Temporal and Spatial Metabolic Shifts Revealing the Transition from Ulcerative Colitis to Colitis‐Associated Colorectal Cancer
Ruiqi Sun, Yuanyuan Zhang, Xian Zhao, Tian Tang, Yuepeng Cao, Liu Yang, Yuan Tian, Zunjian Zhang, Pei Zhang, Fengguo Xu
Abstract
Patients with ulcerative colitis (UC) have a higher risk of developing colorectal cancer (CRC), however, the metabolic shifts during the UC-to-CRC transition remain elusive. In this study, an AOM-DSS-induced three-stage colitis-associated colorectal cancer (CAC) model is constructed and targeted metabolomics analysis and pathway enrichment are performed, uncovering the metabolic changes in this transition. Spatial metabolic trajectories in the "normal-to-normal adjacent tissue (NAT)-to-tumor" transition, and temporal metabolic trajectories in the "colitis-to-dysplasia-to-carcinoma" transition are identified through K-means clustering of 74 spatially and 77 temporally differential metabolites, respectively. The findings reveal two distinct metabolic profile categories during the inflammation-to-cancer progression: those with consistent changes, either increasing (e.g., kynurenic acid, xanthurenic acid) or decreasing (e.g., long-chain fatty acids, LCFAs), and those enriched at specific disease stages (e.g., serotonin). Further analysis of metabolites with consistent temporal trends identifies eicosapentaenoic acid (EPA) as a key metabolite, potentially exerting anti-inflammatory and anti-cancer effects by inhibiting insulin-like growth factor binding protein 5 (IGFBP5). This study reveals novel metabolic mechanisms underlying the transition from UC to CAC and suggests potential targets to delay the progression.