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If an intestinal inhabitant such as the bacterium Escherichia coli (E. coli) becomes resistant to many antibiotics, it can cause serious health problems if it enters the bloodstream. How can such potentially dangerous multi-resistant bacteria be effectively removed from the gut?

Researchers from the Helmholtz Center for Infection Research (HZI), in collaboration with researchers from Hannover Medical School (MHH), explored this question in their latest study. Their strategy: food competition. Out of more than 430 different E. coli strains isolated from stool samples of donors, they identified some that successfully displaced the multidrug-resistant strains.

Their findings give the scientists hope that their approach could help slow the spread of multidrug-resistant intestinal bacteria and prevent dangerous infections in the future. The study was in the journal Nature Communications.

The microbiome in the gut is vital for our health. This community of various bacteria and microorganisms supports digestion and influences metabolism and the immune system. One intestinal inhabitant found in about 90% of people's intestines is the bacterium E. coli.

"It is a beneficiary that has found its food niche in the intestine and can colonize there permanently," explains Dr. Marie Wende from the department Microbial Immune Regulation at the HZI and the first author of the study. "Apart from a few strains that can cause gastrointestinal infections, most E. coli strains in the gut are harmless. However, if E. coli bacteria enter the bloodstream, it can be dangerous, as they can damage organs or cause sepsis."

However, such infections can usually be effectively treated with antibiotics—unless they are caused by so-called multi-resistant E. coli bacteria, which are resistant to many antibiotics. "Infections with multi-resistant E. coli bacteria lead to around 800,000 deaths worldwide each year. This is an incredibly high number—there is an urgent need for action here," says Prof. Till Strowig, Head of the HZI department Microbial Immune Regulation and corresponding author of the study.

"Multidrug-resistant E. coli bacteria lying dormant in the gut are a risk, as they can enter the bloodstream. People who are seriously or chronically ill or have weakened immune systems are especially vulnerable. In the best-case scenario, the last line of defense against an infection with multi-resistant E. coli bacteria is a reserve antibiotic." However, reserve antibiotics often cause serious side effects and are only available in limited quantities.

Competition from within their own ranks

A preventive approach that eliminates multi-resistant E. coli bacteria from the gut before complications develop would therefore be more sensible and sustainable. This is exactly where the current study comes into play.

The researchers took advantage of the competitive pressure for food resources in the gut. They introduced more than 430 different E. coli strains, which they had isolated from stool samples of healthy donors, into a competition—essentially an eating contest—against a multi-resistant E. coli strain provided by the Medical Microbiology Department of the MHH.

In their extensive laboratory tests, the team compared one of the normal E. coli strains against the multi-resistant strain. They used the intestinal contents of sterile mice as a food and growth medium.

"We investigated whether and to what extent the growth of the multidrug-resistant strain changed in the presence of the other E. coli strains," explains Wende. "Some strains were actually able to strongly inhibit the growth of the multidrug-resistant strain and appeared capable of depriving it of its nutritional basis."

The researchers examined the promising food competition candidates more closely in further studies using a mouse model. "We were able to show that these E. coli strains could also successfully contain the multidrug-resistant E. coli strain in the mice's intestines," says Wende. "We also tested the most effective strain against another multi-resistant strain. It was just as successful in suppressing it."

Even stronger together

To further explore the protective effects of the E. coli strains, the researchers repeated the entire test procedure described earlier. This time, they tested the three most successful E. coli strains against a broader range of multi-resistant E. coli strains. They also included another competitor: the intestinal bacterium Klebsiella oxytoca, which shares similar but not identical food preferences with E. coli.

"Our hypothesis was that combining two different bacterial strains could potentially enhance the protective effect against multi-resistant E. coli strains," explains Wende. "And this was indeed the case: the combination of protective E. coli and Klebsiella oxytoca proved to be highly effective against multidrug-resistant E. coli strains that single E. coli strains could not efficiently displace. The combination was able to completely eliminate them in the mouse model."

Strowig states, "Our study shows that specifically selected bacterial strains can successfully displace multi-resistant pathogens from the intestine as food competitors. In this way, dangerous infections in vulnerable patient groups could be avoided in the future, and the further spread of multi-resistant intestinal bacteria could also be contained."

In further studies, the researchers aim to thoroughly characterize the E. coli strains that are particularly effective in displacing multidrug-resistant E. coli strains. Are these strains harmless, or do they produce toxins harmful to humans? Are they recognized by the immune system, or can they easily evade detection? Does their effectiveness against multi-resistant pathogens change when other bacteria are present in the microbiome? And do they themselves develop resistance to antibiotics?

"We want to investigate these questions comprehensively. Before selected E. coli strains can be used as food competitors preventively or therapeutically against multi-resistant E. coli strains, a great deal of research work is still required," Strowig says.