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Discovery & Development Clinical Trials, Drug Discovery

Meet the Microbiome Matchmaker

Maria Zimmermann-Kogadeeva is a computational biologist and Group Leader at the European Molecular Biology Laboratory (EMBL) – and one of many researchers involved in a recent study into the effects of drugs for cardiac disease on the microbiota of the gut (1).

Together with other scientists at EMBL and international collaborators, Zimmermann-Kogadeeva is exploring the cause and effect of medicines on microbiome diversity, in addition to making some surprising discoveries along the way. Some drugs, it seems, may offer the (unintended) benefit of boosting gut health…

Credit: Massimo Del Prete/EMBL
It is hard to say whether or not the microbiome is truly a “young” field, since it actually has its roots in early bacteriology studies. As early as the 17th century, the first microscope was invented. People at that time had already identified some microbes.

What’s your background?
 

My background is in mathematics and computer science, but from very early on in my studies, I felt drawn to life science applications. And that’s why I joined an interdisciplinary lab that was interested in microbial metabolism for my PhD. During my time there, I was developing computational methods to probe metabolic alterations in bacteria under different conditions.

Very quickly, I became even more excited about microorganisms and the role they play in our life. For my postdoctoral training, I decided to move into the human microbiome field. I wanted to understand the metabolic relationships between microbes and their hosts – and how this can affect our health.

For the last two years, I’ve been working in a computational microbiome group toward my second postdoc. I’ve focused on bioinformatics analysis of microbial communities as well as large-scale human cohort studies. My colleagues and I have been using statistics and computational pipelines to determine the network of relationships between microbes, host health and disease, and host phenotypes.

Can you give unfamiliar readers a quick 101 on the microbiome?
 

We should start by defining two terms that are often used interchangeably: “microbiome” and “microbiota.”

Strictly speaking, microbiota is the collection of microorganisms living in and on our bodies, including bacteria, fungi, viruses, and small eukaryotes. “Microbiome” refers to their collective genetic content. Essentially, the microbiome is the genome of microbiota. 

Which type of microbiota has your work focused on?
 

We studied the most rich microbial community in the human body – the gut microbiota.There are literally trillions of microorganisms living in that particular environment. It is distinct in terms of temperature and available nutrients, and it is mainly anaerobic; there is very little oxygen in some parts of the intestine.

All these properties render the gut very different, for example, to human skin. Our skin is oxygen-exposed and much less rich in nutrients. When you study a certain type of microbiota environment associated with a certain disease or health outcome, you have to distinguish based on such differences. But in principle, all microbiota matter.

Have recent years seen an increasing focus on the microbiome across bioscience?
 

It definitely feels like that! I think that one of the reasons for this is the development of sequencing technologies. With high-throughput sequencing, we can identify the DNA contents of different samples with very high precision. Both this and the cost of the sequencing measurements are now syncing with the development of technologies. In short, sequencing is becoming more and more accessible to different researchers who want to assess the diversity of microbiota.

All that said, it is hard to say whether or not the microbiome is truly a “young” field, as it actually has its roots in early bacteriology studies. As early as the 17th century, Antonie van Leeuwenhoek had already identified some microbes in human saliva and faecal material using the first microscopes.

What question did you want to address with your study?
 

Our recent study specifically targeted cardiometabolic disease, one of the main causes of intestinal ischemia (bowel death) and disability worldwide. We defined “cardiometabolic disease” broadly as cardiac failure, heart failure, acute coronary syndromes, but also included diabetes and obesity.

A main goal was to investigate the relationships between microbiota composition, disease progression, and response to treatment. Indeed, this was the big umbrella question of the consortium because we had hypothesized that microbiota may play a role in how the disease progresses and how patients respond. Our part of the project was focused on medical drugs that treat cardiometabolic disease, in particular, we asked: “What is the interrelationship between drugs, the microbiome, and treatment outcomes?”

We profiled more than 2000 patients from three different countries. Then, a consortium of medical professionals queried careful measurements of patients’ phenotypes, information about their diet, information about their blood markers, health markers, and also their microbiome composition. 

This large dataset allowed us to identify the relationships between drug intake, microbiome composition, blood metabolites, lipoproteins, and more. The considerable size of the cohort also allowed us to separate associations and changes in the microbiome or blood metabolites that are associated with disease from changes that are associated with the drug intake, and also from changes that are associated with other parameters – diet, smoking, or exercise, for example

Another important finding in our study is that there are large combinatorial effects of drugs on both metabolic markers in blood and microbiome composition.

What kind of effects did drugs have on the microbiome?
 

We found changes that are associated with more diseased microbiomes, but we also found changes that are associated with healthy microbiomes. It’s actually quite hard to define a “healthy” or “diseased” microbiome, but one of the commonly accepted markers is microbiome diversity – the more diverse, the better.

Another marker would be the abundance of antibiotic-resistance genes. If a patient is treated with a high quantity of drugs over an extended period of time, their microbes might actually acquire more and more genes that help them resist antibiotic treatments. Such a scenario can become a major health burden not only for a particular patient but also for healthcare and society.

What research should come next?
 

I see at least two directions that are important for this type of study.

One is in further clinical studies. We brought in 2000 patients from three different countries: France, Germany, and Denmark. That was a solid start, because it meant that we had a high diversity of patients. The higher the numbers, the more generalizable the results. 

We need to try to record and consider as many contributing health and lifestyle factors as possible. We don’t want to look at the effects that are not direct, but to draw actionable points from such studies, we have to validate them either experimentally or in further clinical studies.

On that point, I think that further studies should definitely be more targeted. For example, for some of our hypotheses on combinatorial effects, it will be important to design – if possible – a human intervention study.

I would also want to see more mechanistic laboratory studies. With human cohorts we can identify associations, but there is no direct way to distinguish cause from consequence. We may know that people took metformin and then saw certain microbes become more abundant in their guts, but we don’t necessarily know that metformin was behind this.

What we can do is design experiments in laboratory conditions; for example, we could treat microbes with drugs in vitro, and monitor how those drugs affect microbial growth for single microbes and microbial communities. By combining a top-down approach with human studies and a bottom-up approach with experimental controlled studies, we can try to prove the mechanistic links between drug treatment and microbial response.

What impact do you think your research or subsequent research could have on the drugs of the future?
 

In subsequent studies, we can definitely think about creating more and better therapies designed in a personalized manner. That way, we will have a more informed way of determining the best possible drug administration regimen or drug combination for a particular patient based on their microbiome composition or blood biomarkers.

Another potential direction is drug repurposing. In some cases during our study, we saw drug combinatorial effects when statin was administered with aspirin. These resulted in a better profile of the patients’ atherogenic lipoproteins in the blood. Aspirin is not designed for that, but it seems that if you administer aspirin with statin, it improves the effect of statin. We don’t know exactly what the mechanism is – for now it remains an observation. Nevertheless, more data and more clinical studies could help to make new combinatorial and drug repurposing applications possible.

What other potential benefits could studies into drug combinations turn up?
 

Another recent study at the European Molecular Biology Laboratory examined the collateral damage of antibiotics on the gut microbiota. This study took a bottom-up approach, so it was the opposite of ours; however, several researchers from the team were involved in both studies, including Sofia Forslund, Michael Kuhn, and Peer Bork.

We’ve known for some time that antibiotics affect our gut microbiota, but the EMBL researchers systematically analyzed the molecular mechanisms of antibiotic effects on the gut microbes, and looked for a way to compensate for such effects.

To achieve this, they screened other drugs that, in combination with antibiotics, would protect the gut microbes while letting the antibiotics work on the pathogens. Again, there is potential here for us to design combination therapies that actually improve the outcome of the main therapy.

Together with a large interdisciplinary team, Forslund, Kuhn, and Bork found that in laboratory conditions, a drug used for cardiometabolic disease actually protects the microbiome when used in combination with antibiotics.

Looking at both studies together shows how we are seeking an understanding of microbiome disease associations from different angles; hopefully, we’ll be able to find a match where we understand the mechanisms well enough to take actionable steps in improving human health care.

Do you think research on the microbiome will help bring about the radical new “century of biology” predicted by some?
 

I’m obviously biased, but considering the importance of the microbiome for so many different aspects of our health, I do hope that the work done at the EMBL contributes to the next generation of life science applications!

The microbiome field is developing at a fast pace, thanks to sequencing technologies and the ability to culture microbes. The confluence of experimental breakthroughs, sequencing, and other high-throughput multiomics measurements will definitely bring us toward a more holistic view of microbes and microbiota-host interactions. Hopefully, at some point, we will be able to control the microbiome composition and metabolic function for improved human health and wellbeing.

Headshot Credit: Massimo Del Prete (EMBL)

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  1. Sofia K Forslund et al., “Combinatorial, additive and dose-dependent drug–microbiome associations”, Nature (600), DOI: 10.1038/s41586-021-04177-9
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