Characterization of the Intestinal Metabolic Profiles Following Photon FLASH Irradiation

Objective Ultra-high dose rate radiotherapy, commonly referred to as FLASH radiotherapy, is a transformative focus in radiotherapeutic research. This study aimed to identify intestinal contents based metabolic biomarkers of photon FLASH. Methods C57BL/6J mice were exposed to 0 Gy, 10 Gy, 12 Gy, or 14 Gy of photon FLASH irradiation (FLASH-IR) without a conventional irradiation. The intestinal contents were collected 3.5 d post-iiradiation, and subjected to liquid chromatography-mass spectrometry. Results Metabolomic profiling revealed 25 differential metabolites that were consistently differentially regulated across the comparisons of 10 Gy vs. 0 Gy, 12 Gy vs. 0 Gy, and 14 Gy vs. 0 Gy groups. Notably, a dose-dependent positive correlation was observed for 3-hydroxyanthranilate, while 13 metabolites—including guanosine, adenosine monophosphate, and hydroquinone—exhibited a significant negative correlation with increasing FLASH-IR dose. Further enrichment analysis identified several perturbed metabolic cascades, prominently involving the PI3K-AKT signaling pathway, tyrosine metabolism, and purine metabolism. Conclusions These findings illuminated the intestinal metabolic signatures post photon FLASH-IR, offering insights to optimize FLASH radiotherapy parameters and enhance its therapeutic ratio.