In the simplest terms, health is the sum total of the effect of genes, behaviour, and surroundings. But of course we can’t just change our genes. So, if we want to avoid getting ill, it’s more productive to consider our behaviour and our surroundings as they are the things we can influence. Ghent University, KU Leuven, the University of Antwerp and Hasselt University are pooling their expertise in the first large scale ‘exposome’ research project in Flanders.
Thanks to the mapping of the human genome, the ‘handbook’ of human genetics, scientists now have a better insight into genetic disorders, and this has led to a number of new treatments. At the same time, researchers have realised that it is not possible to explain all disorders as the result of genetic factors. Our behaviour (how often we exercise, what we eat, and how much stress we experience) and the surrounding environment (including air quality and allergens alongside the positive impact of green surroundings) have an impact on our health. The same is true of the micro-organisms that live inside our bodies, and the processes that take place inside us.
Researchers call the combination of all these non-genetic factors the ‘exposome’, and together with your genome, this decides whether you will get ill or stay healthy. “The genome and exposome are very closely linked to one another,” explains Sarah De Saeger (UGent), nutrition expert and coordinator of the Flemish Exposome Project. “For example, you might be genetically predisposed to develop a certain cancer, however it’s your exposome that determines whether you get ill, when, and to what extent. The exposome is therefore maybe even more interesting than the genome in terms of preventative medicine. For, unlike our genome, our exposome is something we can actually influence. We can change our behaviour and also many environmental factors, and thereby reduce the risk of certain disorders.”
Of course to do this, you first need to know which environmental factors have an impact on our health, and to what extent. Thanks to iBOF (a new interuniversity source of funding, eds.), researchers from the universities of Ghent, Antwerp, Hasselt and Leuven will therefore work together in the coming years to map as many as possible of these crucial environmental factors. “We are looking into the big wide world outside our bodies as well as the microworld inside us, and we do this in relation to the whole life span, from foetuses to seniors. This is a unique approach”, explains De Saeger. In the past, researchers often investigated one specific chemical substance and its impact on one disease. Now, we are approaching this from three different perspectives: external pollutants, processes in our body, and genetics.”
The link between our surroundings and our health
The aim of the Flemish Exposome project in the first place is to collect new insights into the impact of environmental factors on the development of intestine-related disorders, including diabetes, obesity, metabolic syndrome, food allergies, and gastrointestinal cancers. De Saeger tells us: “The project brings together two cohort studies (scientific studies which follow one group of people over a long period) along with partners who collect additional data on environmental factors. The Limburg Birth Cohort study, run by environmental epidemiologist Tim Nawrot (Hasselt University) follows children from birth. The researchers take a sample of blood from the umbilical cord at birth, and also store the placenta. This allows them to determine the extent to which the baby has been exposed, for example, to soot particles from air pollution, even before birth. The other cohort study, the Flemish Gut Flora Project, is based at KU Leuven. Here, the research group headed by microbiologist Jeroen Raes is mapping the bacteria that live in our gut (the microbiome). They are also looking for possible links between disturbances to our gut flora and different diseases.”
The samples from both cohorts are then analysed in the labs of the other partner organisations. Toxicologist Adrian Covaci (University of Antwerp) is researching plastic-related pollutants or pesticides which end up in our bodies through our food or dust.
As for Sarah De Saeger herself, she focuses on mycotoxins, poisonous substances that are produced by fungi that unintentionally end up in our foods. Finally, bio-engineer Lynn Vanhaecke (Ghent University) is studying what impact these substances have on our metabolism, microbiome and DNA.
Sarah De Saeger: “After we have mapped the presence of environmental factors, we switch from ‘wet’ lab work to the ‘dry’ research: processing and interpreting all the data we collected. In this way we want to finally identify factors which are different in people who are ill from those who are healthy. For example, it is possible we will see that people who get a lot of mycotoxins through their food, and who do enough exercise, but who are also exposed to polluted air, more often develop a certain food allergy. These are thus correlations, and not relationships of cause-and-effect. Yet these links can be the starting point for new insights and in the end they can lead to research into new treatments or preventative methods.
Tools for prevention
De Saeger believes the Flemish Exposome Project can develop a set of biomarkers for doctors to refer to when they are making a diagnosis. “These biomarkers can set off alarm bells, like: Watch out! This patient has levels of the same biomarker(s) comparable to that of patients with type 2 diabetes, but they can possibly avoid getting the disease if they adapt their lifestyle in a particular way.” The research can also form a basis for types of preventative advice. “For example, it’s possible we might discover that the limit for mycotoxins in food needs to be lowered even further. Policy makers can thus base their decisions on this. The same is true for factors like air quality, social cohesion, green zones in residential areas, healthy food and physical exercise. The ultimate goal is for everyone to be able to enjoy a ‘healthy’ exposome, which reduces the chance of our getting ill.”
The research team led by nutrition expert Sarah De Saeger at Ghent University focuses on mycotoxins, toxic substances in our food that originate in fungi. “It isn’t just a question of the mouldy apple in your fruit bowl. It already begins in the field. For example, there are fungi that grow on wheat and there they start to produce mycotoxins in order to protect themselves against insects. These toxic substances also end up in our food, for example in bread. They are very stable chemical substances, similar to pesticides. In large doses, they weaken our immune system and can even cause cancer.” However, this doesn’t mean you have to throw your bread straight in the bin. “Our food undergoes very strict checks. Unlike in some developing countries, you don’t face any risk of acute mycotoxin-poisoning here. At the same time, we don't know enough about the possible effects of a long-term intake of low doses.” De Saeger and De Boevre are measuring levels of mycotoxins in urine and blood, and will also do this for the samples that come from the Flemish Exposome Project. “We also want to link the mycotoxins to the microbiome. We know that the bacteria in our intestines convert mycotoxins into other substances, but it is not clear whether they get turned into substances that are less or more harmful.”
While Adrian Covaci and Sarah De Saeger are mapping environmental factors from the ‘outside world’, bio-engineer Lynn Vanhaecke is diving into the world in miniature inside the body. She and her colleagues are studying the impact on our health of metabolites, the end products of molecular processes in the body. “We want to chart all of the metabolites which are present in the body. Amongst other sources, these come from the breakdown of nutrients and the microbiome, and are the end point of what we call the ‘biological cascade’. Metabolites have the closest connection to our bodies. As a result, they are also involved in the development of disease.”
Vanhaeke will examine samples of stool, urine, saliva and tissue from the cohort studies in Leuven and Hasselt. “We don’t identify any individual metabolites, but we make an all-inclusive ‘metabolic fingerprint’. In a stool sample, for example, we can find up to twenty thousand metabolites. All of these substances together form a kind of fingerprint that we want to link to food allergies, obesity and diabetes, amongst other things. We are focusing on ‘foreign molecules’ and how these are linked to the onset of disease. We also observe the relation between the metabolic fingerprint with that of the microbiome and pollutants.”
Lynn Vanhaecke is also researching how our DNA reacts to chemical substances. “We are studying which pollutants can attach to our DNA, and what changes or damage they cause through this. We know, for example, that mycotoxins cause damage to DNA. Our body defends itself against this, but if the damage keeps accumulating then it can suddenly become irreparable, causing cancer to develop. We hope that gaining a better insight into the molecular processes can lead to better treatments or methods of prevention. For example, it is quite possible that favourable environmental factors, such as green surroundings or a healthy diet, can promote the repair of molecular damage.”
The Limburg Birth Cohort study run by environment-epidemiologist Tim Nawrot (Hasselt University) follows children from when they are born. The researchers take a sample of blood from the umbilical cord at birth, and also store the placenta. This allows them to determine to what extent the baby has been exposed, for example, to soot particles from air pollution, even before birth. “The chemical substances that a pregnant woman is exposed to through air or diet also have an impact on the foetus. We can see this, for example, from the telomeres, the protective caps on the ends of the chromosomes. There is a link between the length of the telomeres and aging: each time a cell divides, the telomeres get slightly shorter. Cells with shorter telomeres have fewer divisions left and therefore have a shorter life expectancy.”
Until a few years ago, telomeres were only researched in old age, in order to investigate links between diseases of aging. Tim Nawrot demonstrated that telomeres have an effect on health and life expectancy much earlier, starting from day one. “One baby's telomeres can be shorter than another’s. This can be partly explained by genetics, but also by the environment. For example, a mother’s diet and weight during pregnancy have an impact, and also whether she has access to a forest or park. We also found that babies who had more exposure to air pollution during pregnancy have shorter telomeres at birth. So these babies actually have less of a buffer against aging.”
The Limburg Birth Cohort study already numbers over two thousand new-borns. The children are examined again when they are four, and their cardiovascular, cognitive and molecular markers are measured. The oldest children in the study are now ten years old. The researchers hope to be able to follow the children throughout their lives, as this is the only way to fully shed light on the impact of pregnancy on life expectancy. “I won’t be the professor anymore by then!” laughs Tim Nawrot. “But this kind of lifelong study would really be a first in science. Until now, no similar study has ever been carried out on humans. Scientists have done so on zebrafish. In that project, researchers saw that zebrafish that had longer telomeres when they were born lived to be six years old, whereas those with shorter telomeres only reached half that age. Presumably the same is also true of humans. For example, we see that the difference at birth in telomere length is also present at the age of four.”
The data and samples from the Limburg Birth Cohort study will now also be used for the Flemish Exposome Project. This collaboration should also result in new data. “In this way, researchers from the University of Antwerp will analyse which plastic-related pollutants (polluting substances such as phthalates, bisphenol A) have accumulated in the placentas in the Limburg biobank. Meanwhile, the research group headed by Jeroen Raes (KU Leuven) will be charting the children’s microbiome. On the other hand, we will analyse the urine of the participants in the Flemish Gut Flora Project for the presence of soot particles. We have developed a method which will enable us to determine an individual’s total level of exposure to air pollution.”
Professor Nawrot hopes that the results will keep motivating policy makers to work towards better air quality. “Thanks to our research, we know, for example, that the norms for air pollution should not be set on the basis of research conducted on healthy twenty-year-olds. The period of pregnancy and the early years of life are much more important. That is when the impact of air pollution is greater, because the organs of babies and young children are still in the middle of developing.
Everyone’s exposome is strictly personal, because no-one is exposed to exactly the same environmental factors as another person. Yet you share your unique exposome with billions of other creatures: the micro-organisms that live in and on your body. Scientists bundle these intimate inhabitants of our bodies together under the name ‘microbiome’. “In most cases, the micro-organisms are completely harmless,” says microbiologist Jeroen Raes (KU Leuven), who through his work with the Flemish Gut Flora Project has already charted around twenty thousand microbiomes. “In fact, we absolutely need our microbiome in order to stay healthy. You can almost see this like an extra organ that digests our food and optimises our immune system.”
According to Raes, the microbiome is also an important link between the exposome and health. “We know that the microbiome plays a role in processing nutrients and pollutants. At the same time, a microbiome’s composition can be linked to the development of intestinal-related disorders. The microbiome thus finds itself in the middle, but we don’t yet know for sure what role we can attribute to the micro-organisms. Do pollutants cause a disturbance of the microbiome, leading to the development of disorders of the intestines? Or does the composition of your microbiome determine the extent to which you are able to process harmful substances? We don’t know yet, and we therefore hope that the Flemish Exposome Project can offer some answers to these questions, amongst others.”
Toxicologist Adrian Covaci (University of Antwerp) studies plastic-related pollutants which end up in our bodies through our food or dust. These include known endocrine disruptors such as phthalates and bisphenol A, alongside chemical substances which have replaced banned substances and pesticides. Covaci also tests for exposure based on blood and urine samples. “For the Flemish Exposome Project, we will explore the extent to which children and adults from two cohort studies are exposed to harmful substances. We thereby hope to discover possible links with different conditions.” The research is presently in its initial phases. “A research project like this starts with a lot of practical questions: How many samples can we process per day? How do we manage transport? What substances do we want to measure? And how? Etcetera.”
In the first instance, Covaci wants to compare the results with those from the other studies. “This will help us see whether we are confirming the present insights or actually contradicting them. The large scale of the Flemish Exposome Project is unique. In the past, similar research projects were on a smaller scale. We hope that this larger research sample population will lead to more accurate findings, and stronger connections.”