PURPOSE: The ultra-high dose rate (UHDR) radiation shows promise in eradicating tumors while reducing normal tissue toxicities. However, the biological outcomes of UHDR are influenced by various factors, particularly the mean dose rate and instantaneous dose rate. Additionally, the UHDR response at large field sizes is lacking. This study aimed to explore the impact of different dose rate combinations on gastrointestinal biological outcomes following total-body irradiations (TBI) and to examine the involved molecular signaling pathways. METHOD: Female C57BL6/J mice received 10 Gy TBI using three modes: ultra-high mean and ultra-high instantaneous dose rate irradiation (HH mode), low mean and ultra-high instantaneous dose rate irradiation (LH mode), and low mean and low instantaneous dose rate irradiation (LL mode). Mice were euthanized at 3 h and 48 h post irradiation to assess acute normal tissue damage and perform transcriptome sequencing. Furthermore, a subset of mice was monitored for 30 days to evaluate survival. RESULTS: We found that when the instantaneous dose rate is sufficiently high (>
10 CONCLUSION: Our findings underscore the pivotal role of instantaneous dose rate in reducing radiation damages. When the instantaneous dose rate is sufficiently high (>
10