Cambridge scientists have grown ‘mini-guts’ to understand Crohn’s disease and better identify personalised treatment options.
Crohn’s disease is a form of inflammatory bowel disease (IBD). It is a life-long condition causing inflammation of the digestive tract and affects around one in 350 people in the UK. Some evidence indicates that an individual has a greater risk of this condition if a first-degree relative also has Crohn’s disease; however, there has been limited success in identifying genetic risk factors. As a result, it is estimated that only 10% of inheritance is due to variations in our DNA.
The lab-grown ‘mini-guts’ give an exclusive insight into ‘switches’ that modify DNA in gut cells and the important role these cells play in the disease.
Growing over 300 mini-guts to improve understanding
Professor Matthias Zilbauer and colleagues from the University of Cambridge used cells from inflamed guts donated by 160 patients to grow more than 300 mini-guts, known as organoids. The samples were donated by patients with Crohn’s disease and ulcerative colitis, as well as by patients unaffected by IBD.
“The organoids that we’ve generated are primarily from children and adolescents,” said Professor Zilbauer. “They’ve essentially given us pieces of their bowel to help with our research. Crohn’s can be a severe condition to have to deal with at any age.”
Organoids, or mini-guts, are 3D cell cultures that mimic key functions of a particular organ. In this study, researchers mimicked the epithelium, the gut lining. The researchers grew them from stem cells taken from the gut.
Using these organoids, they showed that the epithelia in the guts of Crohn’s disease patients have different ‘epigenetic’ patterns on their DNA compared to those from healthy controls. Epigenetics is where our DNA is modified by ‘switches’ attached to our DNA that turn genes on and off or up and down, leaving the DNA intact but changing how a cell functions.
Professor Zilbauer, a researcher at the Stem Cell Institute at the University of Cambridge, said: “What we saw was that not only were the epigenetic changes different in Crohn’s disease but there was a correlation between these changes and the severity of the disease. Every patient’s disease course is different, and these changes help explain why – i.e. not every organoid had the same epigenetic changes.”
New hope for personalised Crohn’s disease treatment
The researchers hope the organoids could be used to develop and test new treatments to see how effective they are for Crohn’s disease. It also means that tailored treatments for individual patients could be on the horizon.
Co-author Dr Robert Heuschkel, Consultant Paediatric Gastroenterologist at CUH and Lead of the Paediatric IBD Service said: “At the moment, we have no way of knowing which treatment will work best for a patient. Even those treatments we currently have only work in around half of our patients and become less effective over time. It’s a huge problem.”
What goes wrong in the gut lining of people with Crohn’s disease?
The research highlighted a specific pathway implicated in Crohn’s, known as major histocompatibility complex (MHC)-I. This pathway allows immune cells to recognise antigens that are toxins or other foreign substances that induce an immune response in the body. This could include molecules in our food or our gut microbiota.
The team showed that the cells forming in the inner gut lining in Crohn’s disease have increased activity of MHC-I, which can lead to inflammation in specific areas of the gut.
“This is the first time where anyone has been able to show that stable epigenetic changes can explain what is wrong in the gut epithelium in patients with Crohn’s disease,” said Professor Zilbauer.
The epigenetic modifications were stable, explaining why patients appear healed after treatment, however, their inflammation often returns after a few months. This indicates that the drug treats the symptoms but not the underlying cause.
Epigenetic changes are programmed into our cells during the development of babies in the womb. They are influenced by environmental factors, which may include exposure to infections or antibiotics or lack of exposure to infections. The researchers say this may offer one possible explanation for how the epigenetic changes that lead to Crohn’s disease occur in the first place.
