The anti-inflammatory property of ω-3 polyunsaturated fatty acids (PUFA) has been exploited in the management of inflammatory bowel disease (IBD) with promising results. However, it remains unclear if PUFA play a significant role in the resolution of inflammation and promotion of mucosal healing. Krill oil (KO) is a natural product rich in PUFA and the potent antioxidant, astaxanthin. In this study, we attempted to understand the mechanisms through which KO modulates the gut microbiome and metabolome using in vitro and in vivo colitis models and a multi-omics based approach. KO significantly decreased LPS-induced IL1β and TNFα expression in human macrophages in vitro in a dose-dependent manner by regulating a broad spectrum of signaling pathways, including NF-κB and NOD-like receptor signaling, and displayed a synergistic effect with COX2 and IKK2 inhibitors in attenuating inflammatory pathways. Moreover, KO was involved in the resolution of inflammation by promoting M2 polarization and enhancing macrophage-mediated intracellular bacterial killing. Parasite-dependent intestinal mucosal damage and microbial dysbiosis induced by Trichuris suis infection in pigs were partially restored by feeding KO. KO supplementation reduced the abundance of Rickettsiales and several species of Lactobacillus, which were among the important features identified by random forests analysis contributing to classification accuracy for KO supplementation. Several microbial signatures with strong predictive power for the status of both infection and supplementation were identified. The inhibitory effect of KO on histidine metabolism was identified using untargeted metabolomics. KO supplementation reduced several key metabolites related to histamine metabolism by suppressing the expression of a gene encoding l-histidine decarboxylase in the colon mucosa and reducing histamine biosynthesis of microbial origin. Moreover, the pro-resolving properties of KO were validated using a Citrobacter rodentium-induced Th1-dependent colitis murine model. Further, microbial signatures with high prediction accuracy for colitis-related pathophysiological traits were identified in mice. The findings from this study provided a mechanistic basis for optimizing microbiome-inspired alternative therapeutics in the management of IBD. The microbial signatures identified, particularly those with strong predictive accuracy for colitis phenotypes, will facilitate the development of biomarkers associated with appropriate dietary intervention to manage intestinal inflammation.

中文翻译：

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使用体外和体内模型，通过磷虾油来减轻肠道炎症和调节肠道微生物组的机制。

ω-3多不饱和脂肪酸（PUFA）的抗炎特性已在炎症性肠病（IBD）的治疗中得到了广泛应用。但是，尚不清楚PUFA是否在消炎和促进粘膜愈合中起重要作用。磷虾油（KO）是富含PUFA和有效的抗氧化剂虾青素的天然产物。在这项研究中，我们试图了解使用体外和体内结肠炎模型以及基于多组学的方法，KO调节肠道微生物组和代谢组的机制。KO通过调节广泛的信号传导途径（包括NF-κB和NOD样受体信号传导），以剂量依赖的方式显着降低了LPS诱导的人类巨噬细胞中IL1β和TNFα的表达，与COX2和IKK2抑制剂在减弱炎症途径中具有协同作用。而且，KO通过促进M2极化和增强巨噬细胞介导的细胞内细菌杀伤而参与炎症的解决。通过喂猪KO可以部分恢复猪Trichuris suis感染引起的寄生虫依赖性肠粘膜损伤和微生物营养不良。KO补充减少了立克次氏体和几种乳酸杆菌的丰度，这是通过随机森林分析确定的重要特征之一，有助于提高KO补充的分类准确性。鉴定了几种对感染和补充状态具有强预测力的微生物特征。使用非靶向代谢组学确定了KO对组氨酸代谢的抑制作用。KO补充通过抑制结肠粘膜中编码1-组氨酸脱羧酶的基因的表达并减少微生物来源的组胺生物合成，减少了与组胺代谢有关的几种关键代谢物。此外，KO的亲分解特性已使用柠檬酸杆菌诱导的Th1依赖性结肠炎鼠模型进行了验证。此外，在小鼠中鉴定出对结肠炎相关病理生理特征具有高预测准确性的微生物特征。这项研究的发现为在IBD的管理中优化微生物组启发的替代疗法提供了机械基础。确定的微生物特征，特别是对结肠炎表型具有很强预测准确性的特征，