Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China.
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China; Department of Medical Affairs, Xuzhou RenCi Hospital Affiliated to Xuzhou Medical University, Xuzhou, 221004, China.
J Ethnopharmacol. 2024 Apr 6;323:117681. doi: 10.1016/j.jep.2023.117681. Epub 2023 Dec 30.
Mulberry (Morus alba L.) leaf is a well-known herbal medicine and has been used to treat diabetes in China for thousands of years. Our previous studies have proven mulberry leaf water extract (MLWE) could improve type 2 diabetes mellitus (T2D). However, it is still unclear whether MLWE could mitigate T2D by regulating gut microbiota dysbiosis and thereof improve intestinal permeability and metabolic dysfunction through modulation of lipopolysaccharide (LPS) and endocannabinoid system (eCBs).
This study aims to explore the potential mechanism of MLWE on the regulation of metabolic function disorder of T2D mice from the aspects of gut microbiota, LPS and eCBs.
Gut microbiota was analyzed by high-throughput 16S rRNA gene sequencing. LPS, N-arachidonoylethanolamine (AEA) and 2-ararchidonylglycerol (2-AG) contents in blood were determined by kits or liquid phase chromatography coupled with triple quadrupole tandem mass spectrometry, respectively. The receptors, enzymes or tight junction protein related to eCBs or gut barrier were detected by RT-PCR or Western blot, respectively.
MLWE reduced the serum levels of AEA, 2-AG and LPS, decreased the expressions of N-acylphophatidylethanolamine phospholipase D, diacylglycerol lipase-α and cyclooxygenase 2, and increased the expressions of fatty acid amide hydrolase (FAAH), N-acylethanolamine-hydrolyzing acid amidase (NAAA), alpha/beta hydrolases domain 6/12 in the liver and ileum and occludin, monoacylglycerol lipase and cannabinoid receptor 1 in the ileum of T2D mice. Furthermore, MLWE could change the abundances of the genera including Acetatifactor, Anaerovorax, Bilophila, Colidextribacter, Dubosiella, Gastranaerophilales, Lachnospiraceae_NK4A136_group, Oscillibacter and Rikenella related to LPS, AEA and/or 2-AG. Moreover, obvious improvement of MLWE treatment on serum AEA level, ileum occludin expression, and liver FAAH and NAAA expression could be observed in germ-free-mimic T2D mice.
MLWE could ameliorate intestinal permeability, inflammation, and glucose and lipid metabolism imbalance of T2D by regulating gut microbiota, LPS and eCBs.
桑叶（Morus alba L.）是一种广为人知的草药，在中国已有数千年的历史用于治疗糖尿病。我们之前的研究已经证明，桑叶水提取物（MLWE）可以改善 2 型糖尿病（T2D）。然而，目前尚不清楚 MLWE 是否可以通过调节肠道微生物失调来改善 T2D，从而改善肠道通透性和代谢功能，其通过调节脂多糖（LPS）和内源性大麻素系统（eCBs）。
本研究旨在从肠道微生物群、LPS 和 eCBs 等方面探讨 MLWE 对 T2D 小鼠代谢功能障碍的调节作用。
通过高通量 16S rRNA 基因测序分析肠道微生物群。通过试剂盒或液相色谱-串联三重四极杆质谱法分别测定血液中的 LPS、N-花生四烯酸乙醇胺（AEA）和 2-花生四烯酸甘油（2-AG）含量。通过 RT-PCR 或 Western blot 分别检测与 eCBs 或肠道屏障相关的受体、酶或紧密连接蛋白。
MLWE 降低了 T2D 小鼠血清中 AEA、2-AG 和 LPS 的水平，降低了酰基磷酰乙醇胺磷脂酶 D、二酰基甘油脂肪酶-α和环氧化酶 2 的表达，增加了脂肪酸酰胺水解酶（FAAH）、N-酰基乙醇胺水解酸酰胺酶（NAAA）、α/β水解酶域 6/12 在肝脏和回肠中的表达，以及回肠中的紧密连接蛋白 occludin、单酰基甘油脂肪酶和大麻素受体 1。此外，MLWE 可以改变与 LPS、AEA 和/或 2-AG 相关的属的丰度，包括 Acetatifactor、Anaerovorax、Bilophila、Colidextribacter、Dubosiella、Gastronaerophilales、Lachnospiraceae_NK4A136_group、Oscillibacter 和 Rikenella。此外，在无菌模拟 T2D 小鼠中，可以观察到 MLWE 治疗对血清 AEA 水平、回肠 occludin 表达以及肝脏 FAAH 和 NAAA 表达的明显改善。
MLWE 通过调节肠道微生物群、LPS 和内源性大麻素系统，可以改善 T2D 的肠道通透性、炎症以及葡萄糖和脂质代谢失衡。
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