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

描述（由申请人提供）：免疫系统失调是许多自身免疫性和炎症性疾病的基础。虽然遗传因素对多发性硬化症、1型糖尿病和炎症性肠病（IBD）等疾病的影响正在研究中，但新的研究强调了环境因素的重要性。人类微生物群，一个寄居在人类体内的微生物联合体，最近成为疾病的一个关键因素。肠道细菌调节免疫系统的发育和功能，并与IBD和实验性结肠炎密切相关。最近的开创性研究已经在临床前模型中发现特定的肠道细菌可以抑制肠道炎症。因此，开发益生菌治疗IBD是一个很有前途的研究领域。我们的实验室已经描述了一个领先的模型系统，用于研究有益的宿主-细菌共生。脆弱拟杆菌是人类微生物组的一种常见成员，可以改善肠道炎症并治疗实验性结肠炎。我们揭示了令人震惊的新数据，即脆弱芽孢杆菌直接激活自噬

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.