MBL影响肠道微生态对炎症诱发肠黏膜屏障损伤的调节作用及其机制

我们前期发现，肠组织表达的甘露聚糖结合凝集素（MBL）是重要的黏膜免疫分子。最近发现，炎症性肠病患者血浆MBL水平与肠黏膜屏障功能损伤呈正相关；在小鼠急性肠道炎性损伤模型，MBL–/–小鼠肠黏膜病变及屏障功能损伤较WT小鼠轻，且肠道微生态失衡在其中起关键作用。据此提出本项目，拟就上述现象进行较系统的研究：MBL对肠道微生态的影响；MBL通过影响微生态调控肠道黏膜免疫应答及肠上皮细胞功能；解析起关键作用的菌群种类和代谢物及其在肠黏膜屏障损伤中的作用和机制。其创新点及其意义在于：①提出MBL可调控肠道微生态的新观点，从免疫系统与微生态相互作用的角度诠释肠道MBL的黏膜免疫效应；②阐明MBL对肠道微生态与肠黏膜免疫系统相互作用的影响，有助于深入理解MBL失衡有关肠道疾病的免疫病理机制；③揭示MBL—肠道微生态改变—肠黏膜屏障损伤的关系，为靶向MBL调控肠道微生态平衡以治疗相关疾病提供科学依据。

We have previously demonstrated that mannan-binding lectin (MBL) is an important innate mucosal immune molecule. Recently, we observed that the plasma MBL levels in patients with inflammatory bowel diseases positively correlated with intestinal integrity dysfunction. In addition, our preliminary data have shown that genetic MBL ablation strongly resists mice to dextran sodium sulfate (DSS)-induced colonic mucosal damage. MBL loss decreased intestinal pathology correlated with reduced intestinal barrier damage, and we provided evidence that the gut microbiota act as a key role in the difference between DSS-administrated WT and MBL−/− mice. On the basis of these findings, we propose this present grant. We will identify the modulatory function of MBL on the balance of gut microbiota. The mechanism of how MBL influences intestinal mucosal immunity and the function of intestinal epithelial cell will be investigated. Besides, we will also determine the roles and mechanisms of the microbiota species/products in the maintenance of intestinal barrier integrity. The innovation points and the significance of this project lie in: Firstly, the study will put forward a new idea that MBL can regulate intestinal microecology, which elucidates the mucosal immune function of intestinal MBL through the interaction between the immune system and microecology. Secondly, the study will define the effect of MBL on the crosstalk between microbiota and intestinal mucosal immune system, which will help us to understand the immune pathological mechanism of intestinal diseases related to MBL imbalance. Thirdly, this project will elucidate the relationship among MBL levels, intestinal microbiota homeostasis, and intestinal barrier dysfunction, which will substantiate the concept that MBL is a vital regulator of intestinal homeostasis, thus making it a potential target for modulation in the clinical settings of intestinal barrier dysfunction-associated diseases.