Diet and microbiota in type 1 diabetes

描述（由申请人提供）：在许多受共生微生物群影响的人类疾病中，两种类型的糖尿病都是1型糖尿病（T1D），由于胰岛素产生细胞的损失而发展，2型糖尿病（T2D），由于组织中胰岛素诱导信号的衰减而发展。环境对T1D发病率影响的研究提示了饮食改变对该病发病率的影响。然而，我们很明显，所消耗的营养物质是共生微生物群的底物，饮食的变化可以迅速改变微生物群。微生物群的变化可以改变影响宿主的代谢景观。为了在不同的人群中使用保护性饮食，这些人群的微生物群可能有很大的变化，人们应该考虑寻找独立于微生物群变化的最佳饮食。我们已经确定，含有水解酪蛋白（HC）作为蛋白质来源的饮食对糖尿病易感NOD小鼠具有保护作用，与微生物群的存在无关。此外，在HC日粮中添加谷蛋白可以恢复T1D的发育，但这种恢复依赖于肠道微生物群。最后，HC饮食不直接影响免疫系统，但增强了胰岛素生成细胞的活力。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. 调查饮食干预的限制我们将调查接触HC饮食的时间限制，以了解其保护作用；我们将通过转基因表达致糖尿病T细胞受体来测试HC饮食对糖尿病动物的保护能力。我们还将测试谷蛋白在这些模型中的作用。2. 研究不同饮食下小鼠体内胰岛素生成细胞的特性我们将测试小鼠体内β细胞的功能

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.