Ionizing radiation is a common cancer therapy modality. . Radiation-induced gastrointestinal injury is one of the major complications during radiotherapy, leading to altered therapy plans and even cessation of treatment. There are many comorbidities associated with this complication, including obesity, diabetes, co-occurring inflammation and infection, and, as recently recognized, dietary components that contribute to these comorbidities. This dissertation focuses on obesity and a single dietary component, the amino acid methionine and the effects of these on the gastrointestinal track after IR exposure. In the first chapter, I describe development of an animal model of obesity and radiation-induced gastrointestinal toxicity. The NZO/HILtJ mouse strain showed a steep survival curve between 6.37 and 7.4 Gy of total body irradiation. The small intestine at 7.4 and 8.5 Gy was characterized by up-regulation of pro-inflammatory genes and by alterations in tight junction related genes indicative on increased intestinal permeability. In the second and third chapters, I address the effects of methionine and possible mechanisms by which supplementation exacerbates the radiation response under both total body irradiation and local abdominal radiation, focusing on direct tissue damage, alteration in expression of tight junction-related and inflammatory genes, and changes in gut ecology. Methionine supplementation exacerbated a pro-inflammatory state in the small intestine, altered tight junction gene expression to promote increased intestinal permeability, and favored an increase in the proportion of gram-negative bacteria present in the intestinal lumen. Finally, in the fourth chapter, I address the methionine tissue concentration discrepancies that were seen after supplementation with the development of a physiologically-based pharmacokinetic model with the goal of identifying chemical parameters important in intestinal and plasma methionine distribution as well as identifying knowledge gaps in methionine transport and metabolism. The model identified absorption and metabolism as sensitive parameters in predicting plasma and tissue methionine concentration while concurrently highlighting additional gaps in the knowledge of methionine kinetics. Altogether, the data here demonstrate that obesity and diet, and their effects on the intestinal microbiome, are important characteristic to consider when developing a radiotherapeutic plan during cancer therapies.
|Advisor:||Koturbash, Igor, Lumen, Annie|
|Commitee:||Gandy, Jay, Pathak, Rupak, Laiakis, Evagelia|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 82/2(E), Dissertation Abstracts International|
|Keywords:||Gastrointestinal toxicity, Ionizing radiation, Methionine, Microbiome|
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