Arctigenin (AG) 是一种来自药用和食品同源植物牛蒡子 (Arctium lappa l.) 的苯丙素木脂素，以其抗癌、抗炎和抗氧化特性而闻名。然而，AG对代谢紊乱的药理作用仍然有限，基于肠道微生物群的具体机制尚未见报道。本研究旨在评估AG对肥胖小鼠糖脂代谢的调节作用，并探讨与肠道微生物相关的潜在机制。 AG 的抗肥胖功效在高脂饮食 (HFD) 喂养的小鼠中进行了评估。 16S rRNA 基因测序和 GC-MS 用于检测肠道微生物和代谢物水平的变化。采用免疫组织化学、免疫荧光和聚合酶链反应验证了肠道微生物代谢产物参与AG改善肠道稳态和肝脏代谢的分子机制。我们发现AG可显着改善HFD引起的糖脂代谢紊乱、肝脏变性和肝脏代谢紊乱。巨噬细胞M1/M2极化不平衡。此外，AG 还可减轻 HFD 小鼠的肠道屏障损伤、炎症和 Th17/Treg 免疫失衡。重要的是，AG 促进产生短链脂肪酸 (SCFA) 的细菌和 SCFA 水平，从而调节 G 蛋白偶联受体 (GPR)41/43 和 HDAC3 途径，诱导 FOXP3 蛋白表达，从而维持肠道 Th17/Treg 免疫。 AG 还抑制脂多糖 (LPS) 的产生，从而减轻 TLR4/NF-κB 介导的肠道炎症。此外，AG还可以上调肠道MCT1蛋白水平，促进SCFA的吸收，并激活肝脏GPR41/43/109a-AMPK通路来调节脂质代谢，从而减少脂质积累。本研究首次证明AG可以调节肠道微生物群和衍生代谢物。修复肠道损伤，调节肝脏代谢途径，从而改善HFD引起的代谢紊乱。这些发现支持 AG 作为一种新型益生元通过针对肠道微生物群来对抗肥胖和慢性代谢疾病的巨大潜力。版权所有 © 2024 Elsevier GmbH。版权所有。

Arctigenin (AG), a phenylpropanoid lignan from the medicinal and food homologous plant Arctium lappa l., is known for its anti-cancer, anti-inflammatory and antioxidant properties. However, the pharmacological effects of AG on metabolic disorders remain limited, and specific mechanisms based on gut microbiota have not been reported.This study aimed to evaluate the regulation of glycolipid metabolism by AG in obese mice and investigate the potential mechanisms associated with gut microbes.The anti-obesity efficacy of AG was evaluated in high-fat diet (HFD)-fed mice. 16S rRNA gene sequencing and GC-MS were used to detect changes in gut microbes and metabolite levels. Immunohistochemistry, immunofluorescence, and polymerase chain reaction were used to validate the molecular mechanisms of gut microbe-derived metabolites involved in the improvement of intestinal homeostasis and hepatic metabolism by AG.We found that AG significantly ameliorated HFD-induced glucolipid metabolism disorders, liver degeneration and the imbalance of macrophage M1/M2 polarization. In addition, AG attenuated intestinal barrier damage, inflammation and imbalance of Th17/Treg immune in HFD mice. Importantly, AG promoted short-chain fatty acid (SCFA)-producing bacteria and SCFA levels, which regulated the G protein-coupled receptor (GPR)41/43 and HDAC3 pathways to induce FOXP3 protein expression and consequently maintained intestinal Th17/Treg immunity. AG also inhibited lipopolysaccharide (LPS) production leading to attenuation of TLR4/NF-κB-mediated intestinal inflammation. Furthermore, AG upregulated intestinal MCT1 protein levels to promote absorption of SCFA and activated the hepatic GPR41/43/109a-AMPK pathway to regulate lipid metabolism, and thus reduced lipid accumulation.This study first demonstrated that AG could modulate the gut microbiota and derived metabolites to repair intestinal damage and regulate hepatic metabolic pathways, thereby ameliorating metabolic disorders induced by HFD. These findings support the great potential of AG as a novel prebiotic to fight obesity and chronic metabolic diseases by targeting the gut microbiota.Copyright © 2024 Elsevier GmbH. All rights reserved.