Comprehensive medical doctoral thesis presents predictors of inflammatory bowel disease

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Biomarkers for inflammatory bowel diseases
Inflammatory bowel diseases are chronic inflammatory diseases of the gastrointestinal tract. IBD is characterized by an alternating course of the disease that is notoriously difficult to predict and treat adequately. The etiology and course of the disease are complex, heterogeneous, and unpredictable, showing variable clinical patterns: some patients experience frequent episodes of active disease causing disabling symptoms, while others remain in long-term remission after adequate treatment. As such, there is an urgent need for “biomarkers”; these are biological substances or indicators that may reflect a particular medical state or condition in the human body. Biomarkers can help in the early detection of disease, the assessment of disease activity and its complications, and the prediction of treatment efficacy. Therefore, biomarkers may be valuable in improving clinical care by making it more efficient and friendly to IBD patients. In addition, biomarkers can also be used to assess the effects of nutritional and medical (drug-based) treatments. The goal of Arno Bourgonje’s PhD research was to identify and apply biomarkers in IBD patients, with particular emphasis on the underlying disease mechanisms involved.

New biomarker reflects the severity of intestinal inflammation in patients with IBD
One of the biomarkers widely studied by Bourgonje is related to the production of so-called “reactive oxygen species” in the human body. These are highly reactive molecules released during energy production in mammalian cells. These reactive oxygen species can cause severe cellular and molecular damage; this refers to a phenomenon also known as “oxidative stress”. Oxidative stress can be partially counteracted by antioxidants. However, during intestinal inflammation, reactive oxygen species are produced in excess, resulting in tissue damage. Under these circumstances, however, the availability of antioxidants is lower. insufficient in the human body which would help to attenuate oxidative stress.

Bourgonje investigated the potential utility of circulating antioxidant capacity by measuring so-called ‘free thiols’. Free thiols are antioxidant substances that protect against oxidative stress by removing reactive species. His research shows for the first time that IBD patients have significantly lower concentrations of free thiols in their blood compared to healthy people; this also appeared to be the case in patients who were in clinical remission (ie, in the absence of symptoms), indicating the presence of subclinical oxidative stress.

Interestingly, Bourgonje showed that free thiols in the blood are closely related to the severity of intestinal inflammation observed during endoscopic examination in IBD patients: the lower the free thiol levels, the more severe the degree of intestinal inflammation observed. on endoscopic examination. of the intestines. Therefore, this biomarker was able to accurately reflect the degree of disease activity and, presumably, even superior to currently used biomarkers. It is important to highlight that determining the degree of disease activity in patients with IBD is very important, since this information is crucial for therapeutic decision-making.

A fingerstick sampling device to determine disease activity in IBD?
Follow-up research is currently underway to build on these important findings. Bourgonje: “First, there is a need to confirm the value of this biomarker in other patient populations, also from different geographic regions. I am currently working both at UMCG and in collaboration with a group of Australian collaborators to validate the value of the free thiols in a very large group of IBD patients Simultaneously, we are also working with researchers at the University of Twente (Enschede, The Netherlands) to develop a so-called ‘lab-on-a-chip’, which is a device that is designed for the integration of various laboratory tests on a single chip. In such a device, using only one drop of blood, the concentration of free thiols in the blood as a reflection of antioxidant capacity could be determined easily, quickly and safely.” , this should preferably lead to a test that allows patients to monitor the degree of intestinal inflammation at home through a finger prick in the future. Bourgonje: ‘Although this will take many years of additional research, we know that this approach is appreciated by many patients. Such approaches actively involve them in their treatment without the need for a direct transfer to hospital for blood or stool tests.’ He also conducts research with industrial partners on oxidative stress in IBD. Bourgonje: ‘Pharmaceutical companies are developing drugs for IBD patients that protect against oxidative stress by enhancing antioxidant capacity in the intestines. Although the actual efficacy, safety and tolerability of these drugs for patients have not yet been demonstrated, the currently available results look promising.”

Single antibodies in patients with IBD
Using an in-depth characterization of the human immune system, Bourgonje’s research also led to the identification of other biomarkers for IBD. He also focused on “antibodies” in the blood: proteins capable of recognizing and neutralizing foreign molecules (eg, bacteria). Her research shows that there is a wide diversity of specific antibodies in the blood of IBD patients, which could potentially serve as biomarkers of the disease. Until now, only a few dozen specific antibody signatures in IBD patients were known. Recently, however, highly innovative and sophisticated techniques have become available that allow the extensive repertoire of antibodies in humans to be mapped on a much larger and more detailed scale, where more than 300,000 different types of antibody responses can be simultaneously mapped. Bourgonje was one of the first researchers to take advantage of this technique in IBD patients: “Following this approach, we observed unique patterns of several hundred antibodies in IBD patients compared to individuals derived from the general population. Using only a selection of ten antibodies , patients with IBD could already be distinguished very accurately from individuals without IBD.

Who will develop IBD in the future?
Regarding this line of research, Bourgonje is already working on follow-up studies. The Lifelines population-based cohort study longitudinally collects extensive health data and blood samples from more than 167,000 people in the northern Netherlands. Bourgonje: “We are now looking retrospectively at the blood of people who have been diagnosed with IBD, but were not yet diagnosed when they started participating in the Lifelines study more than ten to fifteen years ago. The goal is to look for antibody biomarkers in blood collected years before the IBD diagnosis was made with the aim of developing an antibody-based test that can predict the development of the disease. Bourgonje says that such a test will likely involve different types of antibodies measured in parallel: “I find this part of my dissertation on the characterization of antibody repertoires in IBD is the most promising, because I believe that antibody-based tests have great potential for the development of clinical applications for IBD patients. In addition, such tests could help detect IBD in high-risk populations. (for example, genetically susceptible individuals). This would also provide preventive opportunities, for example through lifestyle and dietary intervention. s that could help prevent or at least delay the onset of the disease.

In-depth characterization of antibodies in other disease states?
The revolutionary technique for determining antibody repertoires in the human body could also be potentially valuable in the context of other human diseases, according to Bourgonje. Bourgonje: “Perhaps this also creates opportunities for early detection and treatment of autoimmune diseases such as rheumatoid arthritis, diabetes and psoriasis.”

About Arno Bourgonje:
Arno Bourgonje (born 1996) studied Medicine at the University of Groningen (RUG) and obtained his medical degree summa cum laude in November 2020. His doctoral research was conducted under the supervision of prof. dr. G. Dijkstra, prof. dr. KN Faber and prof. dr. RK Weersma from the Department of Gastroenterology and Hepatology and prof. dr. H. van Goor of the Department of Pathology and Medical Biology, Groningen University Medical Center. He now works as a physician and postdoctoral researcher at UMCG. His doctoral thesis is entitled: “Biomarker Signatures in Pathophysiology and Therapeutic Interventions in Inflammatory Bowel Diseases: A Multimodal Approach.”
His doctoral thesis comprises a whopping 1,108 pages; making it one of the most comprehensive medical dissertations ever published in the Netherlands. It covers a total of 31 chapters, 27 of which have already been published as scientific articles. His research skills have not gone unnoticed internationally either; he will soon continue his research at the Icahn School of Medicine at Mount Sinai in New York.

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