All ETDs from UAB

Advisory Committee Chair

Robin G Lorenz

Advisory Committee Members

Daniel F Balkovetz

Charles O Elson

John F Kearney

Moon H Nahm

Hubert M Tse

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Type 1 Diabetes (T1D) is defined as the selective immune destruction of insulin producing beta cells within the islet. A new emphasis has been put on the role of the gastrointestinal (GI) tract in T1D; however, there is much more to learn about this relationship. Distinct differences have been observed in the intestinal permeability, barrier function, commensal microbiota, and mucosal innate and adaptive immunity of patients and animals with T1D, when compared to healthy controls. The non-obese diabetic (NOD) mouse and the BioBreeding diabetes prone (BBdp) rat are commonly used to models to study T1D in humans. Most murine studies use the common BALB/c or C57BL/6 as negative controls for T1D studies, which may not be the most relevant control animals. To investigate T1D using the NOD model we used the non-obese diabetic resistant (NOR) mouse as a control model. NOR mice are approximately 80% genetically identical to NOD mice and importantly like NOD mice we have observed that NOR also have a permeable intestine. Comparison between these two models has allowed us to begin understanding why NOR mice are protected from T1D despite many similarities to NOD mice. While comparing NOD and NOR mice we observed a difference in microbiota between the two strains. NOD mice have a higher frequency of Bacteroidetes and a lower frequency of Firmicutes when compared to NOR mice, which is supported by literature when comparing healthy subjects and subjects with T1D. To determine what lead to differing microbiota between the two strains we investigated the role of antimicrobial peptides (AMPs) and mucins in regulation of the microbiota. We observed decreased AMP and mucin expression (mRNA) in the absence of bacteria in NOD mice compared to NOR mice. Importantly a mucus kill assay using E. coli provided functional evidence of a decreased ability of NOD mice to regulate bacteria when compared to NOR mice.

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