Frequently Asked Questions Find everything you need to know about coeliac disease, the gluten free diet and the work we do.
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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.
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.