Iris Jonkers and Sebo Withoff
Hi! We are Iris Jonkers and Sebo Withoff, principal scientific investigators in the Genetics Department of the University Hospital in Groningen, the Netherlands. Together with an excellent group of technicians, doctors, PhD students and postdocs, we are working to try to understand how our genetic code—our DNA—contributes to our risk of developing coeliac disease and the issues that follow.
Our department has a long history of genetic research into coeliac disease, which was spearheaded by Cisca Wijmenga. She and her team performed the first large genetic screen in patients with coeliac disease and identified regions in our genetic code that are more often present in people with the condition and therefore linked to coeliac disease. Now we are trying to understand more precisely how these regions play a role using several different approaches.
Genetic building blocks
Pinpointing the precise genetic building blocks in the regions linked to coeliac disease will make it easier to use the genetic code as a diagnostic tool and to better predict which genes play a role in the disease. However, this is not an easy task. There are over three billion building blocks in our DNA, and thousands of these may play a direct role in coeliac disease. Identifying which ones and their specific effects is the research area of Roeland Broekema and Olivier Bakker. They use large genetic screens to pinpoint the exact building blocks that play a role.
Next, it is very important to understand which genes are affected by the genetic building blocks linked to coeliac disease. These genes drive processes important for coeliac disease. For example, the HLA genes present on our immune cells bind gluten, which triggers inflammation of the small intestine in people with coeliac disease. However, it is not just HLA, but also other genes that our group have linked to coeliac disease that can play a role in this inflammation process. So, investigating linked genes can inform us about the processes that cause the damage to the small intestine after eating gluten. Chan Li, a postdoc in our group is leading our efforts to understand the role of the many genes linked to coeliac disease in these inflammation processes.
While many genes linked to coeliac disease seem to play a role in immune and inflammation processes, we have also identified genes that seem to play a role in the small intestine itself. We think that these genes make the gut of a person with coeliac disease more sensitive to gluten peptides, allowing them to more easily penetrate the gut barrier and trigger inflammation. For now, this is mainly a proposed explanation ie a hypothesis and we are working hard to prove this. In order to do so, we need a good model system that reflects the small intestinal barrier of a person with coeliac disease as accurately as possible. Renee Moerkens and Joram Mooiweer are working hard to make such a model and are generating a miniature living ‘gut-on-a-chip’ from cells of coeliac patients. We are really excited about this, even to us it seems almost science fiction!
With this model, Renee and Joram hope to investigate the genes linked to coeliac disease that we think play a role in the integrity of the small intestine. However, we also want to expand this model by introducing the immune cells that play a role in inflammation of the small intestine of people with coeliac disease. This will give us the opportunity to see how intestinal cells and immune cells respond to each other under the same conditions we see in people with coeliac disease. By also changing the genes linked to coeliac disease in this system, we will be able to directly measure how genes affect the process that leads to the deterioration of the small intestine.
The gut microbiome
Finally, it is not only genes but also factors in our environment that may play a role in coeliac disease. One of these environmental factors is the bacteria that live in our gut, our microbiome. Jelle Slager is exploring the microbiome in faecal samples donated by people with coeliac disease, living in the Netherlands. Jelle is looking to see if there are unique bacteria that may cause or worsen coeliac disease. Next, he will try to grow these bacteria in the lab and introduce them into the ‘gut-on-a-chip’ so that we can see how the bacteria may change the intestine.
Our genetic code plays an important role in coeliac disease, which is why we use the building blocks of DNA and genes as the starting point to understand this disease better. This will not only lead to a better understanding of the disease mechanisms, it may also pinpoint how we can target these mechanisms to treat coeliac disease in patients who do not respond to a gluten free diet. Moreover, we hope that coeliac disease may be a preventable disease in the future. By identifying the people who are most at risk for coeliac disease, based on their genetic code and the environmental factors that they may be exposed to, we can try to intervene and change the environmental factors before coeliac disease initiates. One such environmental factor could be the microbiome, but others may exist. With our Dutch coeliac disease cohort and other large cohorts of healthy individuals, we will search for both genetic and environmental factors and investigate their role in coeliac disease.
This work could not be done without the financial support of the Dutch Research Council, the European Research Council, Stiftelsen KG Jebsen and the Netherlands Organ on Chip Initiative. But, most of all, we are extremely grateful for the help of the many people with coeliac disease who have donated samples of their faeces, blood and intestine, as well as their time and enthusiasm.