Immunometabolic mechanisms of ionizing radiation in a mouse model of gastrointestinal acute radiation syndrome

PURPOSE: Exposure to high doses of ionizing radiation (IR) causes severe health effects, including acute radiation syndrome (ARS). While therapeutic options exist to stimulate hematopoiesis and prevent infection, there is an unmet clinical need to develop safe and effective therapeutics for gastrointestinal-ARS (GI-ARS). MATERIALS AND METHODS: A global transcriptomics time course (day 0, 1, 2, 3, 5, 7, 10 and 18) was conducted on wild-type (WT) mice total body-irradiated with a single dose of sublethal (3 and 6 Gy) or lethal (12 Gy) IR to evaluate the colonic gene expression changes associated with mortality or recovery in GI-ARS. RESULTS: By clustering differentially expressed genes (DEGs), 23 distinct temporal patterns were identified. Three notable clusters were defined by patterns associated with mortality at day 10 and displayed significant functional enrichment within the cluster. The first cluster identified the upregulation of early (day 3) and late (day 10) inflammation, with enrichment of innate immunity genes. The second cluster was also associated with the immune response, but in contrast to the first cluster, was characterized by an initial downregulation followed by an upregulated peak at day 10. This pattern was enriched with adaptive immunity genes. The third cluster was characterized by an early downregulation on days 1 and 2 with a secondary decrease on day 10 with an enrichment of sterol metabolism genes. CONCLUSIONS: This comprehensive system-wide transcriptional analysis provides new insights into the response mechanisms underlying IR-induced intestinal damage and subsequent mortality, along with identification of novel immunometabolic mechanisms with strong potential for therapeutic development in GI-ARS.