Center for High-Throughput Minimally-Invasive Radiation Biodosimetry

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ABSTRACT (30 line limit): Multi-organ radiation-induced injury represents a significant unmet medical need that occurs during accidental exposure, radio-cancer therapy or a targeted terror attack. Substantial federal efforts have been made to mitigate acute radiation symptoms; however, it remains a long-standing and unresolved problem. Intestinal epithelium is the fastest-renewing adult tissue, making it highly sensitive to radiation and thereby the major target of acute injury during environmental overexposure and radiation therapy. The gastrointestinal (GI) tract harbors a complex microbial community that comprises 10-100 trillion microorganisms. The microbiota has known roles in multiple diseases, such as inflammatory bowel disease (IBD), type 2 diabetes, intestinal vascular remodeling and neuronal homeostasis. Recently, there is increasing evidence linking the intestinal microbiota to radiation induced syndromes. We have shown that GI microbiota composition can affect the outcome of high dose total body irradiation (TBI) (Science 2020). We described an unexpected finding that a small percentage of animals can survive lethal TBI and live a normal life span. These elite-survivors harbor a distinct gut microbiota which are protective against radiation. A detailed delineation has narrowed down the bacteria that are beneficial for TBI. Lachnospiraceae plays a vital role in enhancing hematopoietic stem cell regeneration and gastrointestinal epithelial repair post radiation. We further identified propionate, a short chain fatty acid (SCFA) and the key metabolite that acts downstream from Lachnospiraceae, to serve as a potent radio-protectant. More strikingly, tryptophan pathway metabolites (1H-indole-3-carboxaldehyde and kynurenic acid) are also selectively found in the elite-survivors and provide radioprotection. Although we have uncovered the correlation between gut microbiota/metabolites and radiation-induced damage, and the use of these metabolites to mitigate radiation damage, the detailed underpinnings of the mechanism remain under investigation. This proposal aims at elucidating the mechanism of how the microbiota derived metabolites ameliorate radiation injury. We will focus on identifying which cell types and metabolites receptors play the essential role in mediating the radioprotection by SCFA or tryptophan metabolites and confirming whether this function is controlled by the gut microbiota in the radiation model. This work would provide insight into both disease pathophysiology and potential therapeutics, leading to better and more efficient treatments against radiation injury in the cases of radiation exposure after a radiological/nuclear terrorist event, accidental exposure, and radio-cancer therapy.