Groningen, The Netherlands
Our 'Meet the Researchers' initiative is where we give you the opportunity to meet researchers from key centres around the globe. They are working hard to find answers to the questions you want answered, and so that one day no life is limited by gluten.
Our first week in focus featured the super enthusiastic team in the Genetics Department of the University Hospital in Groningen, the Netherlands. Below you can find links to members of the team.
Principal scientific investigators working to understand how our genetic code—our DNA—contributes to our risk of developing coeliac disease.
PhD students working to improve the resolution at which we can pin point the DNA building blocks that contribute to coeliac disease.
Postdoc researcher exploring the causal genes for coeliac disease.
PhD students using Gut-on-Chip technology to study coeliac disease.
Postdoctoral researcher studying the role of gut bacteria—the gut microbiome—in coeliac disease. A member of the Netherlands Organ-on-Chip Initiative (NOCI).
Some of the team in Groningen are funded by the Jebsen Coeliac Disease Research Centre (JCoDiRC), Norway, led by Professor Ludvig Sollid. Our Research Manager, Heidi Urwin, is on the patient advisory council of the JCoDiRC and during the annual retreat is where she had the chance to personally meet the researchers and learn about their great work.
Frequently Asked Questions
I’m sure like most people, I am really interested in the why? Why have I suddenly got coeliac disease - I’m 41 and very recently diagnosed. I have read that you can be born with the coeliac gene, so firstly is this true? And secondly, I’ve read that things like heavy stress on the body and pregnancy can trigger the autoimmune response, is this also true?
Many people are born with genes that can increase the risk for coeliac disease. However, this does not mean that they go on to develop the disease. Other factors outside of the genetics of a person could also play a role. Unfortunately, there is not a lot known about the factors other than genes that could trigger or increase risk of getting coeliac disease.
So, increased levels of stress or childbirth could potentially play a role, but there is no scientific evidence that supports this. A lot of groups are trying to understand the factors other than genetics that play a role, so hopefully we will know more in the future.
I would like to know why all three of my young children have coeliac disease via my husband but none of his nieces or nephews have been diagnosed even though they have parents and grandparents with coeliac disease? Also what is the chance of them going on to develop another autoimmune disease as my middle daughter has continued having problems? And finally, do we have specialist coeliac research teams here in the UK?
Although coeliac disease is clearly in part a genetic disease, genetics alone is not enough to explain why one person gets coeliac disease and another does not. Even in genetically identical people, monozygotic twins, one twin can have coeliac disease and the other may not. Other factors from our environment may also play a role, and these could be different for each person as well. What these factors are is still mostly unclear, so we're unfortunately not able to reduce the risk of getting coeliac disease yet.
With regards to your second question: the chances for getting other immune related diseases in coeliac disease patients are indeed increased. Examples are autoimmune thyroid disease and type 1 diabetes, but there are others as well. The exact chances of developing another autoimmune disease are hard to estimate and differ greatly for different autoimmune diseases, so unfortunately, I can't give you a very clear answer.
Yes, there are researchers in the UK exploring coeliac disease too. Coeliac UK funded researcher, Professor David van Heel also looked into the genetic variants for coeliac disease, you can read about this research on the website. Interestingly, he collaborated with the team at Groningen. More recently, Professor Ramesh Arasaradnam completed a Coeliac UK project exploring the microbiome - find out more information on this project here.
Is anyone working on a pill we can take after being 'glutened' to minimise the awful effects?
Francisco Leon gave an excellent talk at our 2019 Research Conference, summarising therapeutics in development for people with coeliac disease.
Will there be any research undertaken concerning type 3 Bile Acid Diarrhoea (BAD)/Bile Acid Malabsorption (BAM) that is associated with coeliac disease?
I'm unaware of any current research of type 3 Bile Acid Diarrhoea (BAD)/Bile Acid Malabsorption (BAM) in relation to coeliac disease. There is an increased prevalence of Primary biliary cholangitis, which is also an autoimmune disease, in coeliac disease patients. In Primary biliary cholangitis, bile ducts in the liver are damaged causing problems with bile build-up in the liver. There are genetic risk factors that are shared between coeliac disease and Primary biliary cholangitis, but it is unclear what the direct link between the two diseases is.
Could genetics explain why some people develop neurological conditions and others don't and if so is this something that is being looked at?
Unfortunately, we don't know why some coeliac patients develop gluten ataxia and other neurological symptoms. It seems that the antibodies that are produced in the gut in response to gluten can sometimes travel to the brain or nervous system and cause damage there. We are learning more and more that there is a connection between the gut and the brain (called the gut-brain-axis), however research is still studying the basics of this connection. It's not clear how the gut-brain-axis is affected in coeliac patients and if the patients genetic background could affect this. What we want to do in the future is link the gut-on-chip to a brain-on-chip and see if we can model the coeliac disease specific gut-brain-axis. However, we are not there yet and anticipate that this will take some years to set up.
How did Gut-on-Chip come about?
Coeliac disease is a complex disease in which multiple tissues and cell types are involved. Examples of these are epithelial cells of the small intestine, different types of immune cells, and even the microorganisms in the gut (the microbiome). Until recently, it was not possible to grow these tissues together in one experimental setting, so studying the interplay between all these tissues in a coeliac disease model was not possible.
With organ-on-a-chip technology, we now are able to use patient cells, to genetically reprogram them to a very primitive cell type (induced pluripotent stem cell (iPSC) technology) and to differentiate these cells into different cell types including so-called human intestinal organoid cells which basically are similar to the epithelial cells that make up the lining of the intestine (’the epithelial barrier’).
We can seed these cells on a microfluidic chip (a ‘mini-gut) and seed this system with the patient's immune cells and patient-derived microbiota. Because we can circulate growth factors through this system we can now keep these cells alive and interacting for weeks, allowing the study of disease associated processes.
I had a negative blood test, no antibodies, but when I went to the hospital for a biopsy they found the damage and I was diagnosed with coeliac disease. Could my genetics be different to someone who did have antibodies?
This could potentially be the case. However, how your genetics may be different is not clear. We don't know which genes are critical in coeliac disease patients for producing the antibodies and why the levels of these antibodies can be different in each person. The immune system is highly variable amongst individuals, regardless of whether you have coeliac disease or not. Moreover, factors other than genetics could also contribute to the variation in antibodies in coeliac patients.
Are there any genes that predispose people to associated coeliac conditions like type 1 diabetes and thyroid disorders? And might this enable us to predict who might develop these? Also, are there any specific genes associated with Dermatitis herpetiformis and does that tell us why some people develop this coeliac condition?
We know that about 30% of all the genetic regions in the genome that are linked to coeliac disease are also linked to other autoimmune diseases, and that this overlap is especially large for type 1 diabetes. We are really interested in finding out what these regions do exactly, and hope in that way to find out what the shared disease mechanism between type 1 diabetes and coeliac disease is. This would help us predict who is more likely to develop both in the future, but unfortunately, we are not there yet.
As for Dermatitis herpetiformis (DH), we are not really sure why DH happens in some coeliac patients. Unlike other autoimmune diseases, we don’t know the genetic link behind DH, so it’s hard for us to understand how some individuals get DH and others don’t.
When working with the Gut-on-Chip, does it matter if you take cells from the urine or blood of people newly diagnosed with coeliac disease and not on a gluten free diet or people who have been diagnosed for a long time and are on a strict gluten free diet? Would the model work the same or differently?
We don't think that the origin of the cells used to make the gut-on-chip matters very much, but we are still working on making the comparisons at a molecular level. The science behind this is fairly new, so there are many things to learn. We don't think that the time of diagnosis or diet has a great direct effect on how the gut-on-chip behaves after extracting cells from these patients and 'converting' them to the gut-on-chip. However, we do think that the genes of patients may have an effect. Not all coeliac patients have the same genetic background, so some patients may have a genetic background that acts on the gut barrier more strongly. This we also hope to measure with the gut-on-chip by extracting cells from patients with different genetic backgrounds. These differences are of great interest to us!
I've had coeliac disease since I was 6 years old - could the research looking at causal genes explain why I developed coeliac disease as a child but others developed it when they are adults?
Very good question, and definitely something we would also like to know. We do think that there may be a link between the age of getting coeliac disease and the genetic risk an individual has. For example, children with 2HLA-DQ2 genes have a higher risk, and are often diagnosed earlier in life than children with just one HLA-DQ2 or HLA-DQ8. However, it is unclear if other genes may be important for age of onset. Also, many other factors that are not in our genes may also affect when someone could get coeliac disease, so even when a person has a relatively high risk for coeliac disease based on their genetics, they still may not get the disease, early or later in life.
What research is being done on the link with ulcerative colitis ?
Because ulcerative colitis (UC) is also an autoimmune disease, we do look into the similarities between the two, to help understand both. The genetic overlap between UC and coeliac disease is a lot smaller than the overlap between type 1 diabetes and coeliac disease though, so we think they are less alike from a genetic perspective.
My brother was diagnosed with coeliac disease after having terrible gut issues and anaemia. I didn’t have any symptoms but was screened as a family member, surprisingly I was also diagnosed with coeliac disease. Although we are related could differences in genes explain why he had symptoms and I didn’t?
That is very well possible, especially if you are not identical twins, you would still be genetically different from your brother (although more similar than to your next-door neighbour). However, it is not only genetics that drives coeliac disease. Also environmental factors appear to be involved, for instance it has been hypothesised that certain intestinal infections contribute to triggering the disease or make the symptoms more serious. It could very well be that your brother was exposed to one of those environmental factors while you were not, or that you respond differently to these environmental factors because of the genetic differences that still exist.
Is it true that coeliac disease can come about after a childhood illness?
There are some indications that a viral infection, like for example a common cold, could help trigger coeliac disease. It's unclear how strong the effect of a viral infection on coeliac disease onset would be, or how the infection may increase someone's chances of getting coeliac disease. We think it has a small effect at most, because many people don't get diagnosed with coeliac disease until much later in life, when they have encountered many common colds already. Other factors, including genetics or other things that you may encounter in your surroundings, are also likely to play a role. Several groups are trying to understand the link between viral infections, and other environmental factors and coeliac disease.
Are you aware of any large-scale genomic/transcriptomic datasets from coeliac patients which have been published/analysed and uncovered risk genes for coeliac disease/mechanism of action for their dysregulated immune response? Would be interesting to get access to such datasets or see findings.
Our department, with Cisca Wijmenga and David van Heel as lead scientists have performed the largest genetic screen for coeliac disease, including roughly 14,000 coeliac patients and 14,000 non-coeliacs. Most, if not all our knowledge about the role of genetics in coeliac disease comes from this work. We are now in the process of expanding on this by trying to understand the processes on which the genetics associated with coeliac disease have effects. We are using large datasets with RNAseq from blood and cohorts of both the general population and coeliac disease patients. For more details on the role of genetics in coeliac disease, you can have a look at our review published in Trends in Genetics in 2016.
What attracted you to this area of research?
I love looking at the nitty gritty of how DNA interacts with processes in cells and humans. So when I was offered to work on this and answer questions that are related to coeliac disease, I jumped at the opportunity. I am really happy that I can work on a disease that impacts so many people and help understanding it and, hopefully, improve the life of patients and their family in the future.
Are there other disorders/diseases associated with the coeliac gene variants?
Some of the coeliac gene variants are shared with other autoimmune diseases like type 1 diabetes, multiple sclerosis and others. So some of the disease mechanisms may be shared between all these diseases.
I have family members with coeliac disease would I reduce my risk of developing coeliac disease if I had probiotics?
Right now, we don’t know which microbiota have an effect on your chances of getting coeliac disease. However, we and others are actively trying to find the bacteria that have an effect. When we know that, we might be able to give probiotics that help protect you against coeliac disease when you have a high genetic risk and have family members with coeliac disease. To us, that would be the ultimate treatment, prevention is always better than a cure and probiotics is generally considered to be a mild intervention. However, this is unfortunately not possible yet, and may take years to develop.
My Father had coeliac disease and so does my brother (he is my only brother/sister) and also my eldest son is has coeliac disease but my daughter and other son do not. Is your research looking at why this is sporadic?
Genetics, so what you inherit from your father and give to your children, only accounts for some of the risk of getting coeliac disease. So even in monozygotic twins that have identical DNA, one may develop coeliac disease and the other not. Your family members have far less shared DNA, than in the case of identical twins, so the chances of getting coeliac disease in family members may differ based on their genetic background. Moreover, other factors that are not in the DNA are also thought to play a big role in getting the disease.
These factors are not very well known yet, but we think that some virus infections or the gut microbiota may play a role. We need to learn a lot more about these factors from our DNA and our surroundings to be able to understand why one family member gets coeliac disease and the other does not, but we are working on it!
Do you believe there is any benefit to screening for coeliac-related genes to identify individuals who may be susceptible (e.g. in relatives of those with diagnosed coeliac disease?)
The most important coeliac genes, HLA-DQ2 and HLA-DQ8 are not very useful to diagnose people for coeliac disease, but are only used to exclude a coeliac disease diagnosis. The other genes all play a much smaller role in coeliac disease, so including these genes one by one in tests is unlikely to help in identifying susceptible people. However, genetics is moving fast and new methods are being developed that use the complete genetics of an individual to predict how much risk they have for certain diseases. This is something we are also working on and we hope that this may give us a better predictive power to see who is susceptible and who is not in the future.