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

• 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
• 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' 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

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）：免疫系统的失调是许多自身免疫性和炎症性疾病的基础。尽管正在研究对多发性硬化症，1型糖尿病和炎症性肠病（IBD）等疾病的遗传贡献，但新的研究突出了环境因素的重要性。人类微生物组是一个定居人类的微生物联盟，最近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，并与IBD和实验性结肠炎有着强烈的影响。最近的开创性研究表明，特定的肠道细菌可以抑制临床前模型中的肠道炎症。因此，开发IBD益生菌疗法是一个有希望的研究领域。我们的实验室描述了一种研究有益的宿主 - 细菌共生的领先模型系统。人类微生物组的常见成员bacteroides fragilis可以缓解肠道炎症并治疗实验性结肠炎。我们显示出惊人的新数据，即Fragilis直接激活自噬 途径，需要自噬进行其治疗活性。自噬是一种细胞过程，颗粒（例如致病细菌）被降解并破坏。重要的是，自噬基因中的多态性与人IBD高度联系。我们的研究发现了自噬的新作用，作为一种对有益细菌反应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，并且可能对IBD的根本原因具有深远的影响。该项目将调查环境（微生物组）和遗传（自噬）因素合并以促进疾病的新机制。我们将检验以下假设：自噬中的遗传缺陷可能会通过不“传感”并响应有益肠道细菌的保护信号而导致IBD。具体目的包括：1）确定自噬途径的细胞和分子要求； 2）探索自噬作为改善结肠炎的机制； 3）检查由脆弱芽孢杆菌激活的人类细胞中自噬的需求。这些研究有望通过揭示微生物组和自噬之间的先前未批准的联系，从而发现肠道细菌与免疫系统之间的新颖而有趣的相互作用。如果成功的话，该项目的发现将大大提高我们为IBD开发安全有效治疗的长期目标。