Clostridium difficile bacterium
Credit: Dr_Microbe/Getty Images

New research being presented at the European Congress of Clinical Microbiology & Infectious Diseases 2023 (ECCMID) this week in Copenhagen identifies a number of different drugs that can help protect against the collateral damage often caused by antibiotics to bacteria in the gut without negatively impacting their effectiveness.

The study, which was conducted by a team of researchers from the European Molecular Biology Laboratory (EMBL) and led by Lisa Maier, PhD, and Camille V. Goemans, PhD, studied how 144 different antibiotics affect the abundance of the most common gut bacteria and provided insights into how the deleterious effects of antibiotics can be mitigated.

“Many antibiotics inhibit the growth of various pathogenic bacteria. This broad activity spectrum is useful when treating infections, but it increases the risk that the microbes in our gut are targeted as well,” said Maier, who is also a group leader at the University of Tübingen in Germany.

The human gut microbiome comprises trillions of microorganisms that help regulate digestion, work along with the immune system to ward off harmful bacteria and viruses, and provided the body with metabolites and nutrients. Unfortunately, antibiotics are known to cause damage to beneficial microbes in the microbiome in addition to the bacteria they are tasked with killing. This creates an imbalance in the gut flora that can lead to recurrent gastrointestinal problems caused by Clostridioides difficile infections as well as long-term health problems such as obesity, allergies, asthma, and other immunological or inflammatory diseases.

While these effects have been known for some time, there is little information that shows which antibiotics affect which types of bacteria in the human gut—largely due to technology challenges—and whether these effects can be mitigated.

“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 in what way,” said Nassos Typas, PhD, senior scientist and group leader at EMBL Heidelberg whose lab played a central role in the research.

To begin unraveling these questions, the research team analyzed the growth and survival of 27 of the most common bacterial species found in the human gut after treatment with each of 144 different antibiotics. The team also assessed the minimal inhibitory concentration (MIC)—the minimal concentration of an antibiotic required to stop bacteria from growing—for over 800 of these antibiotic-bacteria combinations.

The study showed that in most instances, the majority of gut bacteria had slightly higher MICs than disease-causing bacteria and, as a result, would not be affected by commonly used antibiotic concentrations.

However, the study showed that two common classes of antibiotics—tatracyclines and macrolides—halted healthy bacteria growing at much lower concentrations than those required to stop the growth of disease-causing bacteria. Further, the drug also killed more than half other bacteria tested, which could potentially alter the composition of the gut microbiome for a long time.

“We didn’t expect to see this effect with tetracyclines and macrolides, as these antibiotic classes were considered to have only bacteriostatic effects—which means that they stop bacterial growth, but don’t kill bacteria,” said Goemans, a postdoctoral fellow in the Typas group. “Our experiments show that this assumption 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 they just inhibited.”

With this information, the team then turned to search for other drugs that could be used to help protect and preserve these microbial species. They combined the antibiotics erythromycin (a macrolide) and doxycycline (a tetracycline) with a set of 1,197 pharmaceuticals to identify suitable drugs that would protect two abundant gut bacterial species (Bacteriodes vulgatus and Bacteriodes uniformis) from the antibiotics.

The investigators discovered that several drugs such as the anticoagulant dicumarol, the gout medication benzbromarone, and two anti-inflammatory drugs, tolfenamic acid and diflunisal, provided protection and didn’t compromise the effectiveness and the antibiotics against disease-causing bacteria.

“Our approach that combines antibiotics with a protective antidote could open new opportunities for reducing the harmful side effects of antibiotics on our gut microbiomes,” said Maier. “No single antidote will be able to protect all the bacteria in our gut—especially since those differ so much across individuals. But this concept opens up the door for developing new personalized strategies to keep our gut microbes healthy.”

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