A Pediatric Microbial Community to Dissect Host-Commensal Interactions in Type 1 Diabetes

项目总结 1型糖尿病(T1D)是一种影响全球数百万人的自身免疫性疾病。的发病率。 T1D正在上升，特别是在年幼的儿童中。尽管在预测谁是 由于存在患T1D的风险，目前还没有有效的治疗方法来预防这种疾病。无论是遗传还是 环境因素增加了发生T1D的风险。某些人类白细胞抗原(HL A) 单倍型主要阻止T1D的发生，但这一机制值得注意 对自身免疫的保护还没有被很好地理解。NOD小鼠，最广泛使用的T1D模型，不 表达主要组织相容性复合体(MHC)II类E分子。MHCII E基因的转基因表达 NOD小鼠中的分子(Eα16/NOD)完全阻止T1D，反映了对T1D的显性保护 人类。利用这些Eα16/NOD小鼠作为T1D显性遗传保护的模型，我们最近 证明了对自身免疫的保护是通过塑造早期生命的免疫系统来运作的 共生微生物区系。在小鼠模型中建立针对T1D的人类白细胞抗原II类显性保护模型可能提供 支持我们开发基于微生物区系的疗法以预防T1D的长期目标的关键见解 人类。由于肠道微生物群的复杂性和高度变异性，决定了 由免疫系统调节的特定微生物菌株是有问题的。的发展。 具有明确的成体微生物群落的诺生菌小鼠是该领域的重要进展，因为 它们简化了系统的复杂性和可变性，并允许进行控制良好的机械性研究。 然而，缺乏研究儿科疾病的诺生菌小鼠模型。我们利用了Eα16/Nod 从T1D基因保护小鼠模型中产生一种新的灵芝小鼠模型的早期生命 微生物群落，我们称之为儿科社区或“儿科社区-A”。PedsCom-A是由9种细菌组成的联合体 从断奶前糖尿病保护性Eα16/NOD小鼠肠道分离的菌株。我们假设 MHCII分子在肠道微生物群发育早期的形成中发挥着重要作用，并且 这些微生物反过来影响免疫系统的发育，以预防T1D。AIM 1考试 9种细菌在PedsCom-A结节中的相互作用机制及定植动态 小鼠和NOD小鼠表达MHCIIE分子(Eα16/NOD)。Aim 2检查PedsCom-A 微生物可预防NOD和Eα16/NOD小鼠的T1D。这些目标的成功实现将提供至关重要的 关于哪些早期微生物受到MHCII E分子表达的影响而产生 糖尿病保护微生物群，以及构成PedsCom的这9种微生物是否足以 预防易患糖尿病的NOD小鼠的T1D。此外，PedsCom-A鼠标是一种创新的工具 研究早期寄主-微生物区系的相互作用。

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease that affects millions of people worldwide. The incidence of T1D is rising, especially in young children. Although significant progress has been made to predict who is at risk for developing T1D, there are no effective therapies to prevent this disease. Both genetic and environmental factors contribute to the risk of developing T1D. Certain human leukocyte antigen (HLA) haplotypes dominantly protect against the development of T1D, yet the mechanism of this remarkable protection from autoimmunity is not well-understood. NOD mice, the most widely used model of T1D, do not express a major histocompatibility complex (MHC) class II E molecule. Transgenic expression of the MHCII E molecule in NOD mice (Eα16/NOD) completely prevents T1D, mirroring dominant HLA protection from T1D in humans. Using these Eα16/NOD mice as a model of dominant genetic protection from T1D, we recently demonstrated that protection from autoimmunity operates by the immune system shaping the early-life commensal microbiota. Modeling of HLA class II dominant protection from T1D in murine models may provide critical insights to support our long-term goal of developing microbiota-based therapies to prevent T1D in humans. Due to the complexity and high levels of variability of the intestinal microbiome, determining the specific microbial strains that are modulated by the immune system is problematic. The development of gnotobiotic mice with defined adult microbial communities has been an important advance in the field because they simplify the complexity and variability of the system and allow for well-controlled, mechanistic studies. However, a gnotobiotic mouse model to study pediatric disease is lacking. We have leveraged the Eα16/NOD mouse model of genetic protection from T1D to generate a new gnotobiotic mouse model of the early-life microbiome which we call Pediatric Community or “PedsCom-A”. PedsCom-A is a consortium of 9 bacterial strains isolated from the intestine of pre-weaning diabetes-protected Eα16/NOD mice. We hypothesize that MHCII molecules play a major role in shaping the intestinal microbiome early in development, and these microbes in turn impact the development of the immune system to prevent T1D. Aim 1 examines the mechanisms of interaction and colonization dynamics of these 9 bacteria in PedsCom-A colonized NOD mice and NOD mice expressing the MHCII E molecule (Eα16/NOD). Aim 2 examines whether PedsCom-A microbes prevents T1D in NOD and Eα16/NOD mice. Successful completion of these aims will provide critical information on which early-life microbes are influenced by expression of the MHCII E molecule to generate a diabetes-protective microbiome, and whether these 9 microbes that constitute PedsCom are sufficient to prevents T1D in diabetes-prone NOD mice. In addition, PedsCom-A mice are an innovative tool for investigating early-life host-microbiota interactions.