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

饮食的影响

• 批准号: 7941018
• 负责人: Li Wen
• 金额: $ 49.14万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941018
• 关键词: Accounting; Address; Affect; Age; Age-Months; Allergic Disease; Animal Model; Asthma; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacteria; Biological Models; Bystander Suppression; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Dendritic Cells; Dermatitis; Developing Countries; Development; Diabetes Mellitus; Diet; Disease; Disease Outcome; Effector Cell; Environment; Environmental Risk Factor; Epidemiologic Studies; Exposure to; Failure; Female; Food; Food Hypersensitivity; Friends; Genetic Predisposition to Disease; Genus Mycobacterium; Health; Helminths; Housing; Human; Hygiene; Hypersensitivity; Immune response; Immune system; Inbred NOD Mice; Incidence; Individual; Infiltration; Inflammatory; Inflammatory Bowel Diseases; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Lactobacillus; Lead; Mediating; Modeling; Mononuclear; Monozygotic twins; Mucosal Immunity; Mus; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Outcome; Parasitic infection; Play; Prediabetes syndrome; Prevalence; Prevention strategy; Probiotics; Process; Regulatory T-Lymphocyte; Role; Shapes; Skin; Stimulus; System; T-Lymphocyte; Time; United States; Western World; adaptive immunity; commensal microbes; design; diabetic; environmental change; human disease; immunoregulation; improved; insight; macrophage; male; microorganism; mouse model; public health relevance; response; type I and type II diabetes

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.

描述（由申请人提供）：众所周知，除了许多疾病的遗传易感性外，环境因素在决定易感个体是否发生疾病方面起着关键作用。但目前尚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有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，美国和世界范围内的过敏（皮炎或食物过敏），哮喘，肥胖和1型糖尿病（T1D）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。虽然遗传易感性，如MHC，在1型糖尿病，一种免疫系统介导的疾病中发挥重要作用，但疾病过程明显受环境因素影响，因为a）同卵双胞胎中T1D结果存在显著不一致，B）T1D的发病率在西方世界要高得多。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，肠道细菌是过敏、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，另有5700万人患有糖尿病前期（来自CDC的公共信息）。最近的研究表明，肠道细菌与饮食诱导的肥胖和2型糖尿病有关。然而，我们对早期暴露于某些细菌是否也是影响T1D发展的重要环境因素的认识和理解存在重大差距。我们将使用人类T1D的小鼠模型来解决这一重要差距。我们相信，一旦我们了解了肠道细菌如何影响T1D发展的基本机制，我们将能够为公众提供更好的知识，并有希望设计预防策略。为了提高我们对益生菌机制的认识和理解，从而改变T1D发展中的肠道植物群，并通过改变肠道植物群来确定潜在的预防策略，我们针对该挑战主题提出了两个具体目标。目标1.探讨益生菌食品对糖尿病发生发展的影响。目标二。目的探讨肠道树突状细胞（DC）在糖尿病发病中的作用。 公共卫生相关性：众所周知，除了许多疾病的遗传易感性之外，环境因素在决定易感个体是否发展疾病方面起着关键作用。但目前尚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有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，美国和世界范围内的过敏（皮炎或食物过敏），哮喘，肥胖和1型糖尿病（T1D）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，包括饮食。虽然遗传易感性，如MHC，在1型糖尿病，一种免疫系统介导的疾病中发挥重要作用，但疾病过程明显受环境因素影响，因为a）同卵双胞胎中T1D结果存在显著不一致，B）T1D的发病率在西方世界要高得多。此外，T1D的上升与过敏和哮喘的上升相关。为了解释这些发病率和患病率的变化，有人提出了“卫生”或“老朋友”假说。这就假定，环境中微生物暴露的减少会导致免疫调节的失败。这些“老朋友”可能是非致病性的非嗜盐分枝杆菌或乳酸杆菌，或者是在发展中国家发现的引起寄生虫感染的蠕虫。这个想法是，这些生物体通过影响树突状细胞的成熟来刺激调节性T细胞，并减少致病性效应细胞。这可能具有增加耐受性和旁观者抑制的作用，但也可能存在其他重要的研究机制。最近的研究表明，肠道细菌与各种人类疾病，包括过敏和糖尿病。然而，在我们的知识和理解中，对于肠道细菌是否作为影响过敏和糖尿病的重要环境因素，存在着显著的差距。我们将使用人类T1D的小鼠模型来解决这一重要差距。了解肠道细菌如何塑造我们的免疫系统，包括先天性和适应性免疫，对于解释包括自身免疫性疾病在内的炎症性疾病如何发展和设计预防和治疗这些疾病的新策略至关重要。本研究的总体假设是，“友好”的肠道细菌作为一种环境因素，可以通过树突状细胞（DC）启动的粘膜免疫来保护糖尿病的发展。我们将研究1）新生儿环境和益生菌饮食对改变肠道植物群和糖尿病发展的影响，2）树突状细胞（DC）在塑造肠道植物群和糖尿病发展中的作用。我们相信，一旦我们了解了饮食和植物植物群如何影响T1D发展的基本机制，我们将能够为公众提供更好的知识，并有望设计预防策略。虽然我们使用的是糖尿病模型系统，但我们研究的影响超出了T1D，可能适用于过敏、哮喘和其他可能受环境影响的疾病。