Periodic Reporting for period 1 - GlycanTrigger (GLYCANS AS MASTER TRIGGERS OF HEALTH TO INTESTINAL INFLAMMATION TRANSITION)
Période du rapport: 2023-01-01 au 2024-06-30
GlycanTrigger is a project funded by the European Union, within the Horizon Europe Research and Innovation Actions (RIA). The long-term goal of GlycanTrigger is to unlock a new checkpoint that regulates health to chronic inflammation transition by proposing mucosa glycans modifications as a master switch towards the early perturbation of host-microbial interactions and the consequent activation of both innate and humoral immune systems. Ultimately, we want to intercept or revert this master switch and thereby exploit/analyse whether this constitutes an opportunity to prevent the development of chronic inflammation in at-risk individuals.
Chronic inflammation is the underlying cause of numerous diseases, including Crohn's disease (CD), which may have a preclinical phase with immunological changes occurring before symptoms manifest. To improve disease prediction and prevention, our innovative approach seeks to understand the health-to-intestinal inflammation transition using CD as a disease model. The GlycanTrigger project will investigate when, why and how changes in glycosylation at the surface of the gut mucosa, constitute an early trigger of the health-to-inflammation transition. We will address how changes in glycosylation of the gut mucosa act as a primary event that dysregulates not only local mechanisms, but also systemic mechanisms associated with health to inflammation transition. Although high-risk/high-gain, our project is based on appropriate and long-standing expertise and fundamental biological principles that the consortium has helped establish and is thus likely to lead to (i) breakthrough biomedical concepts in the driving factors that trigger the health to chronic inflammation transition and to (ii) novel predictive tools for early detection of at-risk individuals to develop chronic inflammation, as well as to (iii) a novel intervention strategy that will be tested for disease prevention. In the longer term, the results of GlycanTrigger will improve health literacy through better-informed management of health status, diet and life-style to maintain a healthy gut.
Our strategy for understanding the transition from health to gut inflammation is comprehensive and includes the impact of mucosa glycans on local and systemic mechanisms.
Chronic inflammation is the underlying cause of numerous diseases, including Crohn's disease (CD), which may have a preclinical phase with immunological changes occurring before symptoms manifest. To improve disease prediction and prevention, our innovative approach seeks to understand the health-to-intestinal inflammation transition using CD as a disease model. The GlycanTrigger project will investigate when, why and how changes in glycosylation at the surface of the gut mucosa, constitute an early trigger of the health-to-inflammation transition. We will address how changes in glycosylation of the gut mucosa act as a primary event that dysregulates not only local mechanisms, but also systemic mechanisms associated with health to inflammation transition. Although high-risk/high-gain, our project is based on appropriate and long-standing expertise and fundamental biological principles that the consortium has helped establish and is thus likely to lead to (i) breakthrough biomedical concepts in the driving factors that trigger the health to chronic inflammation transition and to (ii) novel predictive tools for early detection of at-risk individuals to develop chronic inflammation, as well as to (iii) a novel intervention strategy that will be tested for disease prevention. In the longer term, the results of GlycanTrigger will improve health literacy through better-informed management of health status, diet and life-style to maintain a healthy gut.
Our strategy for understanding the transition from health to gut inflammation is comprehensive and includes the impact of mucosa glycans on local and systemic mechanisms.
In GlycanTrigger, we are investigating when, why and how changes in gut glycome trigger health to chronic inflammation transition. To understand how intestinal inflammation develops from a healthy state, we started to analyse tissue samples from CD patients who had undergone surgery comparing samples from patients who experienced a relapse and inflammation six months post-surgery, with those that remained in remission without inflammation. This is a perfect scenario mimicking a health to intestinal inflammation transition.
Using advanced techniques, such as mass spectrometry imaging (MSI) and spatial transcriptomics, we deeply characterized these samples to determine the gut mucosa glycome profile during health to inflammation transition. Additionally, imaging mass cytometry (CyTOF) was also used for detailed tissue analysis in terms of the glyco-immune profile. Our preliminary findings revealed that the composition of gut glycome changes significantly from a healthy state to inflammation, affecting the immune system and triggering inflammation.
Complementary, experiments carrying out in glycoengineered mice, recapitulating gut mucosa glycome alterations revealed changes in gut microbiota and altered levels of beneficial short-chain fatty acids, alongside an increased risk of intestinal inflammation. Specific immunological pathways were identified at the level of gut mucosa.
In addition, we also identified a unique glycosylation pattern in serum antibodies (IgGs) in the preclinical phase of CD patients. We further found that these altered IgG glycoforms were linked to higher levels of anti-microbial antibodies, specifically ASCA (anti-Saccharomyces cerevisiae antibodies), years before CD developed. This Glycome-ASCA hub was detected many years before CD diagnosis and was found to activated immune cells in a way that promoted inflammation.
Using advanced techniques, such as mass spectrometry imaging (MSI) and spatial transcriptomics, we deeply characterized these samples to determine the gut mucosa glycome profile during health to inflammation transition. Additionally, imaging mass cytometry (CyTOF) was also used for detailed tissue analysis in terms of the glyco-immune profile. Our preliminary findings revealed that the composition of gut glycome changes significantly from a healthy state to inflammation, affecting the immune system and triggering inflammation.
Complementary, experiments carrying out in glycoengineered mice, recapitulating gut mucosa glycome alterations revealed changes in gut microbiota and altered levels of beneficial short-chain fatty acids, alongside an increased risk of intestinal inflammation. Specific immunological pathways were identified at the level of gut mucosa.
In addition, we also identified a unique glycosylation pattern in serum antibodies (IgGs) in the preclinical phase of CD patients. We further found that these altered IgG glycoforms were linked to higher levels of anti-microbial antibodies, specifically ASCA (anti-Saccharomyces cerevisiae antibodies), years before CD developed. This Glycome-ASCA hub was detected many years before CD diagnosis and was found to activated immune cells in a way that promoted inflammation.
We have provided compelling preliminary evidence supporting that changes in the gut mucosa glycome composition are occurring in the transition from health to inflammation in CD. We demonstrated that these changes impact immune responses and gut health significantly. Additionally, our research identified potential therapeutic strategies, including glycan supplementation and microbiome interventions, which could revolutionize CD treatment and prevention. The findings also highlight the importance of early detection and personalized medicine in managing CD. Moving forward, continued research, strategic partnerships, and supportive frameworks will be crucial to realizing the full potential of these results.