Influence of Toll-like receptor 4 on gut microbiota composition and development of autoimmunity in an animalmodel of human type 1 diabetes

• Applicant: Dr. Elke Gülden
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2013 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 239325408

Type 1 Diabetes is the most abundant metabolic disease among children and juveniles which is caused by immune-mediated destruction of autologous, insulin-producing beta cells. This process is mainly controlled by antigen presenting cells like macrophages and regulatory T cells, whose activity depends on the expression of Toll-like receptor 4. Thus, in my PhD thesis, I focused on the characterisation of the role of TLR4 in the pathogenesis of insulin-deficiency diabetes in the NOD mouse, which is currently the best characterised model of human type 1 diabetes.My studies of TLR4-deficient NOD mice revealed a significant effect of TLR4 on Diabetes pathogenesis and on the activity of the involved immune cell populations.Apart from an accelerated diabetes development, I also found an accelerated body weight development, while no changes in food intake occurred.Since recent findings show an influence of gut microbiota on energy harvest from the diet and as a consequence on body weight, this project aims at the elucidation of the role of the gut microbiota in the diabetes development of the TLR4-deficient NOD mouse. This project aims at proving the hypothesis that an altered microbiota composition in the gut is responsible for the increased body weight and accelerated diabetes development of TLR4-deficient NOD mice. It is conceivable that the anticipated altered gut flora results in a reduced expression of tight junctions in the intestine that leads to increased gut permeability. As a consequence the animals should exhibit increased serum level of bacterial antigens such as LPS or heat shock proteins. The presence of the xenogene bacterial antigens will presumably lead to cross reactions with autologous antigens and finally result in autoimmunity. Since the anticipated elevated beta cell stress due to the increased body weight of NOD TLR4-/- mice would result in an increased presentation of autoantigens on the beta cells, an enhancement of the autoimmunity is anticipated. The goal of this project is the verification of this hypothetical development of autoimmunity in the TLR4-deficient mouse model.The anticipated findings will be an important contribution to the understanding of the role of gut microbiota and their conserved pattern recognition receptors of the immune system. The outcome of this project should especially help to develop new strategies of intervention by modulation of the gut microbiota composition.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Li Wen