All ETDs from UAB

Advisory Committee Chair

Robin G Lorenz

Advisory Committee Members

Hubert Tse

John Kearney

Richard Lopez

Robin Lorenz

Charles Elson

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Environmental exposures such as diet, use of antibiotics, and lifestyle have significant impact on the health of an individual. One mechanism that acts as a major pathway in these environmental exposures is the role intestinal commensal microbiota play in both metabolic and immunological responses. Metabolic pathways are altered through changes in metabolites provided by commensal microbiota; alterations in microbial make-up can have drastic impacts on metabolic function. Similarly, the development and maturation of the immune system is dependent on the intestinal microbes to induce tolerance and act as both an immune modulator as well as a barrier against pathogens. We have examined the importance of microbial diversity and the role specific microbes play in metabolic diseases such as obesity and onset of type 2 diabetes (T2D). Alterations in the ratio of commensal bacteria belonging to the phyla Bacteroidetes or Firmicutes is one of the largest contributing factors in metabolic disease. Firmicutes tend to have a higher degree of diversity in metabolic genes, allowing for a more efficient use of all dietary antigens compared to Bacteroides. Interestingly, individuals who are obese or who are diagnosed with T2D have a higher number of Firmicutes compared to lean individuals. In the development of immunological diseases, the commensal make-up is equally important. We hypothesized that alterations in commensal make-up can have serious consequences in the development of auto-immune Type 1 diabetes (T1D). We tested this hypothesis by placing NOD/ShiLtJ mice on either neutral (NOD N, pH ~7.0) or acidified (NOD A pH~ 3.2) H2O and monitoring the composition of the fecal commensal microbiota and incidence of T1D. NOD N mice had an increased incidence of T1D by 30wks of age; exhibiting decreased Firmicutes and increases in Bacteroides, Actinobacteria, and Proteobacteria. These alterations in microbiota were seen as early as 2-weeks of age. NOD N mice had decreased levels of FoxP3 expression in CD4+FoxP3+ cells, and decreased CD4+IL17+ cells, and a lower ratio of IL17/IFNγ CD4+ T-cells. Our data indicates that changes in diet alter the commensal microbial environment, the presence of protective Th17 and Treg cells, and incidence of T1D.

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