Microbiome-induced autophagy as a novel therapy for inflammatory bowel disease

微生物组诱导的自噬作为炎症性肠病的新疗法

基本信息

批准号：
8878035
负责人：
Hiutung Chu
金额：
$ 5.6万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878035
关键词：
Affect Animal Disease Models Anti-Inflammatory Agents Anti-inflammatory Area Autoimmune Process Autophagocytosis Autophagolysosome Bacteria Bacteroides fragilis Biological Models Blood Cells Cell Culture Techniques Cell physiology Cells Clinical Colitis Crohn&apos s disease Data Defect Dendritic Cells Development Diagnosis Disease Disease susceptibility Employee Strikes Environment Environmental Risk Factor Genes Genetic Genetic Polymorphism Goals Human Human Microbiome Immune response Immune system Immunosuppression In Vitro Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Insulin-Dependent Diabetes Mellitus Interleukin-10 Intestines Laboratories Lead Link Mediating Medical Membrane Microbe Molecular Multiple Sclerosis Mus Mutation Outcome Pathogenesis Pathway interactions Patients Pattern recognition receptor Pb clearance Play Polysaccharides Pre-Clinical Model Predisposition Probiotics Process Production Proteins Public Health Research Research Project Grants Resources Role Seminal Signal Pathway Signal Transduction Susceptibility Gene Symbiosis T-Lymphocyte Testing Therapeutic Translating Vesicle advanced disease base clinical application commensal microbes effective therapy fascinate genome wide association study immune activation in vivo innovation insight medical complication member microbial microbiome mouse model novel particle pathogenic bacteria prevent public health relevance response social

项目摘要

DESCRIPTION (provided by applicant): Dysregulation of the immune system underlies many autoimmune and inflammatory diseases. While genetic contributions to disorders such as multiple sclerosis, type 1 diabetes and inflammatory bowel disease (IBD) are being studied, new research highlights the importance of environmental factors. The human microbiome, a consortium of microbes that colonize humans, has emerged recently as a critical contributor to disease. Gut bacteria regulate the development and function of the immune system, and have been strongly implicated in IBD and experimental colitis. Recent seminal studies have identified that specific gut bacteria can suppress intestinal inflammation in preclinical models. Thus development of probiotic therapies for IBD is a promising area of research. Our laboratory has described a leading model system for studying beneficial host-bacterial symbiosis. Bacteroides fragilis, a common member of the human microbiome, ameliorates gut inflammation and treats experimental colitis. We reveal striking new data that B. fragilis directly activates the autophagy pathway, and requires autophagy for its therapeutic activity. Autophagy is a cellular process whereby particles (such as pathogenic bacteria) are degraded and destroyed. Importantly, polymorphisms in autophagy genes are highly linked to human IBD. Our research uncovers a new role for autophagy, as a pathway that responds to beneficial bacteria and mediates immune suppression. This connection between the gut microbiome and autophagy has previously not been studied, and may have profound implications to the underlying cause(s) of IBD. This project will investigate novel mechanisms by which environmental (microbiome) and genetic (autophagy) factors merge to contribute to disease. We will test the hypothesis that genetic defects in autophagy may lead to IBD by not 'sensing' and responding to the protective signals of beneficial gut bacteria. Specific aims include: 1) Determining cellular and molecular requirements for B. fragilis activation of the autophagy pathway; 2) Exploring autophagy as a mechanism for amelioration of colitis; 3) Examining the requirement for autophagy in human cells activated by B. fragilis. These studies promise to uncover novel and fascinating interactions between gut bacteria and the immune system, by revealing a previously unappreciated link between the microbiome and autophagy. If successful, discoveries from this project will significantly advance our long-term goal of developing a safe and effective treatment for IBD.

描述（由申请人提供）：免疫系统失调是许多自身免疫性疾病和炎症性疾病的基础。虽然遗传对多发性硬化症、1 型糖尿病和炎症性肠病 (IBD) 等疾病的影响正在研究，但新的研究强调了环境因素的重要性。人类微生物组是寄生在人类身上的微生物群落，最近已成为疾病的关键因素。肠道细菌调节免疫系统的发育和功能，并且与 IBD 和实验性结肠炎密切相关。最近的开创性研究发现，特定的肠道细菌可以在临床前模型中抑制肠道炎症。因此，开发 IBD 益生菌疗法是一个有前途的研究领域。我们的实验室描述了一种用于研究有益宿主-细菌共生的领先模型系统。脆弱拟杆菌是人类微生物组的常见成员，可改善肠道炎症并治疗实验性结肠炎。我们揭示了脆弱拟杆菌直接激活自噬的惊人新数据途径，并且需要自噬来发挥其治疗活性。自噬是一种细胞过程，颗粒（例如病原菌）被降解和破坏。重要的是，自噬基因的多态性与人类 IBD 高度相关。我们的研究揭示了自噬的新作用，它是一种响应有益细菌并介导免疫抑制的途径。肠道微生物组和自噬之间的这种联系以前尚未被研究过，并且可能对 IBD 的根本原因产生深远的影响。该项目将研究环境（微生物组）和遗传（自噬）因素合并导致疾病的新机制。我们将检验这样一个假设：自噬的遗传缺陷可能通过不“感知”和响应有益肠道细菌的保护信号而导致 IBD。具体目标包括： 1) 确定脆弱拟杆菌激活自噬途径的细胞和分子需求； 2）探索自噬作为改善结肠炎的机制； 3) 检查脆弱拟杆菌激活的人体细胞自噬的需求。这些研究有望通过揭示微生物组和自噬之间以前未被认识到的联系来揭示肠道细菌和免疫系统之间新颖且令人着迷的相互作用。如果成功，该项目的发现将显着推进我们开发安全有效的 IBD 治疗方法的长期目标。