“We are only now beginning to really understand the role the microbiome plays in a healthy life, and how it is involved in the development of diseases.”
The microbiome, the world of bacteria, viruses and yeasts on and in our bodies, is a source of fascination for researcher Marcel de Zoete. In this interview, he shares the challenges of this still fairly young research field and what the future holds for treatments based on the microbiome. Discover the latest developments in targeted probiotics, potential therapies for gut inflammation and how our gut bacteria can improve the effect of cancer drugs.
Introduction
Marcel de Zoete PhD is a researcher and associate professor at the Department of Medical Microbiology at UMC Utrecht. He has been researching the microbiome since 2011. “We are only now beginning to really understand the role the microbiome plays in a healthy life, and how it is involved in the development of diseases, such as colon cancer and Crohn’s disease,” he enthuses.
What have we learned so far from research on the microbiome?
“This research took off about 20 years ago. It was first still a part of general microbiology and became its own field in the 2000s. That seems like a long time ago, but in science that’s not a very long time. Until now, we have mainly studied what bacteria are in the intestines, and in other parts of the body. For example, on the skin and in the ears. We have collected an awful lot of information and gained important knowledge. Now we are at a tipping point.”
What exactly do you mean by that ‘tipping point’?
“By that I mean where we are now in microbiome research. Based on the knowledge we have gained, we can already predict a number of things in patients with Crohn’s disease and colon cancer. In those diseases, the microbiome plays an important role. But it is necessary to learn much more about the specific functions of the bacteria in the gut and their role in disease.
We already know that certain bacteria are more common in intestinal diseases, where is the exact role of these bacteria in causing them? What is the underlying mechanism? For example, are they responsible for producing harmful substances, breaking down the mucus layer in the gut, or attaching to intestinal cells? To find these answers, we are now conducting deeper research. This will allow us to take the next step: give these patients better treatments and start preventing the diseases.”
What is the microbiome?
In our intestines live countless bacteria, viruses and yeasts. All these microorganisms together are called the microbiome. It is as big and heavy as a hefty potato. The microbiome consists mainly of bacteria. In our intestines there are between 100 and 200 different species.
The microbiome has several functions. The gut bacteria act as a food processing plant, helping to break down fibers. They also have a protective role, making it less easy for dangerous bacteria such as Salmonella to settle in the gut. In addition, the microbiome supports the immune system in responding properly to pathogens.
The exact composition of gut bacteria varies from person to person. It depends, among other things, on what we eat and the bacteria we come into contact with. And there are many other factors that can affect the microbiome. As a result, everyone has a unique microbiome.
It is important that your microbiome consists of many different bacteria. Here’s how you can make sure of that. The amount of each type of bacteria can fluctuate greatly, for example, due to our diet. For example, people who eat vegetarian food have a significantly different microbiome than omnivores, with often more bacteria that break down vegetables.
How does the microbiome arise?
The microbiome begins to develop when a baby is born. Just before birth, there are no bacteria in the intestines, but that changes from the moment of delivery. This is when the baby first comes into contact with bacteria. It gets these from the mother. Then the baby ingests more bacteria, through drinking milk and touching other people. These bacteria multiply at lightning speed, so the baby’s gut is full of bacteria just a few days after birth. Thus, the microbiome begins to form and continues to develop throughout life. This is influenced by things like the environment, the food you are fed and how healthy you are and live.
In what diseases does the microbiome play a role?
The microbiome plays an important role in gastrointestinal diseases, such as Crohn’s disease, irritable bowel syndrome and colon cancer. The microbiome is also involved in type 2 diabetes.
In addition, links have been discovered between the microbiome and autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. It also seems to affect allergies, asthma and skin problems, such as acne and eczema. Cardiovascular disease may also be linked to our microbiome, as may some liver diseases, such as fatty liver.
Interestingly, our microbiome even seems to be linked to our mental health. Anxiety disorders, depression and other mental illnesses could possibly be influenced by the microorganisms in our bodies.
Do you see that tipping point reflected in your own line of research?
“Absolutely! In America, I developed a method to identify gut bacteria that can trigger an immune response. It works like this: when bacteria get too deep into the mucus layer of the gut, close to the intestinal cells, the immune system produces antibodies. Those antibodies can be able to “push” the bacteria back toward the intestinal tract, where they actually belong.
With my technique, I was able to see which bacteria have those antibodies on them. As it turns out, each person has about 5 types of these bacteria, and they vary from person to person. Because these bacteria trigger increased preparedness of our immune system, they are potentially dangerous, even though they are not direct pathogens. We also learned that people with certain intestinal diseases, such as irritable bowel syndrome, sometimes have different types of these bacteria in their gut than healthy people. Then we investigated many of these bacteria further. For example, we discovered a bacterium that is very good at breaking down the mucus layer of the intestine.”
What does your current research focus on?
“We are investigating the mechanisms of bacteria in the gut. So how exactly they work and how that contributes to disease and health. To take the bacteria that break down the mucus layer as an example: how does it do that? We also want to know about bacteria that destroy intestinal cells and secrete dangerous substances.
What makes it complicated is that there are many different types of bacteria and they don’t do the same things to everyone. Bacteria work together and can reinforce each other. Some bacteria can’t do much with the mucus layer themselves, but if another bacterium takes the first step in breaking it down, they can build on it. That interplay makes research challenging, but also very interesting.
In our molecular laboratory, we study bacteria at the level of DNA and proteins. We grow the bacteria in oxygen-free chambers, similar to the environment of the intestines in which there is also no oxygen. If we discover a mechanism that plays a role a disease, we see how we can translate that into a treatment. More and more drugs are being developed to inhibit specific bacteria. Such as very specific antibiotics, inhibitors of certain bacterial proteins and viruses that attack bacteria.”
Recently, the first microbiome product became available: a therapy for people with severe bacterial intestinal inflammation.
What do you think of this drug?
“This new product is actually a pill containing bacteria from feces. The pill contains good bacteria that can reduce the bad bacteria in the gut. In this case, the bad bacteria are the Clostridium difficile bacteria, which produce a lot of toxins and cause intestinal inflammation. People who have taken a lot of antibiotics may suffer from an overgrowth of C. difficile, which can disrupt their entire microbiome. The drug contains different types of bacteria taken from the stool of healthy people, cleaned and made into pills. It is a form of targeted probiotics. Probiotics are bacteria with a positive effect on health that we can add to the microbiome.
“There are more and more customized microbiome products coming. In the future, patients first test whether such a product is right for them.”
The makers have researched well how it works and which patients can benefit from it. This is a big difference from supermarket probiotic drinks, which are very general and have no lasting effect, if any at all. However, this new product is not yet customized. Because everyone’s microbiome is different, in the future you would actually want a specific product for each patient. Nevertheless, this is a wonderful development in my field.”
What other drugs based on the microbiome are currently in development?
“Work is currently underway on microbiome products that could help with certain cancer drugs. These drugs, called checkpoint inhibitors, make the immune system work harder to attack cancer cells. The microbiome plays a role in this, although we don’t yet understand exactly how it works. One thought is that certain bacteria in the gut may enhance the immune system’s response. If we can get the right bacteria into the gut at the right time, this cancer treatment could work better.
Not all patients benefit from checkpoint inhibitors; it only works in a subset of people with cancer. So the microbiome may play a role here. Currently, several research groups around the world are working on microbiome products that can enhance the effect of checkpoint inhibitors. These developments are still in the early stages, but are moving quite rapidly. I can so imagine that in the future patients could be given a bacterial shot a week before their cancer treatment to make their checkpoint inhibitor work better.
We do have to realize that this product, too, is not yet personalized. Not all microbiome products will work for everyone. We do aim for customized microbiome products, where we first test which product is best for whom. We can do that, for example, by sequencing the microbiome.”
What is that, sequencing the microbiome, and what can you do with it?
“Sequencing allows us to find out the composition of the microbiome in someone’s intestines, i.e. exactly which bacteria are present there. It’s like a picture of what’s in the gut at that moment. We can see what bacteria are there and in what percentages they occur. So we are taking a snapshot. It also makes sense to track changes over time to see if the microbiome is “fluctuating.
We are currently sequencing patients who are participating in scientific studies and are receiving a new treatment for an intestinal disease, such as Crohn’s disease or ulcerative colitis. We are comparing the differences between these patients and healthy people. That’s how we gain more insight. Sequencing can also help in better understanding these diseases, for example, by determining which bacteria and proteins play an active role. We are trying to discover which bacteria and factors we want precisely not to have in the gut.”
Do you also work with industry?
“Yes we do, and I also think it’s very important that we do. After all, we want to be able to apply our research results in practice as well as possible. At UMC Utrecht, patient care comes first, and we need companies to convert our discoveries into products that can help patients. Companies have a lot of expertise in bringing products to market and are increasingly doing good basic research. That’s why it’s important to collaborate with industry early on. That way we can make progress together.”
How can people themselves take good care of their own microbiome?
“It is important to have a diverse microbiome. By that I mean that there are many different types of bacteria in your gut. You achieve that by eating a healthy and varied diet and with a healthy lifestyle: regular exercise and not drinking too much alcohol.
We have to be careful with antibiotics. If it is not necessary, it is better not to take it. Antibiotics kill both bad and good bacteria and cause chaos in your gut. It is also wise not to eat too much red meat because it increases the risk of colon cancer. Drinking probiotic drinks from the supermarket also does not currently contribute much to good gut health.
Eating vegetables is very good, because of the fiber in them. Healthy bacteria in your gut love fiber, and convert it into a certain substance called butyrate, which in turn is very healthy for our gut.”
