Predictors for chronic bowel disease presented

UMCG PhD student Arno Bourgonje identified new predictors of chronic intestinal diseases

UMCG PhD student Arno Bourgonje (26) wrote perhaps the most extensive medical dissertation ever published in the Netherlands. A dissertation of more than 1100 pages and 31 chapters.

Under the supervision of four supervisors from the UMCG departments of Gastroenterology and Liver Diseases and Pathology and Medical Biology, Bourgonje conducted doctoral research into the predictive value of biomarkers for inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. He found an important new biomarker that shows the severity of intestinal inflammation in IBD patients and is conducting follow-up research that should eventually lead to a home test for IBD patients. He is also conducting follow-up research with the help of Lifelines into the possibility of predicting which people have a high chance of developing IBD in the future.

Biomarkers for inflammatory bowel disease
Inflammatory bowel diseases are chronic inflammatory diseases of the gastrointestinal tract. IBD is characterized by a variable disease course that is difficult to predict and treat. The disease is complex, unpredictable and occurs in varied forms: in some phases patients experience many complaints and in other phases the disease progresses quietly. As a result, there is a great need for ‘biomarkers’; these are biological substances that can reflect a certain medical condition or condition in the body. Biomarkers can aid in the early detection of disease, assessment of disease activity and complications, and prediction of treatment effectiveness. Biomarkers can therefore be valuable in improving the efficiency and patient-friendliness of the care for patients with IBD. In addition, the effects of nutrition and medical treatments can also be assessed with biomarkers. The aim of Arno Bourgonje’s PhD research was to identify and apply biomarkers in patients with IBD, with a special focus on the underlying disease mechanisms involved.

New biomarker shows severity of intestinal inflammation in IBD patients
One of the biomarkers that Bourgonje has researched relates to the production of so-called ‘oxygen radicals’ in the body. These are highly reactive molecules that are released during energy production in the human cell. These oxygen radicals can cause molecular damage; this is also referred to as ‘oxidative stress’. This oxidative stress can be partly counteracted by antioxidants. Relatively more damage caused by oxygen radicals occurs in intestinal inflammation. The protective effect of antioxidants in the human body is insufficient.

Bourgonje investigated the influence of the antioxidant capacity in the blood (by measuring so-called ‘free thiols’). Free thiols are antioxidant molecules that protect against oxidative stress by neutralizing oxygen radicals. His research shows for the first time that patients with IBD have significantly lower blood concentrations of these free thiols than healthy subjects; even if the patients have no complaints. This indicates the presence of oxidative stress.

Bourgonje subsequently showed that this antioxidant capacity in blood is closely related to the severity of the intestinal inflammation in patients with IBD: the lower this value, the more severe the degree of intestinal inflammation as observed in intestinal examination (endoscopy). This biomarker thus showed the degree of disease activity even better than the biomarkers known so far. It is precisely the knowledge of the extent to which IBD is already active that is very important to know because this largely determines the exact treatment.

Prick fingertip to determine stage IBD
It certainly does not end with these important findings. Bourgonje: ‘First, the value of this biomarker still needs to be confirmed in other patient groups, including those from other countries. At the moment I am working at the UMCG and with a group of Australian researchers to repeat the same study in a very large group of patients with IBD. In collaboration with the University of Twente, we are also developing a so-called ‘lab-on-a-chip’, which is a device that integrates various laboratory functions on a single chip. In such a device, the concentration of this biomarker of antioxidant capacity in the blood can be determined with just one drop of blood.’ Preferably, this should eventually lead to a test with which patients can measure the degree of intestinal inflammation at home with a finger prick. Bourgonje: ‘It is true that many years of research will precede this, but we know that this approach is appreciated by many patients. As a result, they are more actively involved in their treatment and do not have to come straight to the hospital for blood or stool tests.’ He is also conducting research into oxidative stress in IBD together with industry. Bourgonje: ‘The industry is developing drugs for patients with IBD that protect against oxidative stress by strengthening the body’s antioxidant capacity. Although the actual effectiveness of these drugs for patients has yet to be demonstrated, the published results so far are promising.’

Unique antibodies in IBD patients
With an analysis of the human immune system, Bourgonje also found other biomarkers for IBD in his research. He focused on ‘antibodies’ in the blood: proteins that are able to identify foreign molecules (such as bacteria) and render them harmless. His research shows that there is a wide diversity of specific antibodies in the blood of patients with IBD, which may serve as biomarkers for IBD. Until now, only a few dozen specific antibody responses were known in patients with IBD. Recently, however, highly innovative and advanced techniques have become available to map the very extensive repertoire of antibodies in humans, whereby more than 300,000 different types of antibody responses can be mapped simultaneously. Bourgonje was one of the first researchers to use this on this scale: ‘I used this to observe unique patterns of several hundred antibodies in patients with IBD compared to healthy people. With only a selection of ten antibodies, patients with IBD could be very accurately distinguished from people without IBD’.

Who will get IBD in the future?
Bourgonje is already working on a follow-up study for this as well. Every five years, the large population study Lifelines collects health data and blood samples from 167,000 people in the Northern Netherlands. Bourgonje: ‘We are now looking back at the blood of people who currently have IBD, but did not yet have it when they took part in the Lifelines study ten to fifteen years ago. For example, can we already predict that someone will get IBD in the blood sample from that time before the diagnosis is made with an antibody test?’ If his follow-up research shows that this is indeed the case, a new test could be developed that could be used in the clinic. Bourgonje expects this to be a test in which different types of antibodies are measured: ‘I find this part of my thesis the most promising, because I believe there is a good chance that a new antibody test can eventually be developed for IBD. This would allow you to screen early in high-risk groups who have a high risk of developing IBD in the future. This then provides opportunities for preventive intervention by trying to prevent the onset of the disease or at least delay its onset with the right lifestyle and nutritional advice.’

Also with other diseases
The revolutionary technique of determining the repertoire of antibodies present in a person’s body could also be used in other human diseases, according to Bourgonje. Bourgonje: ‘This may also create opportunities for early detection and treatment of diseases such as rheumatoid arthritis, diabetes, psoriasis and other autoimmune diseases.’

Bron: UMCG / Larissa vd Wal, Joost Wessels