The bacteria in and on our bodies, the microbiome, are important to our health. The gut microbiome influences the body’s response to foodstuffs and medicines. Using TNO’s i-screen, researchers can investigate how the gut microbiome interacts with various substances under various conditions. I-screen will be tested and developed further in association with the pharmaceutical company Pfizer.
I-screen is short for intestinal screening model and offers a convenient way of determining the impact that foodstuffs and medicines have on the gut microbiome, and vice versa. “I-screen is an in-vitro system in which human gut flora are cultured,” explains microbiologist Dr Frank Schuren, senior scientist at TNO who first proposed the i-screen model. “I-screen provides a very close simulation of the human intestinal metabolism, by which I mean the processes that food and medicines undergo after ingestion. Everyone’s gut microbiome is different and will respond differently. I-screen enables us to culture various types and colonies of bacteria, either from healthy volunteers or from patients with a certain condition. We can investigate differences between the gut flora of the various groups and the significance of those differences. I-screen can be exposed to various conditions simultaneously, which makes screening far more cost effective.”
“Using i-screen, metabolites can be identified far sooner – before clinical trials even begin. This will shorten the overall development process”
Important in drug development
“One of the aspects we are researching is whether drugs are metabolized by certain types of gut bacteria. In other words, are they converted into other substances – metabolites – which may or may not be desirable? This is of particular interest to pharmaceutical companies when they are developing new drugs,” says Steven Erpelinck, senior business developer for Predictive Health Technologies at TNO. Once a candidate drug has been identified, it must be subjected to extensive in-vitro and clinical studies to establish its safety, efficacy and mechanisms before the manufacturer can obtain marketing authorization. There is a growing body of evidence to show that gut flora play a role in the transformation of ingested drugs and hence the pharmacokinetics – what actually happens to the drug in the body. Clearly this has implications in terms of safety and effectiveness. “I-screen can quickly show whether a drug is metabolized and it can also identify previously unknown human metabolites,” says Irene Nooijen, the TNO project manager who focuses on operational aspects. “In the past, human metabolites could only be identified at an advanced phase of the testing process, by which I mean the Phase II or Phase III clinical trials. I-screen allows us to do so much earlier, before the clinical trials even begin. This helps to shorten the overall development process.”
“Joint projects like this result in technological innovation which benefits everyone. Other companies are welcome to use this method”
Interesting for pharmaceutical companies
TNO has been testing the i-screen system in collaboration with Pfizer. “The company first expressed interest in the system at a meeting held in Groton, Connecticut. At the table was Scott Obach, senior research fellow with Pfizer’s department of Pharmacokinetics, Dynamics and Drug Metabolism. We conducted a pilot study and went on to analyse ten existing drugs using i-screen. The results confirmed that the system works as intended,” recalls Erpelinck. “We now know that i-screen can show the interaction between gut bacteria and pharmaceuticals. It is an extremely innovative product which would be of great benefit to us as a pharmaceutical company. It is a very good method which can help to answer many research questions,” adds Obach. “Working with the TNO team has been very fulfilling. They have so much knowledge and experience in this area.” Steven Erpelinck is also pleased with the interaction between the two organizations. “Working together has been very pleasant on both the personal and professional level.”
Facilitate drug research
Obach believes that the i-screen system can play an important role in the development of new medicines. “Perhaps it could be used during the drug design or drug discovery phase to verify how a certain substance will behave in the body. That could result in obtaining important knowledge that will facilitate drug research projects and help explain observations we make in human drug metabolism.” Obach acknowledges the added value of collaboration between pharmaceutical companies and research institutes such as TNO. “Joint projects like this result in technological innovation which benefits everyone. Other companies are very welcome to use this method if they wish. The more parties we can involve in the development process, the more efficient it will be. We will have a better end product sooner and at lower cost. That would be a splendid outcome.” Nooijen agrees. “Collaboration with Pfizer is a win-win situation. We help Pfizer and our innovation reaches maturity more quickly.”
“I-screen can be exposed to various conditions simultaneously, which makes screening more cost-effective”
At present, i-screen is a qualitative model. “We can see whether or not a substance is broken down into metabolites,” explains Nooijen. “In future, we hope to be able to say more about the timescale on which the process takes place and how much of the substance concerned is actually metabolized. In other words, we want to know more about the pharmacokinetics.” Alongside quantitative measurements, Obach thinks that a combination of i-screen and Nuclear Magnetic Resonance (NMR) spectroscopy will be of value. Unlike current mass spectroscopy methods, NMR can offer detailed information about the structure of the metabolites detected in the body.