口腔来源的变异链球菌在炎症性肠病发病中的作用及机制研究

Dysbiosis of gut microbiota plays a main role in the pathogenesis of inflammatory bowel diseases(IBD). Besides the gut,oral cavity,as the opening of GI tract,holds the second largest microbiota in human beings.Dysbiosis of oral microbiota has been reported.It is hypothesized that oral cavity may act as a “pathogen pool” and etopic colonization of oral bacteria in the intestine may induce immune dysregulation.However direct evidence is rare up till now.We targeted oral Streptococcus mutans(S.mutans) as a potential pathogen in IBD by comparing oral and gut microbiota between IBD patients and healthy controls. Our preliminary study showed a tendency of aggravating intestinal inflammation by gavage of S.mutans in IBD animal models, and abnormal salivary exosome may be involved. In this project,we aim to further explore the pathogenic effect of oral S.mutans in IBD by etopic colonization in the colon,and salivary exosome may be an accessary by carrying inflammatory proteins such as PSMA7. This study may help to further understand the pathogenesis of IBD from a new aspect, and may possibly provide more effective therapeutic targets in microbiome-based regimen in the future.

肠道微生物群失衡是炎症性肠病（IBD）发病的重要机制，口腔是仅次于肠道的人体第二大微生物库，也是消化道的“窗口”，IBD患者存在口腔微生物群失衡，据推测口腔可能具有潜在致病菌“蓄水池”的作用，病理条件下口腔的潜在致病菌定植于肠道，引发肠道菌群紊乱，促进IBD发病，但相关研究较少，缺乏直接证据。我们前期比较IBD患者和健康人口腔和肠道微生物群差异，筛选出口腔来源变异链球菌（S.mutans）作为潜在致病菌，给予IBD动物模型灌胃，小样本量初步研究提示S.mutans可加重肠道炎症，IBD患者唾液中异常的外泌体可能参与其中。本研究拟在此基础上扩大样本量，验证S.mutans在IBD中的致病作用，并证实其可能是通过口腔菌的肠道异位定植得以实现，唾液外泌体内含物（如PSMA7蛋白）可能协助S.mutans肠道定植。本研究可为深入了解IBD发生发展提供新思路，为开发微生物精准治疗提供有效靶点。

炎症性肠病（inflammatory bowel disease，IBD）是发病机制尚不清楚的慢性非特异性肠道炎症疾病，溃疡性结肠炎（ulcerative colitis，UC）是其中一种，近年来IBD包括UC的发病率在我国逐年增加。口腔微生物失衡被证实可能通过与肠道微生物关联，从而参与IBD的发病过程。因此本课题对IBD患者与健康人群唾液菌群进行16S rRNA测序，结果提示UC患者与健康人群唾液菌群组成显著不同，UC患者唾液中链球菌属丰度显著增加。随后通过一系列体外细胞实验与体内动物实验，发现口腔来源的变异链球菌在UC的发病过程中具有重要作用，并且整个过程涉及炎性因子，屏障分子，免疫细胞以及肠道菌群的改变。本课题的研究结果有助于明确口腔微生物在UC中的重要地位，深入认识口腔微生物与肠道炎症之间的联系，可能为临床上基于口腔微生物开发IBD的靶向药物提供新的思路。