Diet and microbiota in type 1 diabetes

1 型糖尿病的饮食和微生物群

• 批准号: 8815476
• 负责人: ALEXANDER V CHERVONSKY
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815476
• 关键词: Affect; Animals; Autoimmunity; Bacteria; Beta Cell; Caseins; Cells; Cellular Stress; Development; Diabetes Mellitus; Diet; Diet Modification; Dietary Intervention; Disease; Exposure to; Gene Expression; Germ-Free; Gluten; Gnotobiotic; Health; High-Throughput Nucleotide Sequencing; Human; Immune system; Inbred NOD Mice; Incidence; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Knowledge; Link; Measures; Metabolic; Methods; Microbe; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organism; Outcome; Physiological; Population; Process; Property; Proteins; Protozoa; Regulation; Role; Signal Transduction; Source; Stress; T-Cell Receptor; Testing; Time; Tissues; Transgenic Organisms; Transglutaminases; Uncertainty; Variant; Work; attenuation; cell type; diabetic; fungus; gut microbiota; microbial; microbial community; prevent; protective effect; public health relevance; reconstitution; research study; restoration; transglutaminase 2

DESCRIPTION (provided by applicant): Among many human maladies that are affected by commensal microbiota are both types of diabetes -Type 1 (T1D), which develops due to the loss of insulin producing cells, and Type 2 (T2D), which develops due to the attenuation of the insulin-induced signaling in the tissues. The studies of environmental influences on T1D incidence evoked the possibility of dietary modification of the disease incidence. However, it was obvious to us that consumed nutrients are substrates for commensal microbiota, and changes in the diet can rapidly change the microbiota. Changes in microbiota can change the metabolic landscape affecting the host. For using protective diet in diverse human populations, which can have significant variation in microbiota, one should consider finding optimal diet that would be independent of microbiota variation. We have established that diet containing hydrolyzed casein (HC) as the protein source was protective in diabetes-prone NOD mice independently of the presence of microbiota. Moreover, addition of gluten to HC diet restored T1D development, but this restoration was dependent on intestinal microbiota. Finally, HC diet did not directly affect the immune system, but enhanced the vigor of insulin-producing cells. To further uncover the mechanisms behind protective properties of the HC diet, we will pursue the following aims. 1. Investigate the limits of dietary intervention We will investigate the time limts of exposure to HC diet to elicit its protective effect; We will test the ability of HC diet to protct animals with diabetogenesis enhanced by transgenic expression of diabetogenic T cell receptors. We will also test the role of gluten in these models. 2. Investigate the properties of insulin-producing cells in mice on different diets We will test the functions of beta cells in mice on different diets to reveal the signs of stress; We will measure insulin resistance in mice on regular and HC diet. The contribution of gluten to beta cell stress will be investigated. 3. Investigate the microbial connection to gluten's pro-diabetic action. We will study the changes in microbiota induced by addition of gluten to HC diet; We will study a possible role of microbiota in regulation of tissue transglutaminase expression.

描述(申请人提供)：在许多受共生微生物区系影响的人类疾病中，既有1型糖尿病(T1D)，它是由于胰岛素产生细胞的丧失而发生的，也有2型(T2D)，它是由于组织中胰岛素诱导的信号减弱而发生的。环境对T1D发病率影响的研究提出了改变饮食对发病率的影响的可能性。然而，对我们来说，很明显，摄入的营养物质是共生微生物区系的底物，饮食的变化可以迅速改变微生物区系。微生物区系的变化可以改变影响宿主的新陈代谢格局。为了在不同的人群中使用保护性饮食，这可能会在微生物区系中产生显著的变化，人们应该考虑寻找不受微生物区系变化影响的最佳饮食。我们已经确定，以水解酪蛋白(HC)为蛋白质来源的饮食对易患糖尿病的NOD小鼠具有保护作用，而不受微生物区系的影响。此外，在HC日粮中添加面筋恢复了T1D发育，但这种恢复依赖于肠道微生物区系。最后，HC饮食没有直接影响免疫系统，但增强了胰岛素产生细胞的活力。为了进一步揭示HC饮食保护特性背后的机制，我们将追求以下目标。1.调查饮食干预的限度我们将调查暴露于HC饮食的时间限制，以获得其保护作用；我们将测试HC饮食对转基因表达糖尿病T细胞受体促进糖尿病发生的能力。我们还将测试面筋在这些模型中的作用。2.研究不同饮食条件下小鼠胰岛素分泌细胞的特性 在不同的饮食上揭示压力的迹象；我们将测量常规饮食和高脂饮食小鼠的胰岛素抵抗。面筋对β细胞应激的贡献将被研究。3.研究面筋蛋白降糖尿病作用的微生物联系。我们将研究在HC饮食中添加面筋引起的微生物区系的变化；我们将研究微生物区系在 组织转谷氨酰胺酶表达的调节。