An international team of researchers, led by Salomé Pinho from the Institute for Research and Innovation in Health at the University of Porto (i3S), has discovered a unique glycosylation signature in antibodies (molecules of the immune system) that is detectable in the blood many years before the development of symptoms and clinical diagnosis of Crohn’s Disease.
The identification of this altered glycoform of antibodies may be responsible for the onset of inflammation up to six years before diagnosis and symptomatology. The revelation of this mechanism at a pre-clinical stage (before symptoms and diagnosis) paves the way for the identification of a biomarker capable of predicting the onset of the disease and potentially preventing it.
In this pioneering work, the results of which were published in the prestigious scientific journal Nature Immunology, the team studied for the first time what happens in the transition from health to disease, specifically for the intestinal inflammation that characterizes patients with Crohn’s Disease. To this end, they focused specifically on the characterization of the composition of glycans (complex sugars) that modify the antibodies circulating in the body.
In collaboration with Mount Sinai Hospital, New York, USA, and the US Department of Defense, thousands of serum samples from individuals (military personnel) in a pre-clinical phase, up to six years before the development and diagnosis of Crohn’s Disease, were analyzed.
The samples were collected at four time points (one closer to diagnosis and the others, four and six years prior to diagnosis).
Samples of blood from patients with established disease, as well as from first-degree relatives of patients with Crohn’s Disease and from healthy individuals, were also analyzed, obtained in collaboration with the Gastroenterology service of the Santo António University Hospital Center in Porto and the Gastroenterology service of Beatriz Ângelo Hospital and Hospital da Luz in Lisbon.
In collaboration with researchers from Croatia, the glycosylation profile of antibodies in circulation was characterized using advanced technology. The researchers found a unique alteration in the composition of glycans in these circulating antibodies, which is detectable up to six years before diagnosis and remains constant throughout the period preceding clinical symptoms.
This groundbreaking discovery thus opens doors for the identification of a non-invasive biomarker capable of predicting the diagnosis of Crohn’s Disease and, therefore, stratifying the risk of developing the disease.
The discovery “opens doors” for disease prevention
The team also discovered that ASCA antibodies, which are normally detected in 40% to 60% of patients with Crohn’s Disease and were thought to have no influence on the disease’s development, “have a glycoform that is pathogenic and starts triggering the inflammatory response many years before the disease is diagnosed,” says Salomé Pinho, leader of the “Immunology, Cancer & GlycoMedicine” group and affiliated professor at the Faculty of Medicine (FMUP) and the Institute of Biomedical Sciences Abel Salazar (ICBAS) of U.Porto.
“We have demonstrated that this ASCA glycoform, detected in the pre-clinical phase, triggers a pro-inflammatory immune response through the activation and reprogramming of innate immune cells, such as dendritic cells and NK cells.” This means, emphasizes Joana Gaifem, one of the first authors of the study and a junior researcher in the i3S group, “that we have identified a potential cause or one of the causes of this disease as well as a potential target for future approaches to prevent Crohn’s Disease.”
This discovery of a potential new predictive biomarker for Crohn’s Disease reveals a new target that could open doors for disease prevention,” adds Cláudia Rodrigues, co-first author of the article and a student in the PhD Program in Biomedical Sciences at ICBAS, conducting research at i3S.
Clinical trials set to begin in 2025
As part of the European project GlycanTrigger, also led by Salomé Pinho, and based on these discoveries, the consortium team, which includes gastroenterologist Joana Torres from Hospital da Luz-Lisbon and gastroenterologist Jean-Frederic Colombel from Mount Sinai-New York, will begin a clinical trial in 2025 with patients who have had part of their intestine surgically removed due to Crohn’s Disease.
“We will conduct an intervention post-surgery (after the removal of the segment of the intestine that is diseased) aiming to modulate glycosylation, thus addressing one of the potential primary mechanisms of the disease, and try to understand the impact on the immune system of the intestine and the intestinal microbiome,” explains Joana Torres. Patient recruitment will commence at that hospital at the beginning of 2025.
Meanwhile, adds Salomé Pinho, “as the samples provided by the US Department of Defense are limited to young military personnel, predominantly male and actively engaged in military service, the next step will be to validate the predictive performance of the glycomarker in other studies.”
About Crohn’s Disease
Crohn’s disease is a chronic inflammatory bowel disease that is immune-mediated and causes inflammation of the digestive tract. Common symptoms include diarrhea, abdominal pain, fatigue, and weight loss, among others. It can affect all age groups but is typically diagnosed in adolescents and young adults.
In recent years, both in Portugal and worldwide, there has been an increasing incidence of this pathology, which currently has no cure. There are, however, several treatments available aimed at controlling the excessive inflammatory response that characterizes this condition.
In many cases, it is possible to manage the disease, preventing individuals from experiencing flare-ups for long periods. Nonetheless, it continues to be a disease with a significant impact on patients’ quality of life, with a portion of individuals not responding to currently available treatments and requiring surgery, underscoring the importance of investigating new paradigms, namely early diagnosis of the disease and prevention of its onset or complications.