The main disruptive factor is human

The greatest challenges of our time depend on the smallest organisms: For example, a stable climate or
effective strategies against infectious diseases can only be achieved with intact microbial communities.
Scientists in the Cluster of Excellence »Balance of the Microverse« are investigating how these complex
systems function, how resistant they are to disturbance and how to restore their balance. In this interview, the Cluster's spokesperson, Prof. Dr Kirsten Küsel, reports on the current state of research.

Interview by Ute Schönfelder

At present, the Jena Cluster of Excellence »Balance of the Microverse« brings together almost 70 research groups from nine different institutions. Why are microorganisms of such interest for research?

Microorganisms are not only of interest for research, but for all of us—for all life on Earth. Microbial life originated on Earth about four billion years ago. Through a variety of processes, microorganisms have played a crucial role in shaping the planet’s geochemical and geological properties, thereby facilitating the development of life as we know it.

Plants, animals, and, not least, we humans have co-evolved with microorganisms, leading to complex, mutually dependent relationships. Our health and well-being therefore depend on finely balanced interactions with these microbial communities. When the balance of these pivotal microbiomes is disturbed, problems arise. These disturbances can be the result of natural environmental changes. However, the main disrupting factor is human.

Could you give us an example?

Let’s take a look at the human gut. It is one of the most densely populated ecosystems of all. The large intestine contains up to one billion bacteria per gram of intestinal contents. This intestinal microbiome is considered an organ in its own right and can weigh up to two kilograms. Its importance extends far beyond digestion. However, if we eat the wrong food, such as heavily processed fast food, or take broad-spectrum antibiotics, we interfere with this microbiome. We disrupt its balance. This can lead to a reduction in beneficial bacteria and allow pathogenic bacteria and fungi to proliferate.

These dysbioses are associated with an array of diseases. The consequences can be life-threatening. While we’re sitting here and chatting for an hour, around 1,250 people around the world are dying of sepsis, which is often associated with microbiome disbalance.

Should we then avoid antibiotics to treat infectious diseases?

No, absolutely not. All the same, their improper use leads to the development of bacterial resistance, which
reduces their efficacy. Susceptible bacteria are eliminated, while resistant bacteria survive and proliferate.
We’re in the midst of an antibiotic crisis! This means we need to think differently. Instead of focusing solely on eliminating specific bacterial species, we should pay more attention to the balance of the microbiome or, if disrupted, restoring it.

How exactly can we restore balance in a microbial ecosystem?

Restoring balance in microbial ecosystems requires a profound understanding of the underlying relationships
and controlling factors. This is exactly what we’ve worked on in the first funding period our Cluster of Excellence »Balance of the Microverse«. We’ve been able to identify chemical mediators and analyse their roles and dynamics. We’ve developed innovative methods to precisely investigate microbial interactions in both spatial and temporal terms. It turns out that there are fundamental principles that determine the microbial balance in different systems, regardless of whether we are talking about a body of water, the soil, or the human gut.

All the same, a body of water is radically different to the human gut. What parallels can you draw between these different systems?

Many relationships that we have long known from ecology can also be applied to the »human ecosystem«. Let's take a lake as an example. The water is home to diverse microbial communities, including microalgae, which are crucial to the balance of the lake as they fix large amounts of CO2 and produce oxygen. However, if the nitrogen and phosphorus levels in the lake rise too high, perhaps due to overfertilization, this can lead to explosive growth of the microalgae—known as algal bloom. The ecosystem »tips over« into a different state. The algae can produce toxins, leading to fish kills and potential health risks for humans.

This idea of »tipping points« is a well-established phenomenon in ecology. We see similar processes in the human gut: a disbalance in the microbiome can fuel the growth of unfavourable or even dangerous species, such as Clostridium difficile. These can overgrow the healthy gut microbiome and cause serious health problems. Both in the lake and in the gut, disruptions to the balance can lead to unfavourable species becoming dominant and destabilizing the entire system.

Does a disturbance of the balance automatically lead to the microbial ecosystem tipping over?

No. Not every disturbance necessarily causes a system to tip over. How a system responds to disturbance
depends on their type and intensity. Some systems can regain their stability and regenerate following a disturbance, while others are more susceptible and tip over more easily. This is what we’re aiming to investigate
in our Cluster in the years ahead: how resistant different systems are to disturbance and how this relates to the interactions between microorganisms.

To achieve this, we’re looking at these interactions as networks that can be described in mathematical terms in order to make predictions—about a given system’s vulnerability, how much it can withstand, whether there are indications of tipping points, and how resilient it is. As a general rule, systems with greater diversity are more stable. A diverse microbial community can react better to changes and absorb disruptions, which increases the resilience of the entire ecosystem.

How do you approach your research in the Cluster of Excellence?

Building on our insights to date, that chemical and biological interactions regulate the structure and transitions between different states in the microbiome, we will investigate various model systems over different timescales, from the molecular level to the global microverse. This means we will look at processes that occur in a fraction of a second, such as chemical mediators binding to receptor molecules, as well as the role of chemical mediators formed by microorganisms in the human oral cavity thousands of years ago.

Besides the »human ecosystem«, what other systems are you examining in the Cluster and how do they
differ?

We’re trying to cover the entire diversity of microorganisms on Earth by looking at different model systems
from three major areas into which they are grouped: firstly, freshwater systems and the soil; secondly, the
oceans; and thirdly, microbiomes associated with higher organisms. These are three extremely different
habitats.

In groundwater, we find considerably fewer microorganisms per unit volume than in the human gut, which offers fewer opportunities for interactions. In addition, the energy supply in groundwater is extremely limited. There is no daily nutritional intake and no sunlight as an energy source. Consequently, the groundwater is home to very different microbes.

Microorganisms in groundwater are often equipped with a much smaller genome—which saves energy. When a cell divides, the entire genome has to be duplicated. In the gut, there’s so much energy that even microbes with large genomes can grow quickly and proliferate. Microorganisms in groundwater tend to be in energy-saving mode, they live on »low flame«. Rather than self-producing everything they need to survive, they cooperate and recycle entire cell fragments from their surroundings to save energy and resources.

How can we apply the findings gleaned in the Cluster of Excellence in practice—in medicine, for example?

Our Cluster’s approach is to forge a bridge between ecological concepts and medical applications. As I mentioned before, we’re finding that similar principles regulate dynamics and balance in all microbial communities. This knowledge can be translated to the human microbiome, especially with regard to personalized therapies.

The gut microbiome varies from person to person and is influenced by factors such as diet, lifestyle, and age. This means that, if we’re seeking to treat a patient with an infectious disease, finding out which pathogen we’re dealing with is only part of the solution. We also have to look at the patient’s personal microbiome to find a tailored treatment that’s exactly right for them.

In addition to applications in medicine and other scientific fields, you’re also hoping to engage the public with your research results. How are you going about this?

We are using a lot of different approaches. We are focussing on public relations work in Jena and far beyond. A central component is our award-winning film »Into the Microverse«. During the Long Night of Sciences, we once again showed the film to a packed planetarium in Jena and combined it with illustrative experiments that captivated the audience. The film introduces the fascinating world of microorganisms to a wide audience and is now being shown in planetariums around the world.

Beyond this, we’re developing materials for schools in order to make young people aware of the importance of a functioning microcosmos, given its decisive role in shaping our lives and our environment. Another focus is preserving unique microbial model systems.

Our current project on traditional yoghurt production in Mongolia is an excellent example. Incredibly, these yoghurt cultures have maintained their stability for 5,000 years, while modern yoghurt cultures die off after just a few generational cycles. This system impressively demonstrates the practical benefits of a stable microbial community. Unfortunately, this traditional practice is now under threat. With this in mind, we’re seeking not only to improve our understanding of such systems but also to increasempublic awareness of their importance, thereby contributing to sustainable development.