Treg-IgA-梭杆菌稳态失衡致IBS内脏高敏感的机制研究

Recent studies has revealed that the disturbance of intestinal microbiota may participate the pathogenesis of irritable bowel syndrome (IBS). But which genus in this huge and complex community is critical to IBS remains unknown. In our previous study, Fusobacterium .significantly increased in the gut microbiota of maternal separation rats and subgroup of Irritable bowel syndrome (IBS) patients. And its abundance significantly correlated with visceral hypersensitivity. In this study we aim to reveal how the Fusobacterium lead to visceral hypersensitivity in IBS patients.We proposed that a Treg-IgA-Fusobacterium axis exists between the host and microbiota.We will validate the mechanism of this study through clinical study, animal and cellular experiments. We will further explore how stress or other IBS conditions disrupt the Treg-IgA-Fusobacterium axis and cause Fusobacterium overgrowth, which may finally lead to colorectal mucosal micro-inflammation and visceral hypersensitivity.This may finally contribute to the pathogenesis of how dysbiosis leads to visceral hypersensitivity in IBS patients. New targets in the gut microbiota will be identified for the IBS management.

晚近研究发现，肠道菌群紊乱可能参与肠易激综合征（IBS）的发病。肠道菌群数量庞大，种类繁多，具体哪种细菌参与IBS发病以及如何参与，目前尚无定论。我们的前期工作发现部分IBS患者及母婴分离大鼠肠道梭杆菌数量增加，且与内脏高敏感相关。为阐明梭杆菌在IBS内脏高敏感发生中的机制，本研究首先提出梭杆菌与宿主之间形成Treg-IgA-梭杆菌轴的概念，其次通过临床病例、动物实验及细胞培养多个步骤验证Treg-IgA-梭杆菌轴的存在及稳态维持机制，并应用肠道菌群高通量测序与基因芯片转录组数据的多组学联合分析等先进技术探讨应激导致Treg-IgA-梭杆菌稳态失衡--梭杆菌过度定植--结肠粘膜微炎症--内脏高敏感这一过程的发生机制，最终阐明肠道菌群失调导致IBS内脏高敏感的机制，为特异性地干预和纠正IBS患者的肠道菌群紊乱提供科学依据及准确靶点。

肠易激综合征（IBS）常伴有肠道菌群失调和内脏高敏感状态，我们前期研究发现，伴有内脏高敏感的IBS患者以及内脏高敏感动物模型都可以观察到具有特征性的肠道菌群改变，这提示肠道菌群失调参与了内脏高敏感的发生。本项目将详细阐明IBS患者代谢组学及肠道菌群特征；明确具核梭杆菌对肠道菌群和内脏高敏感状态的影响，探讨具核梭杆菌通过非定植依赖的方式发挥作用的机制；挖掘并证明FomA蛋白是具核梭杆菌影响肠道菌群和加剧内脏高敏感的关键作用蛋白，并进一步探讨FomA蛋白的作用机制。本研究将为挖掘IBS内脏高敏感的发病机制，探索IBS内脏高敏感新的有效的治疗靶点提供思路。