The link between oral bacteria and gut disease

口腔细菌与肠道疾病之间的联系

• 批准号: 10322394
• 负责人: Nobuhiko Kamada
• 金额: $ 39.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-08 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322394
• 关键词: Adherent Culture; Aggravated Colitis; Antibiotics; Bacteria; Chronic; Clinical; Cohort Studies; Colitis; Crohn' s disease; DNA Damage; Data; Development; Disease; Enterobacter; Epithelial; Epithelial Cells; Experimental Models; Flare; Gastrointestinal tract structure; Gnotobiotic; Goals; Growth; Impairment; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1 beta; Interleukin-10; Intervention; Intestinal Mucosa; Intestines; Klebsiella; Knowledge; Lamina Propria; Ligature; Link; Mediating; Mucous Membrane; Mus; Mutagens; Oral; Oral cavity; Oral mucous membrane structure; Organoids; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Periodontitis; Persons; Play; Population; Process; Proteins; Public Health; Relapse; Reporting; Research; Risk; Role; Saliva; Testing; Ulcerative Colitis; United States; antimicrobial; base; commensal bacteria; commensal microbes; dysbiosis; gastrointestinal; genotoxicity; gut colonization; gut inflammation; gut microbiota; in vivo; innovation; insight; macrophage; microbiota; novel; novel therapeutic intervention; oral bacteria; oral microbial community; pathobiont; therapeutically effective; treatment strategy

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.

项目概要/摘要： 潜在的致病性寄生虫种群，即致病生物的异常积累被认为是 导致炎症性肠病（IBD）的发病机制。然而，什么细菌可以被归类为 与疾病相关的致病菌以及这些致病菌如何促进IBD的肠道炎症仍然存在 不太了解。该提案的长期目标是开发新的治疗策略， 靶向IBD相关致病菌及其下游炎症通路，而不影响有益的 肠道细菌。我们的初步数据和最近的研究表明， 在IBD患者的肠粘膜中， IBD。本申请的目的是确定口腔粘膜异位定植的机制， 致病菌在IBD中促进肠道炎症。我们的初步数据表明，口腔炎症诱导 口腔内致病菌的扩张。口腔中致病菌的积累导致口腔中的 肠道中的定植水平。通过口服给药定殖的具有致菌性IBD倾向的IL-10缺陷小鼠 致病菌发展为严重的结肠炎，而被健康的口腔微生物定殖的小鼠则不会。而且我们 初步数据还表明，口腔致病菌诱导结肠上皮细胞中的DNA损伤， 固有层巨噬细胞。基于这些初步结果，我们的核心假设是， 最初发现于生态失调的口腔粘膜中，通过异位肠促进IBD的发病 定殖及其遗传毒性活性。这一假设将通过以下三个具体问题来检验： 目的：在目的1中，我们将研究口腔致病菌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，我们将定义口腔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菌驱动的炎症体蛋白， 体外和体内炎症。在目标3中，我们将确定口服给药的遗传毒性活性的程度。 致病菌有助于它们的产大肠杆菌能力。拟议研究的理由是， 口腔致病菌引起肠道炎症的途径的鉴定将导致新的和创新的 治疗IBD的方法此外，抑制口腔中致病菌的生长（例如，通过治疗口腔 炎症）还应通过限制致大肠杆菌的供应来降低发作/IBD恶化的风险。

项目成果

Mucolytic bacteria license pathobionts to acquire host-derived nutrients during dietary nutrient restriction.

粘液溶解细菌允许病原体在饮食营养限制期间获取宿主来源的营养物质。

• DOI: 10.1016/j.celrep.2022.111093
• 发表时间: 2022
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Sugihara,Kohei;Kitamoto,Sho;Saraithong,Prakaimuk;Nagao-Kitamoto,Hiroko;Hoostal,Matthew;McCarthy,Caroline;Rosevelt,Alexandra;Muraleedharan,ChithraK;Gillilland3rd,MerrittG;Imai,Jin;Omi,Maiko;Bishu,Shrinivas;Kao,JohnY;Alteri,Ch
• 通讯作者: Alteri,Ch

Exploring the Oral-Gut Linkage: Interrelationship Between Oral and Systemic Diseases.

• DOI: 10.1016/j.mucimm.2023.11.006
• 发表时间: 2023-11
• 期刊: Mucosal immunology
• 影响因子: 8
• 作者: Kyoko Yamazaki;Nobuhiko Kamada

The oral-gut axis: a missing piece in the IBD puzzle.

• DOI: 10.1186/s41232-023-00304-3
• 发表时间: 2023-11-06
• 期刊: Inflammation and regeneration
• 影响因子: 8.1

Pathogenic associations between oral and gastrointestinal diseases.

• DOI: 10.1016/j.molmed.2022.05.006
• 发表时间: 2022-12
• 期刊: TRENDS IN MOLECULAR MEDICINE
• 影响因子: 13.6
• 作者: Newman, Kira L.;Kamada, Nobuhiko
• 通讯作者: Kamada, Nobuhiko

Machine learning-assisted immune profiling stratifies peri-implantitis patients with unique microbial colonization and clinical outcomes.

• DOI: 10.7150/thno.57775
• 发表时间: 2021
• 期刊: Theranostics
• 影响因子: 12.4
• 作者: Wang CW;Hao Y;Di Gianfilippo R;Sugai J;Li J;Gong W;Kornman KS;Wang HL;Kamada N;Xie Y;Giannobile WV;Lei YL
• 通讯作者: Lei YL