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Development of a microaerobic human intestinal organoid model to determine the role of the gut microbiome in Crohn’s disease
The Humane Research Trust is funding a research project to understand the role of the gut microbiome in Crohn’s disease. Researchers at the University of East Anglia will make use of lab-grown human intestinal cells with a microaerobic chamber model to advance disease understanding. This research will shed light on the causes of Crohn’s disease and inform the development of new therapies.
Crohn’s disease is a life-long illness in which part of the bowel becomes inflamed, affecting 120,000 people across the UK. There is no cure for the condition. Existing treatments help patients manage the symptoms such as inflammation but often come with severe side effects. This treatment approach is also expensive; Crohn’s disease management costs the NHS around £750 million every year.
Scientists aren’t sure what the exact causes of the disease are, though studies suggest an involvement of environmental and genetic factors. Firstly, patients may have genetic mutations that reduce the body’s ability to remove bacteria from the gut. They also tend to have less diversity in the microbial species present in the gut, a phenomenon called microbial dysbiosis. Additionally, patients suffer with a leaky gut lining/barrier, called the intestinal epithelium. These factors compound and produce an immune response against the bacteria in the gut, resulting in chronic inflammation.
The mechanisms underlying the condition are complex and require careful consideration. At present, many scientists use mice to conduct relevant research. However, there are key differences between mice and humans, both anatomically and in terms of gut microbiota composition.
With human-based alternatives, there are other issues that researchers face. They cannot rely on human colon cancer cells, which lack the specific genetic characteristics associated with Crohn’s disease. Additionally, they do not produce the mucus layer that provides nutrients for the microbiome. An additional difficulty is that most gut bacteria are sensitive to oxygen, meaning they quickly die in cell culture.
The Humane Research Trust is funding a research project at the University of East Anglia that will use a new model to overcome these challenges. The study will investigate whether microbial dysbiosis is a cause or a consequence of Crohn’s disease. Dr Stephanie Schüller, the project's principal investigator, says the new model could be adapted to other intestinal conditions. This includes ulcerative colitis, irritable bowel syndrome (IBS), and colorectal cancer.
The Trust granted the Andrew Berwitz Award to this innovative project. The award is named in honour of Andrew Berwitz, who served the charity as trustee and treasurer for 29 years.
In the new research model, the research group will culture human stem cells in an environment mimicking the human intestine. This forms a collection of cells that resemble the intestine, called ‘organoids.’ Over time, the cells will differentiate into various intestinal cell types, including ‘goblet cells’, which produce mucus. The model makes use of a system called a vertical diffusion chamber to replicate the oxygen levels in the gut. They maintain low oxygen levels on just one side of the epithelium, supporting the survival of oxygen-sensitive bacteria.
The scientists will optimise the environment by making alterations to enhance the growth and maintenance of the organoids and microbiota. This includes introducing ‘continuous flow’, which is when they keep the culture medium moving through the chamber, to support long-term incubation.
Following the optimisation process, the researchers will begin culturing organoids derived from both Crohn’s disease patients and healthy donors in the presence of microbiota from the opposite group. This ‘cross-over’ design will enable them to observe the effects of diseased microbiomes on healthy organoids, and the effects of healthy microbiomes on diseased organoids.
They will look at factors like microbiome composition, metabolite production, epithelial function, and inflammatory response. This will clarify whether microbial dysbiosis is a driving factor in Crohn’s disease, or a symptom. “This understanding is essential to develop efficient therapies that address the cause rather than the symptoms,” explains Dr Schüller.
“By using human-derived epithelia, the system will be more physiologically relevant to Crohn’s disease than current mouse models. If similar studies replaced the use of mice with our model system, this would save approximately 33,000 to 67,000 mice.”
