Antibiotics not only fight pathogens, they also damage the beneficial bacteria in our intestines. The side effects therefore include gastrointestinal complaints such as diarrhea, but also newly emerging allergies and inflammatory bowel diseases. Researchers have now systematically examined the effects of 144 antibiotics on the 27 most common gut bacteria. According to this, some antibiotics, which should only inhibit the growth of the bacteria, have a fatal effect on several bacterial strains – and can thus upset the microbiome in the long term. Additional medication may help reduce the harmful effects.
Trillions of bacteria live in our intestines. They help us utilize nutrients, prevent disease-causing bacteria from spreading, and can even affect our mood. However, if you have to take antibiotics because of a bacterial disease, this also disrupts the microbiome in the intestine. “Many antibiotics inhibit the growth of pathogenic bacteria. This broad spectrum of activity is useful in the treatment of infections, but increases the risk that the beneficial bacteria in the intestine will also be attacked, ”explains Lisa Maier from the European Molecular Biology Laboratory in Heidelberg.
Investigated effects on intestinal bacteria
Together with her team, she has now laid the foundations for a better understanding of the effects of antibiotics on helpful intestinal bacteria and, if possible, of containing them. “So far, our knowledge of the effects of different antibiotics on individual members of our microbial communities in the gut has been patchy. Our study contributes significantly to our understanding of which types of antibiotics influence which types of bacteria in which way, ”says Maier’s colleague Nassos Typas.
For 144 antibiotics, the researchers analyzed how they affect the growth and survival of 27 bacterial strains that are commonly found in the intestine. They determined the so-called minimum inhibitory concentration (MIC) for more than 800 antibiotic-bacterial strain combinations, i.e. the minimum concentration required for an antibiotic to inhibit the growth of a certain bacterial strain. “Overall, the intestinal bacteria examined here had slightly higher MICs than those specified for pathogens,” the researchers report. This means that when the antibiotic concentration is just enough to damage pathogens, most intestinal bacteria are not yet affected.
Bacteriostatic or bactericidal?
According to the researchers, an exception is the commonly used class of antibiotics called tetracyclines. These antibiotics damage the beneficial intestinal bacteria at a concentration in which they cannot harm pathogens. Actually, tetracyclines are only supposed to inhibit the growth of bacteria, i.e. have a bacteriostatic effect. Maier and her colleagues found, however, that tetracyclines instead kill various strains of intestinal bacteria, i.e. have a bactericidal effect. Maier and her colleagues also came to the same conclusion for macrolides, another class of antibiotics that are also considered bacteriostatic.
“We did not expect this effect,” says Maier’s colleague Camille Goemans. “Up until now, it was assumed that these classes of antibiotics only stop the growth of bacteria, but do not kill them. The experiments show that this assumption does not apply to about half of the intestinal microbes examined by us. For example, doxycycline, erythromycin and azithromycin, three commonly used antibiotics, killed several common types of intestinal bacteria while only inhibiting the growth of others. “
This result could explain why antibiotics lead to significant, long-term changes in the gut microbiome in some patients. “It is conceivable that the microorganisms killed by the antibiotic are more likely to unintentionally disappear from the community, while the inhibited microorganisms can recover more easily after treatment is terminated,” the authors say.
Antidotes could mitigate damage
Next, the researchers set out to find ways to limit this damage. “In previous studies, we were able to show that drug combinations have different effects on different types of bacteria. We have therefore now investigated whether a second drug can prevent the harmful effects on the intestinal microbes while the antibiotics at the same time maintain their effectiveness against pathogens, ”explains Typas. “The additional drug could be used as a kind of antidote that reduces collateral damage from antibiotics to gut bacteria.”
The researchers tested the extent to which they could mitigate the harmful effects of the antibiotics erythromycin and doxycycline on almost 1,200 drugs without impairing their intended effects. In fact, they found what they were looking for: “The strongest antidotes were the anti-coagulant drug dicumarol, the gout drug benzbromarone and two non-steroidal anti-inflammatory drugs, tolfenamic acid and diflunisal,” the researchers said. In further experiments, they showed that the antidotes helped to save beneficial intestinal bacteria from the effects of the antibiotic, both in artificial microbial communities in the laboratory and in bacteria from human stool samples and in living mice, while pathogens continued to be combated.
More research needed
“This concept must be further developed before it can be used,” the researchers write. For example, the dosage and the composition of possible antidotes must be tested in order to optimize their distribution in the body and to minimize the undesirable effects of their primary effect in this case. “This concept opens the door for the development of new personalized strategies to protect intestinal bacteria,” says Maier.
Source: Lisa Maier (European Molecular Biology Laboratory, Heidelberg) et al., Nature, doi: 10.1038 / s41586-021-03986-2