Time-series Multi-Omics Profiling Decodes Phase-specific Repair Cascades in Radiation-induced Intestinal Injury

Abstract

Radiation-induced intestinal injury (RIII) is a common complication of tumor radiotherapy. However, there is currently a lack of specific therapeutic drugs to mitigate RIII. Although intestinal injury and repair are dynamic molecular biological processes, there is a lack of systematic understanding of the time-dependent molecular events and regulatory networks involved in these processes in the irradiated intestine, particularly the co-regulatory mechanisms between gene expression and metabolism. In this study, the whole abdomen of C57BL/6J mice was irradiated with 12 Gy of γ-rays. The intestinal tissues were collected at 1, 2, 3, 5, and 7 days after irradiation (D1, D2, D3, D5, and D7). The degree of injury was evaluated by histopathological staining. Time-series transcriptome analysis was performed using RNA-seq, and untargeted metabolomics analysis was performed using UPLC-MS/MS. Multi-omics data, combined with bioinformatics analysis methods and RT-qPCR verification, were integrated to systematically analyze the dynamic changes in gene expression and metabolic pathways during RIII repair. After irradiation, the intestinal tract of the mice experienced two stages of injury: acute injury (D1–D3) and rapid repair (D5–D7). The T cell-related immune response continues to play a key role in the injury and early repair. An analysis of the transcriptome and metabolome data, combined with functional enrichment analysis, revealed that different time points showed unique biological characteristics. The early stage (D1–D3) is characterized by enhanced cell adhesion and extracellular matrix remodeling, accompanied by disorders of amino acid and lipid metabolism. The peak of injury (D3) revealed the coexistence of activation of the detoxification system and depletion of intestinal epithelial functional metabolites. The repair stage (D5–D7) involves immunometabolism reprogramming, which involves adaptive regulation of tryptophan metabolism, steroid synthesis, and other pathways. These findings lead us to suggest a hypothesis of multi-stage dynamic evolution of RIII, which warrants further investigation in future studies. By integrating time-series transcriptomics and metabolomics, this study provides preliminary evidence for the multi-stage dynamic evolution of RIII, which provides an important basis for the development of precise intervention strategies for RIII.