基于仿生人体大肠芯片模型的Akkermansia对肠粘膜保护和损伤机制研究

The interaction between gut microbiota and intestinal mucosa play a major role in health and disease in humans. The chronic state of low and normal level inflammation caused by the barrier breakage of intestinal mucosa can lead to a variety of human chronic diseases, such as obesity, IBD and Crohn’s disease etc. Therefore, the maintenance of the integrity of the structure and function of intestinal mucosa is a key measure to prevent and treat those chronic diseases. It has contradiction between the repair ability on intestinal mucosa and the natural degrading ability on mucin of Akkermansia. The protective or damaged mechanism on mucosal barrier of Akkermansia is still unknown. The characteristics of precise regulation and real-time monitor make the human bionic gut-on-chip as an ideal platform to study the interaction between anaerobic intestinal bacteria and intestinal mucosal barrier. The aim of the project is to establish the injury and protection model of intestinal mucosa based on the new human gut-on-chip, and to further study the protective or damaged mechanism of Akkermansia on intestinal mucosa. Finally, the animal models were used to verify the models and mechanism of injury and protection on the human gut-on-chip. The project can establish an ideal in vitro platform to study the interactions between gut microbiota and intestinal mucosa. Moreover, it is expected to clarify the molecular mechanism of protection and injury on intestinal mucosal barrier by gut bacteria Akkermansia. Therefore, it could provide direct evidence for the deep understanding of the interaction between gut microbiota, intestinal mucosa and disease.

肠道粘膜屏障破损所引起的炎症可导致多种疾病的发生，如：肥胖和糖尿病。维护肠粘膜结构和功能的完整性是预防和治疗相关疾病的关键。肠道微生物与肠粘膜的互作，在疾病的发生和发展过程中起重要作用。然而，现有模型无法模拟肠道微环境，研究肠粘膜和菌群互作。基于微流控芯片技术构建的仿生人体大肠芯片能模拟肠道生理环境，为研究肠粘膜和菌群的互作提供理想平台。肠道菌Akkermansia在逆转肥胖和治疗糖尿病中展示出巨大潜力，然而，该菌对肠道粘膜的保护和损伤机制不明。本项目拟在构建的仿生人体大肠芯片基础上，建立肠道粘膜屏障损伤和保护模型；探究Akkermansia对肠道粘膜损伤和保护机理；最后，采用动物模型对大肠芯片研究结果进行验证。本项目可为研究肠道菌与肠道粘膜的相互作用建立理想体外研究平台，同时有望阐明Akkermansia影响肠道粘膜屏障的分子机制，为理解肠道微生物、肠道粘膜与疾病的因果关系提供直接证据。

肠道粘膜屏障破损所引起的炎症可导致多种疾病的发生，如：肥胖和糖尿病。维护肠粘膜结构和功能的完整性是预防和治疗相关疾病的关键。肠道微生物与肠粘膜的互作，在疾病的发生和发展过程中起重要作用。然而，现有模型无法模拟肠道微环境，研究肠粘膜和菌群互作。基于微流控芯片技术构建的仿生人体大肠芯片能模拟肠道生理环境，为研究肠粘膜和菌群的互作提供理想平台。壳寡糖作为肠道益生元具有抗炎、减肥、缓解糖尿病的功效，与其对肠道和肠道微生物的调控有关，但机制不清楚；肠道菌Akkermansia（AKK）在逆转肥胖和治疗糖尿病中展示出巨大潜力，但该菌对肠道粘膜的保护和损伤机制不明。壳寡糖益生元、肠道微生物和肠道粘膜屏障三者之间相互作用影响肠道环境和宿主疾病进程，其中相互作用机制不明，需进一步研究。. 本项目拟在构建的仿生人体大肠芯片基础上，建立肠道粘膜屏障损伤和保护模型；探究壳寡糖、肠道微生物和肠道粘膜屏障三者之间相互作用；采用动物模型对大肠芯片研究结果进行验证；最后，阐明壳寡糖和AKK对肠道粘膜的损伤和保护机理。重要研究结果包括：（1）完成体外肠道粘膜屏障器官芯片的构建；（2）发现壳寡糖可以缓解葡聚糖硫酸钠（DSS）引起的小鼠肠道炎症，调控小鼠肠道菌群的组成，提高小鼠肠道AKK丰度，保护小鼠肠道粘膜屏障；（3）壳寡糖可以直接促进肠道粘膜屏障修复；（4）低浓度AKK可以直接促进肠道粘膜屏障修复，高浓度AKK能够损坏肠道粘膜屏障，肠道粘膜蛋白能促进AKK增值；（5）壳寡糖并不能直接促进AKK增殖，而可以通过促进肠道粘膜屏障修复间接促进AKK生长。. 本项目为研究寡糖益生元、肠道菌与肠道粘膜的相互作用建立了理想体外研究平台和模型，同时阐明了壳寡糖、AKK影响肠道粘膜屏障的分子机制，为理解寡糖益生元、肠道微生物、肠道粘膜与疾病的因果关系提供了直接证据，进一步拓展了益生元的传统概念。为开发基于寡糖益生元和肠道微生物，靶向肠道粘膜屏障，调节肠道炎症、肥胖、糖尿病等慢性代谢行疾病的新型功能食品，提供了理论依据。