Commensal Exopolysaccharide Protection from Inflammation

共生胞外多糖预防炎症

• 批准号: 8888736
• 负责人: Katherine L. Knight
• 金额: $ 20.06万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8888736
• 关键词: Acute; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Autoimmune Process; Autoimmunity; Bacillus subtilis; Bacteria; Binding; Cells; Chronic; Citrobacter rodentium; Colitis; Data; Development; Disease; Disease model; Dose; Experimental Autoimmune Encephalomyelitis; Food; Food Hypersensitivity; Generations; Grant; Human; ITGAM gene; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Intestines; Intraperitoneal Injections; Lead; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Oral; Ovalbumin; PPAR gamma; Peritoneal; Peritoneal Macrophages; Permeability; Probiotics; Process; Regulatory T-Lymphocyte; Reproduction spores; Signal Transduction; Site; T-Lymphocyte; TLR2 gene; TLR4 gene; Testing; Therapeutic; Time; Wild Type Mouse; YM1 doxorubicin analog; allergic response; cell type; cytokine; design; enteric pathogen; human disease; macrophage; mucosal site; pathogen; prevent; protective effect; public health relevance; receptor; research study; response; therapy development; transcription factor

 DESCRIPTION (provided by applicant): Inflammatory diseases at both mucosal and non-mucosal sites are responsible for disease in millions of people worldwide. We found that a single oral dose of a common probiotic bacteria, Bacillus subtilis protects mice from intestinal inflammation caused by infection with an enteric pathogen, Citrobacter rodentium. B. subtilis is effective if administered as many as 3 days after C. rodentium, a time at which the pathogen has already induced early inflammatory processes. These findings suggest that B. subtilis may not only prevent inflammation, but more importantly, attenuate it. We have identified and purified a molecule, exopolysaccharide (EPS) from B. subtilis that when introduced by itself in a single intraperitoneal injection, prevents colitis induced by enteric pathogens. EPS binds F4/80+CD11b+ macrophages, and we have data indicating that protection by EPS is mediated by M2 macrophages in a TLR4-dependent manner. Further, we found that a 2nd (TLR2-dependent) cell type is required for protection by EPS. We hypothesize that EPS induces the generation of M2 macrophages which secrete cytokines that either render inflammatory T cells non-responsive, or induce development of regulatory T cells. Here, we will establish if M2 macrophages mediate protection and if EPS stimulates these cells via TLR4 signaling. Further, we will test if M2 macrophages secrete anti-inflammatory cytokines and if they inactivate T cells or induce regulatory T cells. Finally, we will use three disease models (food allergy, autoimmunity and inflammatory bowel disease) to test if EPS is effective in acute and/or chronic inflammatory diseases. We have preliminary data indicating that B. subtilis and EPS can protect from food allergy which affects millions of people. Experiments proposed in this grant will enhance our molecular understanding of how probiotic molecules function to treat and/or prevent disease, and lead to the rational application of small therapeutic probiotic molecules to humans.

 描述（由申请人提供）：粘膜和非粘膜部位的炎症是导致全世界数百万人患病的原因。我们发现，单次口服剂量的常见益生菌枯草芽孢杆菌可以保护小鼠免受肠道病原体啮齿类柠檬酸杆菌感染引起的肠道炎症。如果在啮齿类梭菌感染后 3 天施用枯草芽孢杆菌，则枯草芽孢杆菌是有效的，此时病原体已经诱导了早期炎症过程。这些发现表明，枯草芽孢杆菌不仅可以预防炎症，更重要的是可以减轻炎症。我们从枯草芽孢杆菌中鉴定并纯化了一种分子，即胞外多糖（EPS），当将其单独引入单次腹腔注射时，可以预防肠道病原体引起的结肠炎。 EPS 结合 F4/80+CD11b+ 巨噬细胞，我们有数据表明 EPS 的保护是由 M2 巨噬细胞以 TLR4 依赖性方式介导的。此外，我们发现 EPS 的保护需要第二种（TLR2 依赖性）细胞类型。我们假设 EPS 诱导 M2 巨噬细胞的产生，这些细胞分泌的细胞因子要么使炎症 T 细胞无反应，要么诱导调节性 T 细胞的发育。在这里，我们将确定 M2 巨噬细胞是否介导保护作用以及 EPS 是否通过 TLR4 信号传导刺激这些细胞。此外，我们将测试 M2 巨噬细胞是否分泌抗炎细胞因子，以及它们是否使 T 细胞失活或诱导调节性 T 细胞。最后，我们将使用三种疾病模型（食物过敏、自身免疫和炎症性肠病）来测试 EPS 是否对急性和/或慢性炎症性疾病有效。我们的初步数据表明，枯草芽孢杆菌和 EPS 可以预防影响数百万人的食物过敏。这笔资助中提出的实验将增强我们对益生菌分子如何发挥治疗和/或预防疾病作用的分子理解，并导致治疗性益生菌小分子在人类中的合理应用。