Effect of diet & commensal bacteria on diabetes outcome in NOD mouse

描述（由申请人提供）：众所周知，在许多疾病中，除了遗传易感性外，环境因素在决定易感个体是否患上疾病方面起着关键作用。然而，目前还不清楚这些环境因素是什么。环境因素主要是与我们的皮肤和粘膜系统直接相互作用的因素。流行病学研究表明，在过去的二十年里，过敏（皮炎或食物过敏）、哮喘、肥胖和1型糖尿病（T1D）在美国和世界范围内急剧上升。此外，这些人类健康问题的增加与我们环境的变化有关，包括我们的卫生。尽管遗传易感性（如MHC）在1型糖尿病（一种免疫系统介导的疾病）中起着重要作用，但疾病过程在很大程度上受到环境因素的影响，因为a)同卵双胞胎的T1D结局存在显著差异，b)西方世界T1D的发病率要高得多。然而，人们对这些环境因素如何影响疾病发展知之甚少。越来越多的证据表明，共生菌是过敏、炎症性肠病和糖尿病（1型和2型）的重要环境因素之一。在过去的20年里，糖尿病也在全球范围内大幅增加。2008年，仅在美国就有大约2400万糖尿病患者，其中570万人尚未确诊。据估计，还有5700万人处于糖尿病前期（来自美国疾病控制与预防中心的公开信息）。最近的研究表明，共生菌与饮食性肥胖和2型糖尿病有关。然而，对于早期接触某些细菌是否也是影响T1D发展的重要环境因素，我们的知识和理解存在重大差距。我们将使用人类T1D小鼠模型来解决这一重要的空白。我们相信，一旦我们了解了共生菌如何影响T1D发展的基本机制，我们将能够为公众提供更好的知识，并有望设计出预防策略。为了提高我们对益生菌在T1D发展中的作用机制的认识和理解，从而改变共生肠道菌群，并通过改变肠道菌群来确定潜在的预防策略，我们提出了两个特定的目标。目的1。探讨益生菌食品对糖尿病发病的影响。目标2。探讨肠道树突状细胞（DC）在糖尿病发生中的作用。

DESCRIPTION (provided by applicant): It is known that, in addition to genetic susceptibility in many diseases, environmental factors play a critical role in determining whether susceptible individuals develop the disease. However, it is not clear what these environmental factors are. The environmental factors are mostly the factors that have direct interaction with our skin and mucosal systems. Epidemiological studies have shown the sharp rise of allergy (dermatitis or food allergy), asthma, obesity and type 1 diabetes (T1D) in the US and worldwide in the past two decades. Furthermore, the rise of these human health problems is correlated with changes in our environment including our hygiene. Although genetic susceptibility, such as the MHC, play an important role in type 1 diabetes, an immune system-mediated disease, the disease process is significantly shaped by environmental factors as a) there is a significant discordance in T1D outcome in identical twins and b) the incidence of T1D is much higher in the Western world. However, little is known about how those environmental factors affect disease development. Increasing evidence suggests that commensal bacteria act as one of the important environmental factors in allergy, inflammatory bowel disease and diabetes (type 1 and type 2). In the past 20 years, diabetes has also been increasing substantially and globally. In 2008 there were about 24 million people with diabetes in the United States alone, with 5.7 million people remaining undiagnosed. Another 57 million people are estimated to have pre-diabetes (public information from the CDC). Recent studies indicated the association of commensal bacteria with diet induced obesity and type 2 diabetes. However, there is a significant gap in our knowledge and understanding of whether early exposure to certain bacteria also acts as an important environmental factor in affecting T1D development. We will address this important gap using a mouse model of human T1D. We believe that once we understand the basic mechanisms of how commensal bacteria affect T1D development, we will be able to provide better knowledge to the public and hopefully to design a preventive strategy. To improve our knowledge and understanding of the mechanism(s) of probiotic bacteria, hence the change of commensal gut flora, in T1D development, and to identify potential prevention strategy by alteration of gut flora, we propose two specific aims for this challenge topic. Aim 1. To investigate the effect of probiotic food on diabetes development. Aim 2. To investigate the role of gut dendritic cell (DC) in diabetes development. PUBLIC HEALTH RELEVANCE: It is known that, in addition to genetic susceptibility in many diseases, environmental factors play a critical role in determining whether susceptible individuals develop the disease. However, it is not clear what these environmental factors are. The environmental factors are mostly the factors that have direct interaction with our skin and mucosal systems. Epidemiological studies have shown the sharp rise of allergy (dermatitis or food allergy), asthma, obesity and type 1 diabetes (T1D) in the US and worldwide in the past two decades. Furthermore, the rise of these human health problems is correlated with changes in our environment including diet. Although genetic susceptibility, such as the MHC, play an important role in type 1 diabetes, an immune system-mediated disease, the disease process is significantly shaped by environmental factors as a) there is a significant discordance in T1D outcome in identical twins and b) the incidence of T1D is much higher in the Western world. In addition, the rise of T1D is correlated with the rise of allergy and asthma. To account for these changes in incidence and prevalence, the "Hygiene" or "Old Friends" hypothesis has been suggested. This postulates that a reduction in exposure to microorganisms in the environment can lead to a failure of immunoregulation. These "Old Friends" could either be non- saprophytic mycobacteria or lactobacilli which are not pathogenic, or helminths that cause the parasitic infections that are found in developing countries. The idea is that these organisms stimulate regulatory T cells by influencing the maturation of dendritic cells and reduce pathogenic effector cells. This may have the effect of increasing tolerance and bystander suppression, but there may also be other mechanisms which are important to investigate. Recent studies indicated the association of commensal bacteria with a variety of human diseases including allergy and diabetes. However, there is a significant gap in our knowledge and understanding of whether commensal bacteria act as important environmental factors in affecting allergy and diabetes. We will address this important gap using a mouse model of human T1D. Understanding how commensal bacteria shape our immune system, both innate and adaptive immunity, is critical to explain how inflammatory diseases including autoimmune disease, develop and to design new strategies for prevention and treatment of those diseases. Our overall hypothesis for the present study is that "friendly" commensal bacteria, as an environmental factor, can protect against diabetes development through mucosal immunity initiated by dendritic cells (DCs). We will investigate 1) the effect of neonatal environment and probiotic diet on changing gut flora and diabetes development, 2) the role of dendritic cells (DCs) in shaping gut flora and diabetes development. We believe that once we understand the basic mechanisms of how diet and commensal flora affect T1D development, we will be able to provide better knowledge to the public and hopefully to design a preventive strategy. Although we use a diabetes model system, the impact of our study is beyond T1D and could potentially apply to allergy, asthma and possibly other diseases that affect by environments.