Researchers in Cambridge have cultivated ‘mini-guts’ in the laboratory in order to gain a better understanding of Crohn’s disease. This process has revealed that ‘switches’ that alter DNA in gut cells play a crucial role in the disease and its manifestation in patients.
Exposure to harmful medications can have a significant impact on patients and their families.
Research suggests that individuals with a first-degree relative who has Crohn’s disease may be at a higher risk of developing the condition, but identifying genetic risk factors has been challenging. It is estimated that only 10% of the risk of inheriting Crohn’s disease is attributed to genetic variations.
Matthias Zilbauer, a Professor of Paediatric Gastroenterology at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust (CUH), stated that the number of Crohn’s disease and IBD cases is increasing worldwide, especially among young people.Children’s Crohn’s disease remains a mystery, as its cause has yet to be determined despite years of research. The challenge lies in accurately modeling the disease, as previous studies have primarily relied on mouse models, which have limitations in providing insights into the human condition.”
“In a recent study published in Gut, Professor Zilbauer and his team utilized inflamed gut cells obtained from 160 patients, predominantly children and teenagers, at CUH. They successfully cultured over 300 mini-guts, also known as organoids, in the laboratory to gain a deeper understanding of the condition. These organoids were derived from samples donated by patients with Crohn’s disease and ulcerative colitis.
The organoids created for this research were primarily obtained from children and adolescents, who generously provided samples of their bowel for the study, according to Professor Zilbauer. He emphasized the bravery and support of the volunteers, without whom such discoveries would not be possible. Crohn’s disease can be a challenging condition to manage at any age.
These organoids are 3D cell cultures that imitate the essential functions of the gut’s lining, known as the epithelium. The researchers developed them from stem cells taken from the gut, which have the ability to regenerate indefinitely.
In the gut, the cells are constantly dividing in order to regenerate the gut epithelium. Organoids were used to study the differences in epigenetic patterns on DNA between Crohn’s disease patients and healthy controls. Epigenetics involves modifying DNA using “switches” that activate or deactivate genes, ultimately altering cell function. Professor Zilbauer, from the University of Cambridge’s Stem Cell Institute, observed distinct epigenetic patterns in the gut cells of Crohn’s disease patients compared to healthy individuals.The epigenetic changes observed in Crohn’s disease varied and were found to be linked to the disease’s severity. The individuality of each patient’s disease progression is evident in these changes, as not all organoids exhibited the same epigenetic alterations.”
The researchers suggest that the organoids could be utilized for the development and evaluation of new treatments, specifically to assess their effectiveness on the gut lining in Crohn’s disease. This development also raises the potential for personalized treatment options for patients.
Co-author Dr. Robert Heuschkel, a Consultant Paediatric Gastroenterologist at CUH and Lead of the Paediatric IBD Service.e, expressed concerns about the current lack of knowledge regarding which treatments are most effective for individual patients. They emphasized that even the existing treatments are only effective for approximately half of the patients and tend to lose their effectiveness over time. This poses a significant challenge. The speaker also mentioned the potential for future advancements in personalized medicine, where cells from a patient could be used to grow organoids for testing different drugs to determine the most effective treatment for that specific individual.
The study focused on a specific pathway related to Crohn’s disease, known as major histocompatibility complex (MHC)-I, which plays a role in allowing immune cells to recognize antigens, such as toxins or pathogens.The foreign substance that triggers an immune response in the body may include molecules found in our food or our gut microbiota. The researchers demonstrated that the cells that make up the inner lining of the gut in individuals with Crohn’s disease show increased MHC-I activity, which can result in inflammation in specific areas of the gut.
“This is the first instance where anyone has been able to demonstrate that persistent epigenetic changes can account for the issues in the gut epithelium in patients with Crohn’s disease,” stated Professor Zilbauer.
The researchers also found that the epigenetic modifications were highly stable, providing a potential explanation for the ongoing issues.
Even after receiving treatment and appearing to be cured, patients may experience a recurrence of inflammation several months later. This is because the drugs are only addressing the symptoms and not the root cause of the issue.
Our cells undergo epigenetic changes early in fetal development, which are influenced by environmental factors such as exposure to infections or antibiotics. The “hygiene hypothesis” suggests that a lack of exposure to microbes may also play a role in this process, affecting the proper development of our immune systems. Researchers believe that this could be a potential explanation for the recurrence of inflammation.Genetic mutations are responsible for the development of Crohn’s disease. The study received significant support from the Medical Research Council and also involved collaboration with the Milner Therapeutics Institute at the University of Cambridge. Professor Zilbauer and his team, in partnership with Cambridge Enterprise, have filed a patent for the technology and are looking for commercial partners to aid in its further development.
