The link between oral bacteria and gut disease

项目摘要/摘要： 潜在致病共生种群的异常聚集，即致病细菌，被认为是 在炎症性肠病(IBD)的发病机制中起重要作用。然而，哪些细菌可以被归类为 疾病相关的致病因子以及这些致病因子如何促进IBD患者的肠道炎症 人们对此知之甚少。这项提议的长期目标是开发新的治疗策略，选择性地 靶向IBD相关致病因子及其下游炎症通路而不影响效益 共生细菌。我们的初步数据和最近的研究表明，口腔细菌是丰富的 在IBD患者的肠粘膜中，并可能参与了肠道内发生的炎症过程。 IBD。该应用的目的是确定口腔异位定植的机制。 病原体在IBD中引起肠道炎症。我们的初步数据表明，口腔炎症导致 口腔内病原体的扩张。致病菌在口腔中的聚集导致增加 肠道内的殖民程度。口服定植的诺生菌IBD易感IL-10缺陷小鼠 病原体会患上严重的结肠炎，而被健康口腔微生物定居的小鼠不会。而且，我们的 初步数据还表明，口腔致病菌可引起结肠上皮细胞DNA损伤 固有层巨噬细胞。基于这些初步结果，我们的中心假设是病原体， 最初发现于营养不良的口腔粘膜，通过异位肠道参与IBD的发病。 定植和它们的遗传毒性活性。这一假设将通过追求以下三个具体假设来检验 目的：在目标1中，我们将检查口腔致病菌的定植对结肠上皮完整性的影响。 我们将确定口腔致病菌在肠道中的定位及其对上皮屏障功能的影响。 体外和体内。在目标2中，我们将确定口服致病菌对肠道炎性小体激活的影响。 巨噬细胞。我们将确定参与口腔致病基因驱动的炎症体蛋白。 体外和体内炎症反应。在目标3中，我们将确定口服的遗传毒性活性的程度 致病细菌对它们的致病能力有贡献。建议进行研究的理由是 确定口腔致病菌引起肠道炎症的途径将导致新的和创新的 治疗IBD的方法。此外，抑制口腔中病原体的生长(例如，通过治疗口腔 炎症)还应通过限制结肠菌的供应来降低红斑/IBD恶化的风险。

Project Summary/Abstract: An abnormal accumulation of potentially pathogenic commensal populations, namely pathobionts, is thought to contribute to the pathogenesis of inflammatory bowel disease (IBD). However, what bacteria can be classified as disease-associated pathobionts and how these pathobionts promote intestinal inflammation in IBD remains poorly understood. The long-term goal of this proposal is to develop new therapeutic strategies that selectively target IBD-associated pathobionts and their downstream inflammatory pathways without influencing beneficial commensal bacteria. Our preliminary data and recent studies have demonstrated that oral bacteria are enriched in the intestinal mucosa of IBD patients and might contribute to the inflammatory processes occurring in the gut in IBD. The objective of this application is to determine the mechanisms by which ectopic colonization of oral pathobionts elicits gut inflammation in IBD. Our preliminary data demonstrate that oral inflammation induces the expansion of pathobionts in the oral cavity. An accumulation of pathobionts in the oral cavity results in increased levels of colonization in the gut. Gnotobiotic IBD-prone IL-10-deficient mice that are colonized by oral pathobionts develop severe colitis, while mice colonized by healthy oral microbiotas do not. Moreover, our preliminary data also demonstrate that oral pathobionts induce DNA damage in colonic epithelial cells and lamina propria macrophages. Based on these preliminary results, our central hypothesis is that pathobionts, originally found in the dysbiotic oral mucosa, contribute to the pathogenesis of IBD through their ectopic gut colonization and their genotoxic activity. This hypothesis will be tested by pursuing the following three specific aims: In Aim 1, we will examine the impact of the colonization of oral pathobionts on colonic epithelial integrity. We will determine the localization of oral pathobionts in the gut and their effect on epithelial barrier functions in vitro and in vivo. In Aim 2, we will define the impact of oral pathobionts on inflammasome activation in intestinal macrophages. We will identify the inflammasome proteins that are involved in oral pathobiont-driven inflammation in vitro and in vivo. In Aim 3, we will determine the extent to which the genotoxic activity of oral pathobionts contributes to their colitogenic capacity. The rationale for the proposed research is that the identification of pathways by which oral pathobionts elicit intestinal inflammation will result in new and innovative ways to treat IBD. Furthermore, inhibition of the growth of pathobionts in the oral cavity (e.g., by treating oral inflammation) should also reduce the risk of flares/IBD exacerbation by limiting the supply of colitogenic bacteria.