Inflammatory bowel disease (IBD) is a very challenging condition for practitioners. The symptoms vary from patient to patient and some of them overlap with those that other conditions present. Moreover, many patients don’t respond to available treatments or develop resistance to them over time.
To try and tackle this challenge, scientists aim to get to the root of the problem. However, researchers still have an incomplete understanding of what causes this disease. One of the main obstacles that have hindered IBD research is the shortage of valid models that mimic the development of the disease.
Much of the knowledge that researchers have about IBD has been learned through animal models, mainly mice. Using animals provide the advantage of allowing scientists to observe the gut’s immune response in a living organism. This methodology gives researchers context: for example, they can test how a drug behaves in contact with the rest of cells and tissues. However, animal models show major limitations. Researchers must induce IBD-like conditions using artificial methods that don’t always resemble the factors that trigger the disease in humans. Moreover, this type of experiments requires a great amount of resources (cost, time and labour) and the results are not always relevant for humans, due to the major differences between animal models and humans.
An alternative to animal models is using in vitro techniques, not only for these limitations but also for the legal implications of working with living organisms. However, until now most of these experiments couldn’t mimic the IBD complexity. For example, intestinal lining cells cultures aren’t stable enough and using patient’s tissue in the lab shows limitations too, as fresh tissue samples, although conserving the 3D architecture of the tissue, are short-lived and aren’t always accessible. In addition, they can only provide data as a snapshot in time, so modelling the intestinal processes is complicated.
In recent years, a new promising research tool has been developed and it may help to overcome the described problems: intestinal organoids.
Intestinal organoids are a 3D model of the intestinal lining, grown in vitro. To build them, scientists can use two approaches. Either they use cells that can turn into any type of cells of the adult body, called pluripotent stem cells, or they take advantage of “adult stem cells” that they obtain directly from a patient’s intestine. Researchers cultivate these cells in an appropriate medium until they close, form, and develop globular-shaped structures. These structures contain all the different gut cell types, organised as they would be in a real intestine.
Organoids show remarkable ability to self-organise and they can reproduce early stages of human intestinal development. Therefore, they allow to research the development and properties of the intestinal lining. But where organoids can make the real difference is in their versatility. As it is an in vitro model, the researcher can control the cells added to the culture. This allows to include in the organoid other cells besides the intestinal ones, getting closer to the physiological reality.
Intestinal organoids can also help to study specific IBD traits. Sites of inflammation in the intestine are at high risk of developing fibrosis, an excessive build-up of connective tissues that replaces functional intestinal lining. The mechanisms behind this process remain partly unknown and using organoid models could shed light on them.
Using organoids also opens the door to screening a great amount of candidate drugs. The high stability of these structures allows researchers to build “living libraries” of organoids from different cellular sources and perform analysis to assess the molecular differences between a healthy intestine and one with IBD. This model design could also lead to optimise treatments before application, reducing the chance of treatment failure and thus, speeding up the drug design process.
Moreover, as organoids can be developed from patients cells, they offer unique insight into the disease on an individual scale, leading to personalised treatments. Theoretically, it could be possible to grow and test patient organoids with different treatments or immune cell compositions. This application could be particularly useful for the significant proportion of patients that are resistant to the current treatment or that develop resistance to them over time.
Organoid cultures are called to revolutionise the field of IBD research. There is even space for improvement: further development could enable generation of intestinal organoids vascularized and innervated, optimise the addition of immune cells and include microbial flora, as it is involved in the development of IBD too. Altogether, organoids are becoming an extremely useful ally in understanding the mechanisms of IBD that remain unknown and thus, improving the patients’ quality of life.
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