The Microbiome Mediates Protections from Colitis Through Pathways Linked to IBD

项目摘要/摘要 免疫系统的失调是许多自身免疫性和炎症性疾病的基础。与…一致 人类基因组，肠道微生物区系调节免疫系统的发育和功能， 调节促炎和抗炎反应之间的平衡。相当多的证据 基于临床前和临床研究表明肠道微生物在炎症性肠病中起关键作用 疾病(IBD)，一种发病率不断上升但治疗有限的特发性肠道疾病家族 选择。同卵双胞胎的符合率为30%-40%，这意味着基因与环境的相互作用。 全基因组关联研究表明，大约200个易感基因座与 与IBD有关。许多变体编码与微生物识别和免疫有关的基因， 提示宿主-微生物的相互作用可能调节免疫健康和炎症之间的平衡 疾病。自噬途径基因的多态性(如ATG16L1)和模式识别 与自噬相关的受体(例如，NOD2)代表了一些最显著的效应大小 在IBD易感性方面。此外，相当多的研究集中在研究Atg16L1和Atg16L1的功能 NOD2在小鼠模型和人类细胞中的表达，并确定了这两种基因产物在传感和杀伤中的作用 致病微生物。因此，目前的理解表明，IBD可能是由 损害对致病菌的免疫力，导致长期接触激活的微生物产品 不受控制的炎症。在这里，我提出了新的发现，有益的肠道细菌，如脆弱类杆菌 需要Atg16L1和NOD2来促进小鼠和人类细胞以及小鼠的抗炎反应 这些基因中缺失的基因并不能保护脆弱杆菌免受结肠炎的侵袭。我提出了一个新颖的、不多余的角色 以前涉及识别和杀死病原菌的基因--即基因突变 与IBD相关的途径会导致对微生物组中有益分子的识别出现缺陷。我的 假设Atg16L1的遗传缺陷可能通过不“感知”和对保护性反应导致IBD 有益肠道细菌的信号。我将在三个具体目标上测试我的假设，其中包括：1)定义 脆弱芽孢杆菌免疫调节所需的细胞途径(S)；2)确定Atg16L1的作用机制 在脆弱芽孢杆菌诱导调节性T细胞过程中；3)确定是否需要NOD2来介导 脆弱芽孢杆菌对小鼠和人类系统的有益影响。换句话说，没有感知和 对抗炎细菌信号的反应可能是慢性肠炎的一个危险因素。这个 该奖项的培训(K99)阶段将由Sarkis Mazmanian博士指导，并将促进 我的研究计划转向一个独立的调查员(R00)。

PROJECT SUMMARY/ABSTRACT Dysregulation of the immune system underlies many autoimmune and inflammatory diseases. In concert with the human genome, the intestinal microbiota regulate development and function of the immune system, modulating the balance between pro- and anti-inflammatory responses. A considerable body of evidence based on preclinical and clinical research suggests that gut microbes play a critical role in inflammatory bowel disease (IBD), a family of idiopathic intestinal disorders with increasing prevalence and limited treatment options. Concordance rates of 30-40% among monozygotic twins implicate gene-environment interactions. Genome wide association studies have implicated roughly 200 susceptibility loci that are significantly associated with IBD. Many variants encode for genes involved in microbial recognition and immunity, suggesting host-microbe interactions may regulate the balance between immune health and inflammatory disease. Polymorphisms in genes of the autophagy pathway (e.g., ATG16L1), and in pattern recognition receptors that are associated with autophagy (e.g., NOD2), represent some of the most significant effect sizes in IBD susceptibility. Further, considerable research has focused on investigating the function of Atg16L1 and NOD2 in mouse models and human cells, and identified a role for both gene products in sensing and killing pathogenic microbes. Current understanding therefore suggest that IBD may be caused by mutations that impair immunity to pathogenic bacteria, leading to chronic exposure to microbial products that activates uncontrolled inflammation. Herein, I present new findings that beneficial gut bacteria such a Bacteroides fragilis require Atg16L1 and NOD2 to promote anti-inflammatory responses in mouse and human cells, and mice deleted in these genes are not protected from colitis by B. fragilis. I propose a novel, non-redundant role for genes previously implicated in recognition and killing of pathogenic bacteria—namely, mutations in genetic pathways linked to IBD result in defective recognition of beneficial molecules from the microbiome. My hypothesis is that genetic defects in Atg16L1 may lead to IBD by not `sensing' and responding to the protective signals of beneficial gut bacteria. I will test my hypothesis in three Specific Aims, which include: 1) defining the cellular pathway(s) required for immune regulation by B. fragilis; 2) Determining Atg16L1 mechanism of action during regulatory T cell induction by B. fragilis; 3) Establishing whether NOD2 is required for mediating the beneficial effects of B. fragilis in mouse and human systems. In other words, the absence of sensing and responding to anti-inflammatory bacterial signals may be a risk factor for chronic intestinal inflammation. The training (K99) phase of this award will be mentored by Dr. Sarkis Mazmanian, and will facilitate the transition of my research program towards an independent investigator (R00).