Abstract
Ionizing radiation-induced intestinal injury (IRIII), a catastrophic disease that occurs after tumor radiotherapy or accidental nuclear radiation, is lack of sufficient medical countermeasures currently. The gut microbial composition affects the intestinal radiosensitivity, and regulation of the gut microbiota through dietary adjustments is a potential solution for mitigating IRIII. Time-restricted feeding (TRF) is an emerging behavioral nutrition intervention with pleiotropic health benefits. Whether this dietary pattern influences the pathogenesis of IRIII remains vague. We evaluated the impact of TRF on intestinal radiosensitivity in this study and discovered that only daytime TRF (DTRF), not nighttime TRF, could ameliorate intestinal damage in mice that received a high dose of IR. Faecal metagenomic and metabolomic studies revealed that the intestinal creatine level was increased by approximate 9 times by DTRF, to which the Bifidobacterium pseudolongum enrichment contribute. Further investigations showed that creatine enable to activate the energy sensor AMP-activated protein kinase in irradiated enterocytes and induce phosphorylation of the downstream effector acetyl-CoA carboxylase, resulting in reduced production of unsaturated fatty acidsand reduced ferroptosis after IR. The administration of creatine mitigated IRIII and reduced bacteraemia and proinflammatory responses. Blockade of creatine import compromised the ferroptosis inhibition and mitigation of DTRF on IRIII. Our study demonstrates a radioprotective dietary mode functioning by reshaping the gut microbiota to suppress IR-induced ferroptosis, thereby providing effective countermeasures for IRIII prevention.