GLYCANS AS MASTER TRIGGERS OF HEALTH TO INTESTINAL INFLAMMATION TRANSITION

慢性炎症是几种疾病的基础。在克罗恩病（CD）中，有越来越多的证据表明临床前阶段的特征是症状前的免疫学变化。在这里，我们提出了一种彻底和创新的方法，以更好地了解CD患者的健康到慢性炎症的转变，这将转化为改善疾病的预测和预防。我们将讨论肠道粘膜糖基化的变化如何作为一个主要事件，不仅使局部机制（施加适应不良的宿主-微生物组相互作用）失调，而且使全身机制（促进抗微生物抗体产生）失调，涉及聚糖模拟的新概念作为健康向炎症转变的早期触发因素- GlycanTrigger。利用我们最近的发现，表明在肠粘膜中复杂分支N-聚糖的表达的变化调节炎性肠病免疫发病机制，我们在这里假设肠糖萼的变化在宿主-微生物组相互作用中施加早期扰动，导致病原体和宿主上皮细胞暴露改变的（糖）新抗原，这触发先天免疫应答的激活。该提案的长期目标是通过综合方法解锁一个新的检查点，调节向慢性炎症的过渡。我们的提案将导致健康向慢性炎症转变的突破性概念，并将新的预测工具转化为用于疾病预防的新型糖干预策略。

Chronic inflammation underlies several diseases. In Crohn´s 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. 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.