How “good” intestinal bacteria could fight dangerous pathogens
Thanks to antibiotics, bacterial infections have largely lost their threat. However, for people with a weakened immune system, for example after an organ transplant, the pathogens are still life-threatening, especially if they have developed multidrug resistance. Maria Vehreschild has set her sights on these bacteria, and “good” intestinal bacteria are her weapon.
While it matures in the womb, the human fetus – including the intestine – is sterile, i.e. free of bacteria and microorganisms. As soon as the child is born, this changes dramatically: Its body is gradually colonized by microorganisms. Most of them gambol around in the gut, where intestinal bacteria account for about a kilogram of an adult’s body weight. As bacteria are, however, much smaller than human cells, we have a kind of counterpart inside our own bodies: It is estimated that there are just as many bacterial cells as body cells – 30 trillion! These are distributed over up to 200 different species, whose ratio and composition change over the course of our lives, even though we each form a “core microbiome” early on. Our diet plays just as much of a role in this as our age. The bacteria (and the other microorganisms) benefit from the constant supply of nutrients, but they do a lot for our body in return, for example by breaking down fiber, producing vitamins and aiding digestive processes. They form a dynamic, very complex ecosystem – which makes it difficult for invaders to gain a foothold. This, too, is very useful for our body, as the microbiome forms a first barrier against bacterial pathogens before the cells of the intestinal mucosa take over.
Although scientists believed for a long time that pathogens could be treated with a broad spectrum of antibiotics that inhibit their proliferation, the limits of this therapy have become increasingly apparent in recent years: Bacteria are very adaptable and can develop resistance, even to several antibiotics at the same time, which makes them life-threatening (see also p. 40, “Resistant pathogens in our sights”).
For healthy people with a good immune system, however, multidrug-resistant bacteria are generally harmless. Many healthy people are infected with multidrug-resistant pathogens without even knowing it and without falling ill themselves. In hospitals, however, this can be dangerous because there is a risk, for example, that multidrug-resistant pathogens can enter the surgical wound during the operation and trigger infections that in turn lead to complications. Particularly susceptible to infections are people with a weakened immune system, which can be caused by diseases such as HIV or diabetes. Patients undergoing chemotherapy for cancer also have a weaker immune system than healthy people.
Transplant recipients are particularly at risk
Patients who have received an organ or stem cell transplant are usually given medication to suppress their immune system even further so that their body does not reject the foreign stem cells or the foreign organ. Another group at high risk of infection from multidrug-resistant pathogens are people with chronic kidney disease who are dependent on dialysis – regular blood washing.
“Dialysis patients, like transplant recipients, are often inpatients. Despite all hygiene measures, resistant bacteria are particularly widespread in hospitals, where there are a lot of sick and weak people. As a result, multidrug-resistant pathogens often colonize above all the skin and intestine of transplant recipients and dialysis patients, which can trigger life-threatening infections later on,” explains Professor Maria Vehreschild, Head of Infectious Diseases at University Hospital Frankfurt. This is corroborated by a retrospective study conducted by Chinese researchers on the frequency of infections with multidrug-resistant pathogens among over 2,100 organ transplant recipients. According to their results, 91 organ transplant recipients (= 4.6 percent) had such infections, 36 of which were fatal.
As a general rule, immunocompromised patients are routinely tested during their hospital stay to determine whether they are carriers of multidrug-resistant bacteria. If this is the case, they are isolated. “If the bacteria detected are methicillin-resistant Staphylococcus aureus (MRSA), which colonize the skin and mucous membranes, it might be possible to remove them using certain cleansing procedures. For multidrug-resistant Enterobacteriaceae pathogens from the intestine, however, no approach has yet proven to work,” says Vehreschild. She hopes that a study she is planning together with partners from the German Center for Infection Research (DZIF) will change this.
Their idea is to transfer microorganisms from the feces (stool) of healthy people to transplant recipients or dialysis patients with multidrug-resistant intestinal bacteria. The intestinal microbiome, as the entirety of all microorganisms is called, transferred to the patient should then compete for nutrients with the multidrug-resistant pathogens and starve them to death. “We know from case series and a clinical study that transferring the microbiome, a process known as fecal microbiota transplantation (FMT), eliminates or at least significantly reduces existing multidrug-resistant bacteria in some people. However, there is not only great uncertainty about the success rate but also dissatisfaction with it, as it is only between 20 and 60 percent,” says Vehreschild.
Microbiome in capsules
What encourages the team that the outcome of the planned study will be better? Firstly, Vehreschild’s extensive experience with FMT. As long ago as 2013, when she was working as a physician at the University of Cologne, Vehreschild carried out the first FMT procedures on patients suffering from recurrent diarrhea caused by infections with the bacterium Clostridioides difficile. She was the first scientist in Europe to produce encapsulated preparations for this treatment method. Patients swallow the capsules, which contain bacteria from the donor’s stool, like they would other drugs in tablet form. Fecal microbiome transplantation is proving very successful for treating persistent Clostridioides difficile infections in individual patients: 80 to 90 percent of those treated are free of the diarrhea pathogen afterwards.
To produce the capsules, a GMP laboratory (GMP = Good Manufacturing Practice) opened at the University of Cologne in 2020, which Vehreschild still heads today alongside her main job at University Hospital Frankfurt. The laboratory recruits potential stool donors, who are thoroughly tested first to see if they are suitable candidates. “The requirements are even stricter than for blood donors. Because we know less about fecal bacteria than about blood components, we have to take even more precautions to rule out all the risks,” explains Vehreschild.
Complex screening
Anyone willing to donate must first answer a very detailed questionnaire. Only those who, on the basis of their answers, can be classified as completely healthy proceed to the next phase – screening: The potential donor’s blood and stool are analyzed to determine, among other things, whether they are colonized with multidrug-resistant pathogens or the donor has a chronic infection. At the end of the day, only around one in ten potential candidates actually donates.
The donor must then pass stool in a laboratory toilet over a period of six weeks. The laboratory staff produce microbiome capsules from it, then check whether these contain enough live bacteria and whether the bacteria are genuinely harmless. Only when these tests are confirmed and the donor has successfully completed a second screening after a six-week interval are the preparations released for treating individual patients or for medical studies. This procedure will also ensure high-quality FMT for the study on multidrug-resistant pathogens.
The second reason why the results of the planned study are likely to be better in comparison to previous case series is that all the individual organ transplant patients or patients with chronic kidney disease will receive different, i.e. personalized, microbiome capsules. To do this, the researchers will first cultivate the multidrug-resistant pathogens from the patient’s intestine in the laboratory. They will then mix the resulting bacterial culture – also in the laboratory – with the microbiome of various stool donors. “We will observe which fecal microbiome best displaces the pathogen culture. We will then use the microbiome that works best for the respective patient,” explains Vehreschild.
There is another aspect where her planned study will differ from previous trials: The research team plans to pre-treat a cohort of study participants with antibiotics prior to FMT. Studies exist which indicate that new bacteria colonize better in the intestine if the microbial competition already established there is first weakened. Comparison with a second patient cohort given placebos instead of antibiotics will show whether this pre-treatment is effective. The intention is for 76 patients from six university hospitals to take part in the study. Vehreschild expects results in three years at the earliest.
Extensive knowledge about the intestinal microbiome
The study comes at precisely the right time. The number of research papers on the microbiome has grown astronomically in recent years. It is becoming increasingly clear that the trillions of microorganisms on and in our body significantly influence our metabolism and immune system. “Knowledge about the intestinal flora and its importance has increased enormously. We have now reached a point where it is becoming interesting for patients,” Vehreschild is convinced.
However, on the way to clinical practice there are also obstacles to overcome that have nothing to do with science. This can be seen in the example of FMT treatment for recurrent infectious diarrhea. Although FMT is recommended, on the basis of study data, in medical guidelines, no microbiome preparation has yet been approved as a drug in Europe. “To have our preparations approved and introduced onto the market, we need a company to conduct a pivotal study with them. So far, however, I have not been able to motivate a company to do this,” regrets Maria Vehreschild.
About / Maria Vehreschild, born in 1979, studied medicine at Charité Berlin and earned her doctoral degree at the Technical University of Munich (TUM). She was a researcher at University Hospital Cologne, qualified as a specialist in internal medicine in 2012, then in hematology and oncology in 2015, and completed her postdoctoral degree (Habilitation) at the University of Cologne. In 2018, she was appointed as Professor of Infectiology at Goethe University Frankfurt and has since been head of Infectious Diseases at University Hospital Frankfurt. In addition, she continues to head the Cologne Microbiota Bank at University Hospital Cologne, which produces microbiota transplant products for clinical studies. Vehreschild is the coordinator of the Thematic Translational Unit “Healthcare-associated and Antibiotic-resistant Bacterial Infections” at the German Center for Infection Research (DZIF).
vehreschild@med.uni-frankfurt.de
The author / Frank Frick, holds a doctoral degree in chemistry and has been working as a freelance science journalist for around 25 years. He writes for magazines, research institutions and research-based companies. He lives in Bornheim near Bonn.
