Crohn’s disease: new therapies from the “mini-intestine” grown in the laboratory

Cambridge scientists have developed ‘mini-guts’ in the laboratory to help understand the Crohn’s diseaseshowing that “switches” that change DNA in intestinal cells play an important role in the disease and how it presents in patients.

New perspectives for the treatment of Crohn’s disease

The researchers say these mini-guts could in future be used to identify the best treatment for an individual patient, allowing for more precise and personalized treatments.

Crohn’s disease is a form of inflammatory bowel disease (IBD). It is a lifelong condition characterized by inflammation of the digestive tract affecting around one in 350 people in the UK, with one in four people presenting before the age of 18. Even in its mildest form, it can cause symptoms that have a major impact on quality of life, including stomach pain, diarrhea, weight loss and fatigue, but can also lead to extensive surgery, hospital admissions, exposure to toxic drugs and have a notable impact on patients and their families.

Although there is evidence that an individual is at greater risk of developing the condition if a first-degree relative has Crohn’s disease, success in identifying genetic risk factors has been limited. As a result, it is estimated that only 10% of heredity is due to variations in our DNA.

Matthias Zilbauer, Professor of Pediatric Gastroenterology at the University of Cambridge and Cambridge University Hospital NHS Foundation Trust (CUH), said: “The number of cases of Crohn’s disease and IBD is increasing dramatically around the world , particularly among younger children, but despite decades of research, no one knows what causes it. Part of the problem is that it has been difficult to model the disease. We’ve had to rely mostly on studies in mice, but these are limited in what they can tell us about the disease in people.”

In research published on Gut , Professor Zilbauer and colleagues used cells from inflamed intestines, donated by 160 patients, mainly patients and adolescents, to CUH to grow more than 300 mini-intestines, known as organoids, in the laboratory to help them better understand the mechanism. condition. Samples were donated from patients with Crohn’s disease and ulcerative colitis, as well as from non-IBD patients.

“The organoids we have generated are mainly from children and adolescents,” said Professor Zilbauer. “They basically gave us pieces of their intestines to help us with our research. Crohn’s disease can be a serious disease to deal with at any age, but without the courage and support of our volunteers, we would not be able to make such discoveries as this.”

Organoids are 3D cell cultures that mimic the key functions of a particular organ, in this case the epithelium, the lining of the intestine. The researchers grew them from specific cells, known as stem cells, taken from the intestine.

Stem cells live forever in the intestine, constantly dividing and allowing the intestinal epithelium to regenerate.

Using these organoids, they demonstrated that epithelia in the intestines of Crohn’s disease patients have different “epigenetic” patterns on their DNA than those of healthy controls. Epigenetics is where our DNA is modified by “switches” attached to our DNA that turn genes on and off – or increase or decrease their activity – leaving the DNA itself intact, but changing how it works a cell.

Professor Zilbauer, a researcher at the University of Cambridge’s Stem Cell Institute, 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. Each patient’s disease course is different, and these changes help explain why: not all organoids had the same epigenetic changes.”

The researchers say the organoids could be used to develop and test new treatments, to see how effective they are on the lining of the gut in Crohn’s disease. It also opens up the possibility of personalizing treatments for individual patients.

Co-author Dr Robert Heuschkel, consultant pediatric gastroenterologist at CUH and head of the pediatric IBD service, said: “At the moment, we have no way of knowing which treatment will work best for a patient. Even the treatments we currently have only work in about half of our patients and become less effective over time. It’s a huge problem.

“In the future, you could imagine taking cells from a particular patient, growing their organoid, testing different drugs on the organoid, and saying, ‘OK, this is the drug that works for this person.’”

Research has highlighted a specific pathway implicated in Crohn’s disease, known as major histocompatibility complex (MHC)-I. This pathway allows immune cells to recognize antigens, which is a toxin or other foreign substance that induces an immune response in the body and which could include molecules in our food or our gut microbiota.

The team showed that cells that form the inner lining of the intestine in Crohn’s disease patients have increased MHC-I activity, which can lead to inflammation in specific parts of the intestine.

“This is the first time that anyone has managed to demonstrate that stable epigenetic changes can explain what is wrong with the intestinal epithelium in patients with Crohn’s disease,” Professor Zilbauer said.

The epigenetic changes were found to be very stable, which could explain why even after treatment, when a patient appears to be cured, the inflammation can return after several months: the drugs treat the symptoms, not the underlying cause.

Epigenetic changes are programmed into our cells very early during the baby’s development in the womb. They are influenced by environmental factors, which may include exposure to infections or antibiotics, or even lack of exposure to infections, the so-called “hygiene hypothesis” that holds that we are not exposed to enough microbes for our immune systems to develop properly.

The researchers say this could offer a possible explanation for how the epigenetic changes that lead to Crohn’s disease occur.

The research was largely supported by the Medical Research Council. It was also supported through collaboration with the Milner Therapeutics Institute, University of Cambridge.

Cambridge Enterprise is working with Professor Zilbauer and his team and has recently filed a patent for this technology. They are looking for business partners to assist in the development of this opportunity.