Highsucrose diet (HSD) was reported as a causative factor for multiorgan injuries. The underlying mechanisms and therapeutic strategies remain largely uncharted. In the present study, by using a metabolomics approach, we identified the soluble epoxide hydrolase (sEH) as a therapeutic target for HSD-mediated gut barrier dysfunction. Specifically, 16-week feeding on an HSD caused gut barrier dysfunction, such as colon inflammation and tight junction impairment in a murine model. A metabolomics analysis of mouse colon tissue showed a decrease in the 5(6)-epoxyeicosatrienoic acid [5(6)-EET] level and an increase in soluble epoxide hydrolase, which is related to HSD-mediated injuries to the gut barrier. The mice treated with a chemical inhibitor of sEH and the mice with genetic intervention by intestinal-specific knockout of the sEH gene significantly attenuated HSD-caused intestinal injuries by reducing HSD-mediated colon inflammation and improving the impaired tight junction caused by an HSD. Further, in vitro studies showed that treatment with 5(6)-EET, but not its hydrolytic product 5,6-dihydroxyeicosatrienoic acid (5,6-DiHET), significantly ablated high sucrose-caused intestinal epithelial inflammation and impaired tight junction. Additionally, 5(6)-EET is anti-inflammatory and improves gut epithelial tight junction while 5,6-DiHET cannot do so. This study presents an underlying mechanism of and a therapeutic strategy for the gut barrier dysfunction caused by an HSD.

中文翻译：

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代谢组学揭示可溶性环氧化物水解酶是高蔗糖饮食介导的肠道屏障功能障碍的治疗靶点


据报道，高蔗糖饮食 （HSD） 是多器官损伤的致病因素。潜在的机制和治疗策略在很大程度上仍是未知的。在本研究中，通过使用代谢组学方法，我们确定了可溶性环氧化物水解酶 （sEH） 是 HSD 介导的肠道屏障功能障碍的治疗靶点。具体来说，以 HSD 为食 16 周会导致肠道屏障功能障碍，例如小鼠模型中的结肠炎症和紧密连接损伤。小鼠结肠组织的代谢组学分析显示 5（6）-环氧二十碳三烯酸 [5（6）-EET] 水平降低，可溶性环氧化物水解酶增加，这与 HSD 介导的肠道屏障损伤有关。用 sEH 化学抑制剂治疗的小鼠和通过肠道特异性敲除 sEH 基因进行基因干预的小鼠通过减少 HSD 介导的结肠炎症和改善 HSD 引起的受损紧密连接，显着减轻了 HSD 引起的肠道损伤。此外，体外研究表明，用 5（6）-EET 处理，而不是用其水解产物 5,6-二羟基二十碳三烯酸 （5,6-DiHET） 处理，显着消融高蔗糖引起的肠上皮炎症和紧密连接受损。此外，5（6）-EET 具有抗炎作用并改善肠道上皮紧密连接，而 5,6-DiHET 则不能。本研究提出了 HSD 引起的肠道屏障功能障碍的潜在机制和治疗策略。