How bacterial members of the microbiome specifically fight Salmonella infections
HZI researchers have identified two mechanisms through which Klebsiella bacteria combat the spread of Salmonella in the gut
The microbiome, i.e. the microorganisms that colonise our gut and help with digestion, weighs around one and a half kilograms. It consists primarily of bacteria and also has a protective effect against pathogens that enter our digestive system through food, for example. An international team led by Dr Lisa Osbelt-Block and the DZIF scientist Prof. Till Strowig at the Helmholtz Centre for Infection Research (HZI) in Braunschweig investigated the mechanisms by which the microbiome counteracts a salmonella infection. Among other things, they discovered that bacteria of the Klebsiella oxytoca species in particular can put salmonella under pressure in several ways. The findings could possibly one day be used to develop a therapy that takes a completely different approach to the currently known treatments for infections: Instead of using antibiotics against salmonella, which have the side effect of weakening the important microbiome, the microbiome could be specifically strengthened and made more resistant to salmonella. The researchers have now published their latest results in the scientific journal Nature Microbiology.
When a person eats something, a battle for food begins in the gut. The various bacteria of the microbiome begin to break down the food and extract nutrients for themselves. In doing so, they not only compete with each other, but sometimes also with dangerous intruders such as salmonella or so-called enterohaemorrhagic Escherichia coli (EHEC). A certain type of bacteria in the microbiome appears to be particularly effective against salmonella, as an international team led by Lisa Osbelt-Block and Till Strowig from the “Microbial Immune Regulation” department at the Helmholtz Centre for Infection Research (HZI) in Braunschweig has now discovered. These bacteria belong to the Klebsiella oxytoca species complex, which act against salmonella in various ways. This opens up fundamentally new therapeutic approaches, the principles of which could also be transferable to the treatment of other infectious diseases.
Bacteria of the microbiome compete with salmonella for nutrients
Exactly how Klebsiella oxytoca affects salmonella can now be read in the renowned journal Nature Microbiology. The research and publication are an international team effort: in addition to the HZI, scientists from the University of Graz in Austria, the Robert Koch Institute (RKI) and the German Center for Infection Research (DZIF) in Braunschweig and Hanover are also involved. The study was financially supported by the European Structural and Investment Fund (ESF), the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) and the Austrian Science Fund, among others.
The first mechanism by which Klebsiella oxytoca puts salmonella under pressure is simply competition for food. "You could describe it like this: Klebsiella oxytoca and salmonella have the same food preferences. They therefore compete for the same nutrients. If more microorganisms want the same thing, this puts pressure on all of them—and because Klebsiella oxytoca is somewhat more assertive, the salmonellae in particular fall behind and starve, resulting in disrupted spread," says Lisa Osbelt-Block.
A toxin previously classified as exclusively harmful can keep salmonella in check
A large proportion of Klebsiella oxytoca strains have the ability to secrete a toxin, which is known to be harmful to the human gut. Surprisingly, the research team has now discovered that the Klebsiella oxytoca toxin is also effective against salmonella. This discovery marks in part a paradigm shift: previously, only negative effects of the toxin were known; the fact that a bacterium of the microbiome releases such a toxin did not appear to be beneficial. "The effect of the toxin on salmonella could explain the release of the toxin in evolutionary terms. Interestingly, strains that can produce the toxin are found particularly in the microbiome of children. In some studies, toxin-producing strains are found in almost every second child. This also makes a little sense none, at least in theory," says Till Strowig, group leader in the DZIF research areas Healthcare-Associated and Antibiotic-Resistant Bacterial Infections and Gastrointestinal Infections.
Nevertheless, the scientists do not see stimulating the release of the toxin as a therapeutic option. "The detrimental effects of the toxin remain prominently in the foreground. Thus, it is preferable to maintain the level of Klebsiella oxytoca at a stable average level in order to prevent or combat salmonella infections," says Lisa Osbelt-Block. The research team has already found indications of how this could be achieved: apparently, a diet high in simple sugars causes Klebsiella oxytoca to release more toxin. A low sugar and carbohydrate diet, on the other hand, causes the bacterium to release less toxin.
A diverse microbiome also protects against salmonella
The researchers are currently exploring alternative, more targeted approaches to modulate the levels of Klebsiella oxytoca and toxin release. "If we can identify effective methods, such as influencing Klebsiella oxytoca through specific dietary changes or the intake of certain substances, it would present an entirely new perspective: Targeted reinforcement of the microbiome," says Till Strowig. In view of the current treatment options for severe salmonella infections, this would be a huge step forward: antibiotics are currently administered—and these always attack the microbiome in the gut. In recent years, the lasting impact of increased antibiotic usage on the microbiome has become increasingly apparent. "Antibiotics reduce the diversity of the microbiome. And a diverse microbiome is known to be healthy and important. Incidentally, this also applies to resistance to salmonella: The more different strains there are in the microbiome, the greater the likelihood that some strains such as Klebsiella oxytoca will compete with salmonella for the remaining resources," says Lisa Osbelt-Block.
A newly established method also enables the investigation of other bacteria in the microbiome
In addition to searching for ways to specifically influence Klebsiella oxytoca and its close relatives, Osbelt-Block, Strowig and their team are also trying to better understand the mode of action of Klebsiella oxytoca. To do this, they are specifically switching genes in the bacterium on and off while it resides in the digestive tract of animals. The researchers have already published a paper on the application of this method in the Journal of Bacteriology in February. The method, which is related to the application of the CRISPR gene scissors, could also be used to analyse the function of other bacteria in the microbiome. There is still a lot to discover here, as experts estimate that the microbiome often consists of more than 500 different species.
Author: Dr Christian Heinrich; Source: Press release of the HZI
