GLYCANS AS MASTER TRIGGERS OF HEALTH TO INTESTINAL INFLAMMATION TRANSITION

Chronic inflammation underlies several diseases.

In Crohns disease (CD), there is mounting evidence of a preclinical phase characterized by immunological changes that precede symptoms.

Here, we propose a thorough and innovative approach to better understand the health-to-chronic inflammation transition occurring in patients with CD that will be translated in improved disease prediction and prevention.

We will address how changes in glycosylation of the gut mucosa act as a primary event that dysregulates not only local mechanisms (imposing maladapted host-microbiome interactions) but also systemic mechanisms (promoting anti-microbial antibodies production), involving the novel concept of glycan mimicry as an early trigger of the health to inflammation transition GlycanTrigger.

Capitalizing on our recent findings showing that changes in the expression of complex branched N-glycans at gut mucosa regulate Inflammatory Bowel Disease immunopathogenesis, we here hypothesize that changes in gut glycocalyx impose early perturbations in host-microbiome interactions, leading to the exposure of altered (glyco)neoantigens, both by pathogens and host epithelial cells which trigger the activation of innate immune response.

Moreover, following our recent discovery that changes in glycosylation can be detected in serum years before CD diagnosis and are correlated with increased levels of pathogenic antimicrobial antibodies (ASCA), we will here pursue the hypothesis that changes in mucosa glycans constitute a major source for the development of anti-glycan antibodies (ASCA), associated with health-to-inflammation transition.

The long-term GOAL of this proposal is to unlock, through an integrative approach, a new checkpoint that regulates the transition to chronic inflammation.

Our proposal will lead to breakthrough concepts in the health to chronic inflammation transition and to novel predictive tools translated in novel glyco-intervention strategies for disease prevention.