Ethanol (EtOH)-induced alterations in intestinal homeostasis lead to multi-system pathologies, including liver injury. ω-6 PUFAs exert pro-inflammatory activity, while ω-3 PUFAs promote anti-inflammatory activity that is mediated, in part, through specialized pro-resolving mediators [e.g., resolvin D1 (RvD1)]. We tested the hypothesis that a decrease in the ω-6:ω-3 PUFA ratio would attenuate EtOH-mediated alterations in the gut-liver axis. ω-3 FA desaturase-1 (fat-1) mice, which endogenously increase ω-3 PUFA levels, were protected against EtOH-mediated downregulation of intestinal tight junction proteins in organoid cultures and in vivo. EtOH- and lipopolysaccharide-induced expression of INF-γ, Il-6, and Cxcl1 was attenuated in fat-1 and WT RvD1-treated mice. RNA-seq of ileum tissue revealed upregulation of several genes involved in cell proliferation, stem cell renewal, and antimicrobial defense (including Alpi and Leap2) in fat-1 versus WT mice fed EtOH. fat-1 mice were also resistant to EtOH-mediated downregulation of genes important for xenobiotic/bile acid detoxification. Further, gut microbiome and plasma metabolomics revealed several changes in fat-1 versus WT mice that may contribute to a reduced inflammatory response. Finally, these data correlated with a significant reduction in liver injury. Our study suggests that ω-3 PUFA enrichment or treatment with resolvins can attenuate the disruption in intestinal homeostasis caused by EtOH consumption and systemic inflammation with a concomitant reduction in liver injury.

中文翻译：

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降低 ω-6:ω-3 PUFA 比例可减轻乙醇引起的肠道稳态、微生物群和肝损伤的改变。


乙醇 (EtOH) 诱导的肠道稳态改变会导致多系统病变，包括肝损伤。 ω-6 PUFA 发挥促炎活性，而 ω-3 PUFA 则促进抗炎活性，该活性部分是通过专门的促消退介质 [例如消退素 D1 (RvD1)] 介导的。我们测试了这样的假设：ω-6:ω-3 PUFA 比例的降低会减弱 EtOH 介导的肠-肝轴变化。 ω-3 FA 去饱和酶-1 ( fat-1 ) 小鼠可内源性增加 ω-3 PUFA 水平，在类器官培养物和体内受到保护，免受乙醇介导的肠道紧密连接蛋白下调。在fat-1和 WT RvD1 处理的小鼠中，EtOH 和脂多糖诱导的 INF-γ、IL-6 和Cxcl1表达减弱。回肠组织的 RNA 测序显示，与喂食 EtOH 的 WT 小鼠相比， fat-1小鼠中涉及细胞增殖、干细胞更新和抗菌防御（包括Alpi和Leap2 ）的多个基因上调。 fat-1小鼠也能抵抗乙醇介导的对异生素/胆汁酸解毒重要的基因的下调。此外，肠道微生物组和血浆代谢组学揭示了fat-1与 WT 小鼠相比的一些变化，这些变化可能有助于减少炎症反应。最后，这些数据与肝损伤的显着减少相关。我们的研究表明，ω-3 PUFA 富集或用消解素治疗可以减轻 EtOH 消耗和全身炎症引起的肠道稳态破坏，同时减少肝损伤。