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.

Public Health Relevance

We propose that hydrolyzed casein containing diet free of gluten prevents type 1 diabetes in a manner that is independent of the commensal microbiota and works through improvement to the function of insulin-producing cells and reducing autoimmunity indirectly. The knowledge generated through this proposal can be used to prevent T1D in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI115683-02
Application #
8971957
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2014-12-01
Project End
2017-11-30
Budget Start
2015-12-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Yurkovetskiy, Leonid A; Pickard, Joseph M; Chervonsky, Alexander V (2015) Microbiota and autoimmunity: exploring new avenues. Cell Host Microbe 17:548-52