High-Sucrose Diet-Induced Reprogramming of Plasma Oxylipin Profiles Reflects Dietary Risk for Gut Barrier Dysfunction

High-sucrose diet (HSD)-induced alterations in colonic oxylipins have been documented as a key contributor to gut barrier dysfunction. However, the impact of HSD on the systemic oxylipin profiles and their potential link to gut barrier impairment remain largely unknown. Here, we report HSD reprograms plasma oxylipin profiles, with implications for monitoring the risk of HSD-induced gut barrier impairment. In a mouse model, HSD altered plasma oxylipin metabolism, preferentially affecting metabolites enriched in the CYP epoxygenase pathway. Among these, 8(9)-epoxyeicosatrienoic acid [8(9)-EET] was significantly increased by 2.4-fold and positively correlated with intestinal impairment and plasma lipopolysaccharide levels (<i>r</i> = 0.55, <i>p</i> = 0.01), a marker of gut barrier disruption. In addition, humans with habitual high-sucrose intake exhibited distinct plasma oxylipin profiles, including a 3.7-fold elevation in plasma 8(9)-EET levels compared to controls, which was also positively associated with plasma lipopolysaccharide (<i>r</i> = 0.44, <i>p</i> = 0.03). We propose that HSD-driven 8(9)-EET accumulation reflects early metabolic stress and may serve as a sentinel indicator of dietary sucrose overload. These findings suggest that plasma oxylipin profiles, particularly 8(9)-EET levels, reflect HSD-induced intestinal injury and offer a valuable tool for assessing the health risks associated with excessive sugar consumption.