幼年形成的不同肠道菌群及MAIT细胞与UC易患性的关系的研究

UC patient requires long-term immunosuppressive therapy, suggests that intestinal mucosal immune deficiency exists. The development of mucosal immunity relies on the stimulation of intestinal microflora, which was set up within 3 years after birth and then keep stable through out the life. Studies have shown that risk factors for UC include birth, feeding and childhood growth environment, indicating the defect formation of intestinal flora could be the mechanism of affected mucosal immunity. Newly discovered MAIT cells are rich in the intestinal tract, relies on bacteria for maturity, which could be a breakthrough in discovering the pathogenesis of UC. Therefore, in order to study the impact of different environments, the mice are grouped by breastfeeding and non-breastfeeding, followed by giving different diet after weaning till 8 weeks to form different intestinal flora. DSS then given to set up UC model to validate the susceptibility of UC. Peripheral blood, small intestine and large intestine specimens, and stool samples are collected at different time points from randomly selected mice for testing MAIT cells and intestinal flora type, and analyzing the distribution of MAIT cells, in order to find out how MAIT cells mature under the stimulation of intestinal flora, also find out UC-related bacteria, which could be great help for understanding the cause of UC and deliver according therapy, and may resolve the continuous use of immunosuppressive therapy.

UC需长期使用免疫抑制剂治疗，提示其肠粘膜存在免疫缺陷。肠粘膜的免疫发育依赖于肠道菌群的刺激，3岁前形成的肠道菌群一生均稳定。UC的易患因素为出生、喂养方式及婴幼年生长环境等，说明婴幼儿期形成异常菌群，发育成有缺陷的粘膜免疫是UC发生的主要机制。新近发现的MAIT具有在肠道富集，依赖于细菌成熟的特点，为探索UC发病机制提供了突破点。因此，本项目模拟婴幼儿成长的不同环境，将小鼠分组予以母乳或非母乳喂养，断奶后分别予以不同饮食喂养至8周龄，制备具有不同肠道菌群的小鼠。并予以DSS造模UC，验证是否不同肠道菌群的小鼠具有不同的UC易患性。并于断奶前后，及DSS造模后不同时间点，抽选小鼠，留取外周血，小肠、大肠，及粪便，检测MAIT细胞和肠道固生型、浮生型菌群，找出不同成长条件下的肠道菌群成熟规律及差异，寻找UC相关菌，分析MAIT分布情况，为最终了解UC病因，解决UC治疗不能停药的难点提供帮助。

UC需长期使用免疫抑制剂治疗，提示其肠粘膜存在免疫缺陷。肠粘膜的免疫发育依赖于肠道菌群的刺激，3岁前形成的肠道菌群一生均稳定。UC的易患因素为出生、喂养方式及婴幼年生长环境等，说明婴幼儿期形成异常菌群，发育成有缺陷的粘膜免疫是UC发生的主要机制。因此，本项目模拟婴幼儿成长的不同环境，将母鼠分组予以干蛋白，高脂及正常饮食干预，断奶后再统一予以正常饮食喂养至8周龄，以其制备具有不同肠道菌群的小鼠。并予以成年后进行DSS造模UC，验证是否不同肠道菌群的小鼠具有不同的UC易患性。并于小鼠0d,3w,8w及DSS造模后等不同时间点，抽选小鼠，留取外周血，小肠、大肠，及粪便，检测肠道菌群，找出不同成长条件下的肠道菌群成熟规律及差异，寻找UC相关菌，为最终了解UC病因，解决UC治疗不能停药的难点提供帮助。目前研究结果确立了母体在围产期摄入高蛋白饮食对后代小鼠成年后易感结肠炎症具有促进作用。生命早期母体暴露于不同饮食条件下的后代具有不同的UC易患性，这为孕期及哺乳期的饮食指导提供理论依据；并为后期寻找UC易患相关菌及其主要分布部位的研究工作打好基础，为UC的治疗提供线索。