“The ecosystem of most immediate relevance to us is not external to us but inside us,” says Bärbel Stecher, who is studying the microbial inhabitants of the human gut and the interactions between them. Why are these organisms so important for our health?
One can learn much about the ‘inner lives’ of humans from Bärbel Stecher, Professor of Medical Microbiology and Public Health at LMU’s Max von Pettenkofer Institute. She studies the gut microbiome, the dynamic cellular community made up of the myriads of bacteria, fungi and viruses that colonize the human gastrointestinal tract (GIT). Other ‘microbiota’ are found on the skin and on mucous membranes. “Did you know that perhaps the most densely populated ecosystems in the world are found inside us? The population density in the human colon is 1012 cells per gram of tissue.”
The density of the gut microbiome is impressive, but its real significance lies in its diversity, and the complexity of the interactions within it. Its members process foods that we cannot digest ourselves, they supply vital nutrients and they help us to fight infections by educating our immune systems. “Bacteria possess enzymes and metabolic pathways that human cells lack,” says Stecher. Moreover, perturbations of the functions provided by the microbiome are thought to be linked to metabolic diseases like type-2 diabetes, allergies, chronic inflammatory bowel syndromes, and even cancers. “Recent studies have confirmed that the gut microbiome has a significant impact on human health,” Stecher says.
Indeed, these findings have already inspired bestsellers, such as Darm mit Charme (English title: “Gut”), whichhas sold over a million copies in Germany alone. Meanwhile, in some areas of healthcare, the gut microbiome has acquired the status of a super-organ. Physicians and dieticians advise patients to take probiotics, and undergo ‘colon rehabilitation’ or even fecal transplantations to combat infections or relieve chronic intestinal inflammation. “Actually, we still don’t understand the relationships between the gut microbiome and general health,” Stecher points out. However, new technologies like metagenome sequencing now enable researchers to uncover associations between disease states and changes in the composition of the microbiota. Such advances have shed light on the roles of certain species and the molecular mechanisms that mediate their interactions with host tissues. The ultimate goal is to exploit the gut microbiome for the diagnosis and therapy of a variety of disorders.
The gut microbiome has a significant impact on human health.
Prof. Bärbel Stecher, Professor of Medical Microbiology and Public Health at LMU’s Max von Pettenkofer Institute
Stecher’s research focuses on the gut microbiome, and more specifically on its bacterial component, which accounts for 95% of its mass, and is functionally the most significant of the body’s microbiota. The bacteria that comprise the gut microbiome are less diverse than was initially assumed, and the number of species found in any given individual lies between 200 and 400. “New DNA sequencing methods, in combination with bioinformatic analyses, as well as classical methods of isolation, cultivation and characterization, have made it possible to describe many more species,” Stecher explains. More than 2000 species have now been identified in gut microbiomes obtained from populations around the world. Each of these species in turn is made up of variants known as strains. “This makes it difficult to determine whether any of the bacteria found in the gut are shared by all human populations,” Stecher says. At all events, the species composition of each person’s gut microbiome is in large measure unique. The implications of this specificity, and the question of what characterizes a ‘healthy’ gut microbiome, are now at the focus of research. “It’s not yet possible to deduce the state of a person’s health on the basis of the gut microbiome,” says Stecher. A broad range of bacterial diversity is generally thought to be advantageous, but the precise metabolic characteristics of many species have yet to be investigated in detail.
The gut microbiome harbors both useful as well as potentially harmful bacteria. Microbiologists already know a lot about some members of the second class, such as Helicobacter pylori and various members of the genus Salmonella. The latter are rod-shaped bacteria, and certain species have long been known to cause gastrointestinal infections in humans. In young children and elderly or immunocompromised patients these infections can be serious. But only in 10-20% of those who pick up the pathogen – usually from contaminated food – does the infection lead to overt illness. The molecular mechanisms responsible for protecting the other 80-90% are largely unknown.
Stecher says that “most people who have an intact microbiome are on the safe side”. In a recent study, she and her team have shown that a bacterium called Mucispirillum schaedleri plays a central role in protecting mice from Salmonella-induced colitis. The evidence suggests that M.schaedleri does so by blocking the production of one of the pathogen’s virulence factors. “We now have some indications that Mucispirillum is present in humans, and could therefore provide protection against the infection.
Evolution of bacteria
To facilitate the study of interactions like this one, Stecher and colleagues assembled a model collection of bacterial species. The cocktail consists of about a dozen well characterized species that are representative of the gut microbiomes of healthy mice, and it can be transplanted into germ-free mice.
Using this approach, researchers can alter the composition of the mouse microbiome and study the effects of the manipulation on the metabolites in the GIT of mice that have particular disease syndromes. In this way, Stecher hopes to learn enough about the molecular mechanisms of the interactions between microbiome and host to be able to move on from correlation to causality. “Our model consortium obviously filled an unmet need,” she says, and it is now well established in the field. “We’re using it to study the mechanisms that protect against gastrointestinal infections, but it can also be employed in the context of Alzheimer’s disease or chronic inflammation of the bowel.”
Such studies are dauntingly complex. “Cataloging the bacterial species that might play a role is not enough. We need to understand the interplay between the different micro-organisms involved. Stecher emphasizes that “changes in the interactions between species, not any single species, are the decisive factor that determines whether or not humans become susceptible to particular pathogens”. She would also like to know what happens when the composition of the gut microbiome is altered in specific ways. Some strains of E. coli, for example, have a “bad reputation”, because they cause diarrhea. “However, E. coli also plays an important role in the gut, and in some environments it provides protection against Salmonella infections.”
In their experiments, she and her colleagues systematically vary the composition of their species consortium, quantify the effects on the metabolites in the gut, and develop models of their impact on diseases ranging from diarrhea to colon cancer. The goal is always to delineate the contribution of the microbiome to the disease of interest and understand its mechanistic basis. In this way, it should be possible to discover which sets of species provide optimal protection against specific diseases.
Her latest project, EvoGutHealth, for which Stecher received one of the coveted Consolidator Grants funded by the European Research Council (ERC) last year, will also use the defined-consortium approach. One aspect of this project interests her particularly. The bacterial strains in the gut tend to mutate at very high rates, which enables them to adapt rapidly to changes in local conditions. Stecher wants to know how this feature facilitates the evolution of the interdependent metabolic circuits which are the hallmark of the microbiome as a whole. “In our germ-free mice, it often takes months before a functional microbiome becomes established,” Stecher explains. “We would like to know how groups of bacterial species adapt to each other’s presence, and we plan to develop genetic model systems to investigate these processes.”
Saving the microbiome
Similar evolutionary processes take place in the gut microbiome over the course of a lifetime. In newborns, the assembly of the microbiome begins essentially during the birth process itself, with the uptake of bacteria that reside in the birth canal and the subsequent incorporation of microbes ingested during breastfeeding. “The diversity of the gut microbiome increases over the first three years of life,” Stecher says. The mechanisms that drive this evolution, and its significance, are still poorly understood. Moreover, little is known about how the formation of the microbiome affects health in later years. Notably, the microbiomes of indigenous peoples tend to be much more diverse than those of individuals in industrialized countries. – Indeed, this difference is often invoked to explain why they are less likely to develop chronic lifestyle diseases like diabetes, allergies and hypertension.
In this context, Stecher mentions an international initiative proposed by microbiologists with the aim of “saving the microbiome”. The idea is to collect microbiomes from different populations and store them securely in a facility dubbed the Microbiota Vault, to ensure that these rich sources of biological diversity can be conserved for research purposes. “I think it’s a cool idea,” says Stecher. As in the case of the Svalbard Global Seed Vault on the Norwegian island of Spitzbergen, in which over 800,000 different samples of plant germplasm are stored, the Microbiota Vault is intended to serve as a reservoir of microbial species that are of particular significance to humans – micro-organisms that we might need in the future for the fight against disease. “It’s certainly a good idea to conserve this resource for future generations, because the microbiome is still a black box. We know many of the species, but we are still in the dark with respect to the functions of 80% of their genes. We have a lot of surprises in store for us!”
Text: Hubert Filser
Prof. Dr. Bärbel Stecher is Professor of Medical Microbiology and Public Health at LMU’s Max von Pettenkofer Institute.