The impact of Helicobacter pylori infection on inflammatory bowel disease suscept

幽门螺杆菌感染对炎症性肠病易感性的影响

• 批准号: 7511415
• 负责人: JOHN Y KAO
• 金额: $ 7.52万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7511415
• 关键词: Address; Animal Model; Bacteria; Bone Marrow; Chronic; Coculture Techniques; Colitis; Condition; Dendritic Cells; Development; Dextran Sulfate; Disease susceptibility; Flare; Gastric mucosa; Gastrointestinal tract structure; Goals; Health; Helicobacter Infections; Helicobacter pylori; IRAK3 gene; Immune response; Immune system; Immunosuppression; In Vitro; Incidence; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Knock-out; Maintenance; Microbe; Mus; Myelogenous; Oral; Pathway interactions; Patients; Peptic Ulcer; Phenotype; Physiologic pulse; Play; Population; Predisposition; Prevention; Probiotics; Production; Pulse taking; Pylorus; Reporting; Research; Risk; Role; Signal Transduction; Small Interfering RNA; Sodium; Sodium Dextran Sulfate; Stomach; T memory cell; T-Lymphocyte; Therapeutic immunosuppression; Vaccination; base; immune function; in vivo; malignant stomach neoplasm; mutant; prevent; response

DESCRIPTION (provided by applicant): Helicobacter pylori colonizes the gastric mucosa of more than half of the world's population. Approximately 10-15% of the infected individuals will go on to develop gastroduodenal ulcers and <3% will develop gastric cancer. Universal vaccination has been proposed and yet the impact of eradicating H. pylori in the 85-90% of otherwise asymptomatic individuals has not been emphasized. One potential negative impact is the possible protective role of H. pylori against the development of inflammatory bowel disease (IBD), a chronic debilitating inflammatory condition of the gastrointestinal tract resulting from a dysregulation of host immune response to resident gut microbes. The broad long-term objective of this proposal is to elucidate the mechanisms of how H. pylori may aid in the prevention of IBD. Several reports indicated lower risk of IBD in patients infected with H. pylori and noted a rising incidence of IBD in regions endemic for H. pylori infection. The mechanism of this association, which is important for defining a causal relationship between H. pylori eradication and increased risk of IBD, is currently unknown. The central hypothesis behind the proposed research is that H. pylori colonization induces regulatory T cells (Tregs) by maintaining toleragenic phenotype of myeloid dendritic cells (DCs) thus decreases host susceptibility to the development of IBD. The rationale for this hypothesis is based on the following observations. First, patients with H. pylori infection were found to have higher Treg response than uninfected individuals. Depletion of Tregs reversed the immunosuppression on memory T cells in those infected with H. pylori. Second, Tregs were shown to play a role in suppressing colitis in mice. Third, our preliminary results show that in vitro, H. pylori maintains the toleragenic phenotype of semi-mature DCs and that, in vivo, H. pylori-pulsed myeloid DCs induce H. pylori-specific Tregs. Thus, the overall goal of this proposal is to examine the role of H. pylori infection in modulating IBD susceptibility. Specific Aims: 1. Study the mechanism of how H. pylori maintains DC toleragenic phenotype. 1.1. To study the role of H. pylori factors (PAI, CagA, VacA) in the maintenance of DC tolerance using knockout strains of H. pylori. C57BL/6 bone marrow-derived DCs will be cocultured with H. pylori mutant strains and TGF-2 production and Tregs induction will be compared. 1.2. To examine the role of TLR-2 signaling and IRAK-M. Using TLR-2 null or IRAK-M siRNA to assess the role of these two pathways in H. pylori-induced DC tolerance. 2. To study the impact of H. pylori-induced Tregs on mouse susceptibility to chronic dextran sulfate sodium (DSS)-colitis. 2.1. To demonstrate the presence of extragastric H. pylori-specific Tregs response induced by H. pylori (oral gavaged H. pylori versus H. pylori-pulsed DC transfer plus oral H. pylori). Mice will be adoptively transferred with PBS-treated DCs or H. pylori-pulsed DCs followed by H. pylori infection. The presence of extragastric H. pylori-specific Tregs will be assessed. 2.2. To study the effect of H. pylori Treg induction on chronic DSS colitis. Mice adoptively transferred with PBS-treated DCs or H. pylori-pulsed DCs followed by H. pylori infection will be treated with DSS to induce chronic colitis. The degree of colitis will be compared to determine the effect of H. pylori-specific Tregs on host susceptibility to colitis. The health relatedness of the project is to understand the impact of H. pylori eradication on the host susceptibility to IBD. The completion of this project will also offer a potential mechanism through which beneficial bacteria (e.g., probiotics) may help to prevent IBD flares. Helicobacter pylori colonizes the gastric mucosa of more than half of the world's population. Approximately 10-15% of the infected individuals will go on to develop gastroduodenal ulcers and <3% will develop gastric cancer. Universal vaccination has been proposed and yet the impact of eradicating H. pylori in the 85-90% of otherwise asymptomatic individuals has not been emphasized. Several reports indicated lower risk of Inflammatory bowel disease (IBD) in patients infected with H. pylori and noted a rising incidence of IBD in regions endemic for H. pylori infection. The mechanism of this association, which is important for defining a causal relationship between H. pylori eradication and increased risk of IBD, is currently unknown. The goals of this proposal are to study how H. pylori may influence the immune system of an individual by inducing suppressive T cells in the host and to show in an animal model of colitis, how H. pylori infection may protect against IBD. The health relatedness of the project is to understand the impact of H. pylori eradication on the host susceptibility to IBD. The completion of this project will also offer a potential mechanism through which beneficial bacteria (e.g., probiotics) may help to prevent IBD flares.

描述（由申请人提供）： 幽门螺杆菌定植于世界一半以上人口的胃粘膜中。大约 10-15% 的感染者将发展为胃十二指肠溃疡，<3% 将发展为胃癌。已提议普遍接种疫苗，但根除幽门螺杆菌对 85-90% 无症状个体的影响尚未得到强调。一个潜在的负面影响是幽门螺杆菌可能对炎症性肠病（IBD）的发展具有保护作用，炎症性肠病是一种慢性的胃肠道炎症性疾病，是由于宿主对肠道微生物的免疫反应失调而导致的。该提案的广泛长期目标是阐明幽门螺杆菌如何帮助预防 IBD 的机制。一些报告表明，感染幽门螺杆菌的患者患 IBD 的风险较低，并指出在幽门螺杆菌感染流行的地区，IBD 的发病率不断上升。这种关联的机制对于确定幽门螺杆菌根除与 IBD 风险增加之间的因果关系非常重要，但目前尚不清楚。这项研究背后的中心假设是，幽门螺杆菌定植通过维持骨髓树突状细胞（DC）的耐受表型来诱导调节性T细胞（Treg），从而降低宿主对IBD发展的易感性。该假设的基本原理基于以下观察。首先，发现幽门螺杆菌感染患者比未感染者具有更高的 Treg 反应。 Tregs 的消耗逆转了幽门螺杆菌感染者记忆 T 细胞的免疫抑制。其次，Tregs 被证明在抑制小鼠结肠炎中发挥作用。第三，我们的初步结果表明，在体外，幽门螺杆菌维持半成熟DC的耐受表型，并且在体内，幽门螺杆菌脉冲的骨髓DC诱导幽门螺杆菌特异性Treg。因此，该提案的总体目标是检查幽门螺杆菌感染在调节 IBD 易感性中的作用。 具体目标： 1. 研究H. pylori维持DC耐受表型的机制。 1.1.使用幽门螺杆菌敲除菌株研究幽门螺杆菌因子（PAI、CagA、VacA）在维持 DC 耐受性中的作用。 C57BL/6 骨髓来源的 DC 将与幽门螺杆菌突变株共培养，并比较 TGF-2 的产生和 Tregs 的诱导。 1.2.检查 TLR-2 信号传导和 IRAK-M 的作用。使用 TLR-2 null 或 IRAK-M siRNA 评估这两种途径在幽门螺杆菌诱导的 DC 耐受中的作用。 2. 研究H. pylori诱导的Tregs对小鼠慢性右旋糖酐硫酸钠（DSS）结肠炎易感性的影响。 2.1.证明胃外幽门螺杆菌特异性 Tregs 反应的存在（口服强饲幽门螺杆菌与幽门螺杆菌脉冲 DC 转移加口服幽门螺杆菌）。将用PBS处理的DC或幽门螺杆菌脉冲的DC过继转移小鼠，然后感染幽门螺杆菌。将评估胃外幽门螺杆菌特异性 Tregs 的存在。 2.2.研究H. pylori Treg诱导对慢性DSS结肠炎的影响。过继转移PBS处理的DC或幽门螺杆菌脉冲的DC然后感染幽门螺杆菌的小鼠将用DSS处理以诱导慢性结肠炎。将比较结肠炎的程度以确定幽门螺杆菌特异性Tregs对宿主结肠炎易感性的影响。该项目的健康相关性是了解根除幽门螺杆菌对宿主对 IBD 易感性的影响。该项目的完成还将提供一种潜在机制，有益细菌（例如益生菌）可以通过该机制帮助预防 IBD 发作。幽门螺杆菌定植于世界一半以上人口的胃粘膜中。大约 10-15% 的感染者将发展为胃十二指肠溃疡，<3% 将发展为胃癌。已提议普遍接种疫苗，但根除幽门螺杆菌对 85-90% 无症状个体的影响尚未得到强调。一些报告表明，感染幽门螺杆菌的患者患炎症性肠病 (IBD) 的风险较低，并指出在幽门螺杆菌感染流行的地区，炎症性肠病 (IBD) 的发病率不断上升。这种关联的机制对于确定幽门螺杆菌根除与 IBD 风险增加之间的因果关系非常重要，但目前尚不清楚。该提案的目标是研究幽门螺杆菌如何通过诱导宿主中的抑制性 T 细胞来影响个体的免疫系统，并在结肠炎动物模型中展示幽门螺杆菌感染如何预防炎症性肠病。该项目的健康相关性是了解根除幽门螺杆菌对宿主对 IBD 易感性的影响。该项目的完成还将提供一种潜在机制，有益细菌（例如益生菌）可以通过该机制帮助预防 IBD 发作。