Mechanism of dietary indole-mediated attenuation Helicobacter-induced inflammation and colitis

膳食吲哚介导的减弱螺杆菌引起的炎症和结肠炎的机制

• 批准号: 9767821
• 负责人: TRACI L TESTERMAN
• 金额: $ 19.74万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9767821
• 关键词: Adoptive Transfer; American; Animal Model; Animals; Anti-inflammatory; Aryl Hydrocarbon Receptor; Attenuated; Bacteria; Cells; Chemicals; Chemopreventive Agent; Clinical; Colectomy; Colitis; Colon; Colon Carcinoma; Colorectal Cancer; Data; Development; Dietary Indole; Dietary Phytochemical; Direct Costs; Disease; Epithelial; Equilibrium; Experimental Models; FOXP3 gene; Facilities and Administrative Costs; Future; Goals; Helicobacter; Helicobacter Infections; Human; Immune response; Immunologics; In Vitro; Individual; Indole-3-Carbinol; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-17; Intestinal Mucosa; Knockout Mice; Knowledge; Lead; Lentivirus Vector; Liver diseases; Malignant Neoplasms; Mediating; MicroRNAs; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Nature; Outcome; Patients; Phase; Phytochemical; Prevalence; Property; Regulation; Regulatory T-Lymphocyte; Risk; Risk Estimate; Role; Sodium Dextran Sulfate; Symptoms; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; United States; Wild Type Mouse; Work; aryl hydrocarbon receptor ligand; attenuation; base; cancer cell; cancer therapy; colon carcinogenesis; colorectal cancer prevention; combat; cruciferous vegetable; design; dietary supplements; diindolylmethane; efficacy testing; experimental study; gut microbiota; hepatobiliary cancer; immunoregulation; in vitro testing; in vivo; insight; intestinal homeostasis; lifetime risk; lost work time; novel; prophylactic; response; targeted treatment; transcription factor; virtual

Project Summary/Abstract Inflammatory bowel disease (IBD) afflicts over one million Americans, causing considerable suffering and lost work time. The direct and indirect costs of IBD were estimated to be between $14.6 and $31.6 billion in 2014. Furthermore, IBD greatly increases the risk of developing colorectal cancer. Bacteria are now believed to be key players in both IBD and colorectal cancer. A number of Helicobacter species infect the human colon and are known to cause colitis and colon cancer in colitis-prone mouse strains. We have exciting data showing that H. muridarum exacerbates dextran sulfate sodium (DSS) induced colitis in wild-type mice. There are no studies on the immune response triggered by H. muridarum. Thus, this EHH species offers a unique experimental model to understand how colitis is triggered in an immunologically normal animal following a chemical insult. Recent studies have shown that dietary indoles, such as Indole-3-carbinol (I3C), derived from cruciferous vegetables, have a number of anti-inflammatory and anti-carcinogenic properties. Our preliminary studies showed that I3C attenuates H. muridarum+DSS-mediated exacerbation of colitis and inflammation in the colon. Furthermore, we noted that I3C treatment decreases the expression of miR-874, which targets FOXP3, and increases that of miR- 30b which targets for RORC (RORγt) as well as increases miR-5112 that targets IL-17. Based on these data, in the current study, we will test the central hypothesis that I3C attenuates colitis and inflammation induced by H. muridarum through alterations in the expression of miRs that promote a switch in T cell differentiation from Th17 to Tregs. The mechanisms of colitis exacerbation involving inflammation by H. muridarum are also not known. Thus, it is critical to understand the nature of immune response against Helicobacter species in IBD. To that end, we will simultaneously explore immunological and regulatory changes induced by these two agents. First, we will examine the T cell responses occurring during DSS-mediated colitis with and without H. muridarum infection and with and without I3C treatment. Our primary focus will be regulatory T cells (Treg), which are critical for intestinal homeostasis. Next, we will determine whether H. muridarum can trigger colitis in Aryl hydrocarbon receptor (AhR)-deficient mice which fail to generate enough Tregs and are more susceptible to colitis. These mice will also be used to test the efficacy of I3C, which has been known to act as an AhR ligand. Finally, we will determine whether specific microRNA species induced by I3C contribute to the Treg response by changing FoxP3 expression both in vitro and in vivo. Together, the insights gained from these experiments will be essential for understanding the mechanisms of action of I3C and could lead to additional highly targeted treatments. This project will not only characterize the nature of immune response triggered by H. muridarum during DSS-induced colitis but also test the mode of action of I3C on H. muridarum-associated colitis. These data will support future explorations to investigate the role of other Helicobacter species in clinical IBD and the potential use of I3C in the treatment of IBD.

项目摘要/摘要 炎症性肠病(IBD)困扰着100多万美国人，造成相当大的痛苦和损失 工作时间到了。2014年，IBD的直接和间接成本估计在146亿至316亿美元之间。 此外，IBD极大地增加了发展为结直肠癌的风险。细菌现在被认为是 在炎症性肠病和结直肠癌中扮演着重要角色。许多幽门螺杆菌会感染人类的结肠和 已知会在易患结肠炎的小鼠身上引起结肠炎和结肠癌。我们有令人兴奋的数据表明 小鼠嗜血杆菌加重葡聚糖硫酸钠(DSS)诱导的野生型小鼠结肠炎。目前还没有研究 关于H.Muridarum引发的免疫反应。因此，这种Ehh物种提供了一个独特的实验模型 为了了解在化学侮辱后免疫正常的动物是如何触发结肠炎的。近期 研究表明，饮食中的吲哚，如来自十字花科蔬菜的吲哚-3-甲醇(I3C)， 具有许多抗炎和抗癌的特性。我们的初步研究表明，I3C 减轻H.Muridarum+DSS介导的结肠炎和结肠炎的加重。此外，我们 指出，I3C处理降低了针对FOXP3的miR-874的表达，增加了miR-874的表达。 30B针对RORC(RoRγt)以及增加针对IL-17的miR-5112。根据这些数据，在 在目前的研究中，我们将检验I3C减轻H. 通过改变miRs的表达促进T细胞从Th17向外分化 敬特雷格斯。由H.Muridarum引起的结肠炎恶化的机制也尚不清楚。 因此，了解IBD中针对幽门螺杆菌的免疫反应的本质是至关重要的。到那时候 最后，我们将同时探讨这两种药物诱导的免疫学和调节性变化。第一, 我们将研究DSS介导的结肠炎在感染和不感染H.Muridarum的情况下T细胞反应。 感染以及接受和不接受I3C治疗的情况。我们的主要关注点是调节性T细胞(Treg)，这是至关重要的 维持肠道内环境平衡。接下来，我们将确定鼠疫杆菌是否会在芳烃中引发结肠炎。 受体(AhR)缺陷小鼠不能产生足够的Tregs，更容易患结肠炎。这些 小鼠也将被用来测试I3C的疗效，I3C已被认为是AhR配体。最后，我们会 确定I3C诱导的特定microRNA物种是否通过改变 Foxp3在体外和体内均有表达。总而言之，从这些实验中获得的见解将是至关重要的 以了解I3C的作用机制，并可能导致更多的高度靶向治疗。这 项目将不仅描述在DSS诱导的过程中由H.Muridarum触发的免疫反应的性质 结肠炎，但也测试I3C对H.Muridarum相关性结肠炎的作用模式。这些数据将支持未来 探讨其他幽门螺杆菌在临床IBD中的作用及I3C在IBD中的潜在应用 IBD的治疗。