Why do some patients with Crohn’s disease still suffer from abdominal pain, even when their treatment is successful? With funding from the Helmsley Charitable Trust, researchers from Belgium and Sweden will spend the next three years examining the underlying mechanisms of this pain.
Approximately 3 out of 1000 people have Crohn’s disease, which is characterised by intestinal inflammation. Although treatment is available for this disease, not all patients benefit from it. Moreover, even when the treatment is successful, quite a few patients still suffer from abdominal pain.
Over the next three years, the labs of Professors Guy Boeckxstaens, Thierry Voet, Marc Ferrante, Séverine Vermeire (KU Leuven/University Hospitals Leuven) and Joakim Lundeberg (Science for Life Laboratory, Sweden) will be examining the underlying mechanisms of this pain. They will combine the use of human intestinal tissue with revolutionary technology to map the DNA and RNA material of single cells. The necessary funding will be provided by The Leona M. and Harry B. Helmsley Charitable Trust through its Gut Cell Atlas initiative.
Disease under control, but the pain remains
Although current medical therapies may be successful, a large group of patients with Crohn’s continue to experience abdominal pain. Scientists have no explanation for this phenomenon yet. Biomedical scientists at KU Leuven will now examine how enterochromaffin (EC) cells may contribute to abdominal pain.
EC cells are located in the mucous layer of the intestinal wall, where they release substances such as serotonin, which signal pain to the brain. Previous research examining the role of EC cells in irritable bowel syndrome found a link between an increased release of substances by EC cells and abdominal pain. Biomedical scientists at KU Leuven and the Science for Life Laboratory will now examine whether this is also the case in patients with Crohn’s disease, where things go wrong in EC cells, and whether it is possible to intervene in that process.
Macrophages as the target of new treatments for Crohn’s disease
In addition to looking for a new way to treat abdominal pain, the researchers also want to find a new way to tackle the intestinal inflammation that occurs in Crohn’s disease. Their focus will be on macrophages, specialised immune cells that play a crucial role in the intestines.
There are many types of macrophages. Professor Guy Boeckxstaens (TARGID unit at KU Leuven): "We’re going to examine which specific subgroup is linked to the intestinal nervous system, especially since we’ve recently discovered that intestinal nerve cells have an anti-inflammatory effect. Once we have identified the macrophages, we’re going to examine this interaction with the nervous system in greater detail. The final step will be looking for substances that we can use to mimic the interaction between macrophages and the nerves in the intestinal wall."
The researchers are hoping to gain more insight into anti-inflammatory mechanisms and to be able to pave the way for a new treatment for Crohn’s disease.
A race against the clock
What is remarkable about this project is that it will not involve any animal testing. Instead, the researchers will use human tissue. "This study will be carried out in close collaboration with Professor Ferrante from University Hospitals Leuven," says Professor Guy Boeckxstaens. "Patients who have to undergo intestinal biopsies or a colonoscopy anyway are asked whether they want to take part in our study." During the operation or endoscopy, a small sample of the intestinal tissue is collected for research purposes.
"That’s when the clock starts ticking," says Professor Boeckxstaens. "It’s a matter of getting the EC cells and macrophages to our lab as quickly as possible so that they are not affected by external circumstances. We want to be able to study them as they functioned in the intestines. Fortunately, the operating theatre is only a five-minute walk from our lab."
It’s a matter of getting the EC cells and macrophages to our lab as quickly as possible so that they are not affected by external circumstances. We want to be able to study them as they functioned in the intestines. Fortunately, the operating theatre is only a five-minute walk from our lab.
Professor Boeckxstaens’s team will be responsible for isolating the cells. Then, the samples will go to Professor Thierry Voet’s lab (Department of Human Genetics at KU Leuven), which will use single-cell-sequencing methods for RNA and DNA to map the properties of the cells and their environment.
Professor Thierry Voet: "This project is possible thanks to novel and ground-breaking techniques, which not only allow us to produce epigenetic and gene expression profiles of single cells, but also to chart how the cells are spatially organised in the human tissue. In this way we can identify and study the relevant cell populations as well as the intraand inter-cellular molecular processes that go awry in disease."
For the spatial analysis of tissue, the team will collaborate with Prof. Joakim Lundeberg (Science for Life Laboratory, Sweden). With all this cellular information, Professor Boeckxstaens’s lab will examine which cells have atypical characteristics and how they interact with the cells around them.
The project has received 3 million dollars in funding from the Helmsley Charitable Trust. The study is part of a collaborative initiative, the Gut Cell Atlas, which aims to map all cells in the gut, among the Translational Research in GastroIntestinal Disorders (TARGID) unit at KU Leuven (Professor Guy Boeckxstaens and Alexandre Denadai Souza), the Department of Human Genetics at KU Leuven (Professor Thierry Voet and postdocs Alejandro Sifrim and Katy Vandereyken), University Hospitals Leuven (Professor Marc Ferrante and Séverine Vermeire), and SciLifeLab Sweden (Joakim Lundeberg)