Induction of protective IL-10- producing B and T cells by defined subsets of resident intestinal bacteria

Sartor博士融合了他在宿主-微生物相互作用和诺生菌的使用方面的国际公认的专业知识 与基因组科学尖端专家高度互补的小鼠(Shehzad Sheik，Terry Furey)； 分子微生物学和生物信息学(Anthony Fodor，Jeremy Faith，Niels van der Lelie)；代谢组学 临床结果的分子预测因子(Ted Denson，Rebekah Karns)和相当大的 A和B核心资源，以确定保护性常驻细菌物种的关键成员，这些物种优先于 诱导IL-10相关保护性免疫反应的新模型和人源化慢性阻塞性肺疾病 在克罗恩病(CD)患者已建立的队列中进行实验性结肠炎并预测临床结果。 假设：肠道细菌亚群激活保护性IL10相关免疫反应 调节粘膜动态平衡和预测疾病的LP调节性B和T淋巴细胞及代谢物 CD患者的进展和并发症。我们通过三个相辅相成的目标来解决这一假设： 目的1：鉴定选择性诱导产生IL-10的调节性LP B和T的驻留菌种 细胞和防止实验性结肠炎(由核心A支持)。 假设：驻留细菌的亚群选择性地激活LP B和T细胞产生IL10，以及代谢 调节粘膜动态平衡的滴度。经鉴定的细菌菌株将预防和逆转慢性实验。结肠炎。 目的2.确定能够逆转结肠炎的细菌种类的保护机制 假设：关键的保护性细菌物种激活免疫和代谢途径，直接 抑制TH1/17免疫反应和致病细菌亚群，预防和逆转慢性结肠炎。 2a.鉴定保护性细菌菌株的代谢物谱，并测试其保护功能。 2B。确定保护性菌株使腔内和粘膜中的非生物细菌图谱正常化的能力。 2C。鉴定保护性细菌株在IL10、LP、T和B细胞中诱导的保护性免疫通路。 目的3.确定保护性细菌种类和LP细胞转录特征是否可以预测 表型成人和儿童CD队列中的疾病进展和术后复发。 假设：在小鼠中发现保护性细菌种类和IL-10相关转录途径 在确定的CD患者队列中提供疾病进展和并发症的新预测因子。 这项具有高度创新性和临床相关性的研究将对免疫学、新陈代谢和 驻留细菌亚群调节粘膜和微生物动态平衡的微生物机制， 预测临床CD进展、并发症，并最终确定新的治疗细菌种类。

Dr. Sartor blends his internationally recognized expertise in host-microbial interactions and use of gnotobiotic mice with highly complementary cutting-edge experts in genome science (Shehzad Sheik, Terry Furey); molecular microbiology and bioinformatics (Anthony Fodor, Jeremiah Faith, Niels van der Lelie); metabolomics (Kun Lu); molecular predictors of clinical outcomes (Ted Denson, Rebekah Karns) and the considerable resources of Cores A and B to identify key members of protective resident bacterial species that preferentially induce IL-10-associated protective immune responses in novel gnotobiotic and humanized models of chronic experimental colitis and predict clinical outcomes in established cohorts of Crohn’s disease (CD) patients. Hypothesis: Subsets of resident intestinal bacteria activate protective IL10- associated immune responses in LP regulatory B and T lymphocytes and metabolites that mediate mucosal homeostasis and predict disease progression and complications in CD patients. We address this hypothesis through 3 complementary Aims: Aim 1: Identify resident bacterial species that selectively induce IL10- producing regulatory LP B and T cells and protect against experimental colitis (supported by Core A). Hypothesis: Subsets of resident bacteria selectively activate IL10-production by LP B and T cells and metabo- lites that mediate mucosal homeostasis. Identified bacterial strains will prevent and reverse chronic exp. colitis. Aim 2. Identify mechanisms of protection of bacterial species capable of reversing established colitis Hypothesis: Key protective bacterial species activate immunological and metabolic pathways that directly suppress TH1/17 immune responses and pathogenic bacterial subsets to prevent and reverse chronic colitis. 2A. Identify metabolite profiles of protective bacterial strains and test their protective function. 2B. Determine the ability of protective strains to normalize luminal and mucosal dysbiotic bacterial profiles. 2C. Identify protective immunologic pathways induced in IL10+ LP T and B cells by protective bacterial strains. Aim 3. Determine whether protective bacterial species and LP cell transcriptional signatures predict disease progression and post-operative recurrence in phenotyped adult and pediatric CD cohorts. Hypothesis: Protective bacterial species and IL10-associated transcriptional pathways identified in mice provide novel predictors of disease progression and complications in defined CD patient cohorts. This highly innovative and clinically relevant study will yield unique insights into immunologic, metabolic and microbial mechanisms by which resident bacterial subsets mediate mucosal and microbial homeostasis, predict clinical CD progression, complications and ultimately, characterize novel therapeutic bacterial species.