, dosages and formulations for antidotes, and to rule out potential long-term effects on the gut microbiome. In the future, the new approach could help keep our gut microbiome healthy and reduce antibiotic side effects in patients, without compromising the effectiveness of our antibiotics as lifesavers.

The study was a collaborative effort, involving researchers from the Typas, Bork, Zeller, Zimmermann and Patil groups at EMBL, as well as colleagues from the University of Tübingen, Ludwig-Maximilians-Universität München and the Max Delbrück Center for Molecular Medicine in Berlin. .