An intestinal simulation for a real disease: testing IBD in vitro

New DealConsortium, Inflammatory bowel diseasesLeave a Comment

If we take the whole human gastrointestinal (GI) tract and set it straight, it would be about nine meters long: more or less the height of a three-stage building. But don’t picture it like a long, plain tube. It has several compartments with different structures, each one with a specific function: the stomach secretes acids to degrade the food, while the small intestine is covered in a finger-like structure that absorbs nutrients. The chemical environment varies along the GI tract and matches the function of each compartment.

This variability becomes a challenge when designing a capsule, as the fate of the drug will depend on how the pill responds to the variety of stresses that it will face during its journey.

“When you take the capsule with a glass of water or with food, it enters in the stomach, where a very strong steering creates a stress on the capsule structure”, explains Dr Massimo Marzorati, co-founder of ProDigest, one of the New Deal partners. “The stomach also produces hydrochloric acid, so the capsule is exposed to a low pH. When it moves to the small intestine, in the duodenum you have the secretion of bile acids and pancreatic juices, and the pH goes up”, adds Dr Marzorati. Most formulations are designed to release the content at a pH around 6, close to intestinal conditions. Our microbiota, the microorganisms living in our gut, is important too, as these microbes can degrade lots of compounds, including drugs.

Regretfully, while playing a decisive role in the outcome of a therapy, these features are impossible to test in a patient. To overcome this limitation, Ghent University and ProDigest developed the SHIME® (Simulator of the Human Intestinal Microbial Ecosystem). “We have a technology platform which simulates the gastrointestinal tract.”, states Dr Marzorati. SHIME® contains several reactors, each one mimicking the features of a specific part of the GI tract. It emulates not only the mechanics by stirring, like movement of the stomach, but also the chemical composition of every compartment. Its applications range from analysing how a nutritional supplement is altered inside the GI tract to testing candidate pill formulations.

This way, it is possible to examine a drug delivery system in near-to-reality conditions in vitro. “Our role in New Deal is to evaluate the formulations developed by other partners for the delivery of the therapeutic molecule in the gastrointestinal tract”, affirms Dr Marzorati.

The New Deal project is developing a novel strategy to treat IBD based on the targeted delivery to the intestine of a therapeutic molecule called siRNA. The SHIME model allows to assess parameters such as the exact location of the GI tract where the capsule starts to dissolve or the molecule stability once it is released from the pill. And it is possible to go a step further too: “Once we know the drug can be released and that is stable, then the next step is to check if it is effective”, adds Dr Marzorati.

The situation within an intestine affected with IBD can be even more difficult to understand. “There is big variability within IBD patients so it is not possible to simply categorise the gastrointestinal features you would show if you had IBD. Nevertheless, there are some common traits”, explains Dr Marzorati. In the intestine of IBD patients, pH tends to be a bit lower and the intestine shows a lower capacity to absorb compounds. Moreover, the most common IBD symptom is inflammation. It causes the detachment of the mucus that covers the intestine. As the mucus is one of the main carbon sources for bacteria, the microbial species living in the gut change. Summing up, the scenario in an IBD intestine is a physically and chemically altered environment and an unbalanced microbial community. Dr Marzorati stresses here the role of the microbiota in the fate of the drug: “Microorganisms have the capacity to degrade lots of compounds. Some drugs have a great effectiveness but once they reach the small intestine, bacteria degrade these molecules and they can’t make their effect anymore.” In this sense, the efficacy of a drug is potentially linked to the microbiota of each individual.

In vitro models have become a powerful tool to emulate the harsh journey of a pill through the GI tract. Even so, Dr Marzorati adds here a clarification.  “You have to be aware of the limitations, so you never oversell what you get within an in vitro model.” With the right amount of caution, technologies like SHIME® are a shortcut in the drug design path and are successful to keep simple something as complex as an IBD intestine. “You should take it as a key start to select the best formulation and avoid testing a lot of candidates in clinical trials”, concludes Dr Marzorati.

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