The impact of TLR1 on dysbiosis and intestinal inflammation

TLR1对生态失调和肠道炎症的影响

• 批准号: 8431167
• 负责人: R William DePaolo
• 金额: $ 8.2万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431167
• 关键词: Bacteria; Cells; Childhood; Colitis; Complex; Data; Desulfovibrio desulfuricans; Diet; Disease; Environment; Etiology; Failure; Gastroenteritis; Gene Mutation; Genetic; Genetic Polymorphism; Goals; Human; Immune response; Immune system; Individual; Infection; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Integration Host Factors; Lactobacillus; Lead; Microbe; Modeling; Mucosal Immunity; Mucositis; Mus; Mutation; Patients; Probiotics; Reactive Oxygen Species; Research Project Grants; Respiration; Risk; Role; Severities; Signal Transduction; Single Nucleotide Polymorphism; Sodium Dextran Sulfate; Surface; TLR1 gene; Therapeutic; Tissues; Ulcerative Colitis; Virulence; Weight Gain; Yersinia; Yersinia enterocolitica; commensal microbes; gut microbiota; insight; microbial; mouse model; neutrophil; novel; pathogen; prevent; public health relevance; reconstitution; sulfate reducing bacteria; treatment strategy

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is caused by the complex interaction of host genetics, environmental insults such as diet or infection, and the gut microbiota. While it is well accepted that commensal microbiota are involved in the etiology of IBD, it is not well understood how changes in the microbiota, termed dysbiosis, occur nor is it understood the impact that dysbiosis has on mucosal immunity. Our preliminary data demonstrate that a polymorphism in human TLR1, which abrogates signaling, is selected in pediatric IBD patients. Using a mouse model, we have found that TLR1-deficient mice infected with Yersinia have a failure to gain weight, demonstrate anti-commensal immune responses and have an altered microbiota ten weeks after infection. Specifically, we see an increase in sulfate-reducing bacteria, which has also been identified in patients with IBD, and a concomitant decrease in probiotic Lactobacillus. Herein, I propose an extension of research project (K01 DK8275) that will examine the cause of dysbiosis in the absence of TLR1-signaling after infection by the enteropathogen, Yersinia enterocolitica. The project will look to identify host factors, pathogenic strategies and the contribution of commensal bacteria that contribute to dysbiosis. Further, we will examine how an altered microbiota may impact inflammation and mucosal immunity. These data will provide important insights into how genetics can influence mucosal immunity as well as suggest a new set of strategies to tailor treatments to patients with particular genetic backgrounds.

描述（由申请人提供）：炎症性肠病（IBD）是由宿主遗传、环境损害（如饮食或感染）和肠道微生物群的复杂相互作用引起的。虽然人们普遍认为共生微生物群与IBD的病因有关，但人们尚不清楚微生物群的变化（称为生态失调）是如何发生的，也不清楚生态失调对粘膜免疫的影响。我们的初步数据表明，在儿童IBD患者中选择了人类TLR1的多态性，该多态性可以消除信号传导。通过小鼠模型，我们发现感染耶尔森菌的tlr1缺陷小鼠体重增加失败，表现出抗共生免疫反应，感染10周后微生物群发生改变。具体来说，我们看到硫酸盐还原菌的增加，这也在IBD患者中被发现，同时益生菌乳酸杆菌的减少。在此，我提出了一项研究项目（K01 DK8275）的扩展，该项目将研究在肠道病原体小肠结肠炎耶尔森菌感染后缺乏tlr1信号的情况下生态失调的原因。该项目将寻求确定宿主因素，致病策略和共生细菌的贡献，有助于生态失调。此外，我们将研究改变的微生物群如何影响炎症和粘膜免疫。这些数据将为遗传学如何影响粘膜免疫提供重要的见解，并为具有特定遗传背景的患者提供一套新的治疗策略。