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

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。人类微生物组，一个殖民于人类的微生物联盟，最近已经成为疾病的关键贡献者。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确定，特定的肠道细菌可以在临床前模型中抑制肠道炎症。因此，IBD的益生菌疗法的开发是一个有前途的研究领域。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。我们揭示了惊人的新数据，B。fragilis直接激活自噬 途径，并且需要自噬用于其治疗活性。自噬是一种细胞过程，其中颗粒（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，作为一种对有益细菌做出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没有被研究过，可能对IBD的根本原因有深远的影响。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。我们将测试这样一个假设，即自噬中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B的细胞和分子需求。fragilis激活自噬途径; 2）探索自噬作为改善结肠炎的机制; 3）检查由B激活的人细胞中自噬的需要。脆弱的这些研究有望揭示肠道细菌和免疫系统之间新颖而迷人的相互作用，揭示微生物组和自噬之间以前未被认识的联系。如果成功，该项目的发现将大大推进我们开发安全有效治疗IBD的长期目标。

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.