Protection from Mucosal Pathology by Gut Microbiota during Colitis

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。虽然多发性硬化症，1型糖尿病和炎症性肠病（IBD）的遗传贡献正在研究中，但大量的新研究强调了环境因素的重要性。肠道微生物组是一种定植于人类胃肠道的微生物联盟，已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，作为一种信号通路，被有益细菌用来介导对结肠炎的保护。肠道微生物组和自噬之间的这种联系以前没有研究过，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）因素合并影响肠道疾病的新机制。我们将测试创新的假设，即自噬的遗传缺陷通过阻止对肠道细菌保护信号的反应而导致IBD。具体目标包括：1）确定B. fragilis激活自噬; 2）了解自噬如何在临床前模型中抑制肠道炎症; 3）检查来自具有自噬基因多态性的IBD患者的细胞以阐明B。fragilis影响人体免疫反应。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。完成后，该项目的发现将大大推进我们开发安全有效的IBD治疗方法的长期目标。

DESCRIPTION (provided by applicant): Dysregulation of the immune system underlies many autoimmune and inflammatory diseases. While genetic contributions to multiple sclerosis, type 1 diabetes and inflammatory bowel disease (IBD) are being studied, abundant new research highlights the importance of environmental factors. The gut microbiome, a consortium of microbes that colonize the human gastrointestinal tract, has emerged 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 signaling pathway that is used by beneficial bacteria to mediate protection from colitis. This connection between the gut microbiome and autophagy has not been previously 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 impact intestinal disease. We will test the innovative hypothesis that genetic defects in autophagy lead to IBD by preventing responses to protective signals from gut bacteria. Specific aims include: 1) defining the signaling pathways by which B. fragilis activates autophagy; 2) understanding how autophagy suppresses intestinal inflammation in preclinical models; 3) examining cells from IBD patients with polymorphisms in autophagy genes to elucidate how B. fragilis impacts human immune responses. 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. Upon completion, discoveries from this project will significantly advance our long-term goal of developing a safe and effective treatment for IBD.