School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
Food Funct. 2024 Mar 4;15(5):2679-2692. doi: 10.1039/d3fo04530g.
High-fat diet (HFD)-induced dyslipidemia is frequently accompanied by gut microbiota dysbiosis and a compromised gut barrier. Enhancing the intestinal barrier function emerges as a potential therapeutic approach for dyslipidemia. The ILC3-IL22-IL22R pathway, which responds to dietary and microbial signals, has not only attracted attention for its crucial role in maintaining the intestinal barrier, but recent reports have also suggested its potential in regulating lipid metabolism. Limonin is derived from the Chinese herb , which has shown potential in ameliorating dysbiosis of serum lipids. However, its underlying mechanisms remain elusive. Consequently, targeting the ILC3-IL22-IL22R pathway to enhance intestinal barrier function holds promise as a therapeutic approach for dyslipidemia. In this study, male C57BL/6 mice were subjected to a 16-week HFD to induce dyslipidemia and concurrently administered oral limonin. We discovered that limonin supplementation dramatically reduced serum lipid profiles in HFD-fed mice, significantly curbing HFD-induced weight gain and epididymal fat accumulation. Ileal histopathological evaluation indicated limonin's ameliorative effects on HFD-induced intestinal barrier impairment. Limonin also moderated the intestinal microbiota dysbiosis, which is characterized by the elevation of Firmicutes in HFD mice, and notably amplified the abundance of probiotic . In addition, supported by flow cytometry and other analyses, we observed that limonin upregulated the ILC3-IL22-IL22R pathway, enhancing phosphorylated STAT3 (pSTAT3) in intestinal epithelial cells (IECs), thereby reducing lipid transporter expression. In conclusion, our study revealed that limonin exerted a promising preventive effect against HFD-induced dyslipidemia by the mitigation of the intestinal barrier function and intestinal microbiota, and its mechanism was related to the upregulation of the ILC3-IL22-IL22R pathway.
高脂饮食（HFD）诱导的血脂异常常伴有肠道微生物失调和肠道屏障受损。增强肠道屏障功能成为治疗血脂异常的一种潜在方法。ILC3-IL22-IL22R 途径对饮食和微生物信号作出反应，不仅因其在维持肠道屏障方面的关键作用而引起关注，而且最近的报道还表明其在调节脂质代谢方面的潜力。柠檬苦素来源于中草药，已显示出改善血脂失调的潜力。然而，其潜在机制仍不清楚。因此，靶向 ILC3-IL22-IL22R 途径增强肠道屏障功能有望成为治疗血脂异常的一种方法。在这项研究中，雄性 C57BL/6 小鼠接受 16 周的 HFD 喂养以诱导血脂异常，并同时给予口服柠檬苦素。我们发现，柠檬苦素补充剂可显著降低 HFD 喂养小鼠的血清脂质谱，显著抑制 HFD 诱导的体重增加和附睾脂肪堆积。回肠组织病理学评估表明柠檬苦素可改善 HFD 诱导的肠道屏障损伤。柠檬苦素还可调节肠道微生物失调，其特征是 HFD 小鼠中厚壁菌门的升高，并显著增加益生菌的丰度。此外，我们通过流式细胞术和其他分析观察到，柠檬苦素上调了 ILC3-IL22-IL22R 途径，增强了肠道上皮细胞（IECs）中磷酸化 STAT3（pSTAT3）的表达，从而降低了脂质转运蛋白的表达。总之，我们的研究表明，柠檬苦素通过减轻肠道屏障功能和肠道微生物群来发挥对 HFD 诱导的血脂异常的预防作用，其机制与 ILC3-IL22-IL22R 途径的上调有关。
