Engineered Microbes to Mitigate Intestinal Radiation Damage

PROJECT SUMMARY/ABSTRACT The major source of early morbidity and mortality resulting from a nuclear incident comes from acute radiation syndrome in the gastrointestinal tract (GI-ARS). Radiation targets the cycling intestinal stem cell (ISC) causing the cells to apoptosis and subsequently affecting the entire intestinal epithelial renewal which originates from the ISC. Although GI-ARS accounts for a significant portion of acute morbidity and mortality after high dose ionizing radiation exposure, there are no therapies or treatments to prevent, mitigate, or treat GI-ARS. We propose to explore the use of the microbiome, which lives in intimate contact with the intestinal epithelium, to deliver growth factors that promote survival and proliferation of radioresistant ISC populations. We have engineered Limosilactobacillus reuteri 6475 (LR6475), a commercially used organism that is inexpensive, easy to store, able to be administered orally in the event of a nuclear disaster, and adept at surviving in the gastrointestinal tract, to deliver key growth factors necessary to promote radioresistant ISC regeneration of the intestinal epithelium. The overarching hypothesis is that LR6475 can serve as a platform to develop mitigating medical countermeasures for GI-ARS. The objective of this proposal is to assess our candidate genetically modified LR6475 in a rodent model of radiation damage for the ability of the medical countermeasure to accelerate recovery from GI-ARS. To achieve this objective, we propose to determine the efficacy of engineered LR6475 as medical countermeasures in humanized microbiome mouse in which the recovery of the ISC population can be tracked. The results obtained at the end of this project will support the continued development of LR6475 as a stockpiled general nuclear countermeasure.