Zhang Ying, Jiang Han, Peng Xiao-Han, Zhao Yan-Lin, Huang Xian-Jie, Yuan Kang, Yang Yi-Fan, Du Yan, Ji Shuai, Tang Dao-Quan
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.
Department of Pharmacy, Suining People's Hospital Affiliated to Xuzhou Medical University, Suining 221202, China.
Phytomedicine. 2025 Sep;145:156970. doi: 10.1016/j.phymed.2025.156970. Epub 2025 Jun 10.
Mulberry (Morus alba L.) leaf is a Chinese herb used clinically to treat type 2 diabetes mellitus (T2DM) and has been proven to improve T2DM by regulating gut microbiota dysbiosis. However, it is currently unclear whether mulberry leaf can improve intestinal inflammation and metabolic dysfunction by restoring gut microbiota to promote short-chain fatty acids (SCFAs) level and thus activate relevant signaling pathways.
This work aimed to explore the role that microbiota-SCFAs-G protein-coupled receptors (GPRs) signaling pathway plays in the anti-T2DM effect of mulberry leaf.
Mice with T2DM, induced by intraperitoneal injection of streptozotocin after four weeks of high-fat and high sucrose diet, were randomly allocated to receive mulberry leaf water extract (MLWE) and ethanol extract (MLEE), metformin (Glucophage), or distilled water for ten consecutive weeks. Changes in metabolic parameters, pro-inflammatory cytokines, fecal microbiota, and bacterial metabolites (lipopolysaccharide (LPS) and SCFAs), were detected. Furthermore, microbiota deprivation was performed to confirm the anti-diabetic effect of MLWE-regulated gut microbiota in pseudo-germ-free T2DM mice.
MLWE and/or MLEE could enhance insulin sensitivity via activating GPR43/109A in colon and adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway in liver, improving the expression of pro-inflammatory factors such as tumor necrosis factor α, interleukin (IL)-1β, IL-6 and IL-10 in liver, elevating intestinal barrier to decrease circular LPS level via enhancing the expression of tight junction proteins such as Zonula occludens-1 and Occludin, and decreasing intestinal inflammation via inhibiting toll-like receptor 9- myeloid differentiation primary response protein 88- interferon-γ signaling pathway in colon, accompanying by the increased abundances of beneficial bacteria, such as Akkermansia, Bifidobacterium, Dubosiella, and Muribaculaceae_unclassified, and the decreased abundances of harmful bacteria, such as Acetatifactor, Clostridiales_unclassified, Colidextribacter, Desulfovibrionaceae_unclassified, GCA-900066575, Lacchnospiraceae_unclassified, Lachnospiraceae_NK4A136_group, Oscillibacter, Murinomas, and Tuzzerella, and the corresponding elevation of fecal SCFAs levels in T2DM mice.
Gut microbiota-SCFAs-GPRs axis and AMPK pathway may involve in the alleviation of inflammation and insulin resistance in T2DM mice intervened with mulberry leaf, which provides new insights to elucidate the potential mechanism of mulberry leaf in the treatment of T2DM.
桑叶是一种临床上用于治疗2型糖尿病（T2DM）的中药，已被证明可通过调节肠道微生物群失调来改善T2DM。然而，目前尚不清楚桑叶是否能通过恢复肠道微生物群以促进短链脂肪酸（SCFAs）水平，从而激活相关信号通路来改善肠道炎症和代谢功能障碍。
本研究旨在探讨微生物群-SCFAs-G蛋白偶联受体（GPRs）信号通路在桑叶抗T2DM作用中的作用。
将高脂高糖饮食4周后腹腔注射链脲佐菌素诱导的T2DM小鼠随机分为连续10周接受桑叶水提取物（MLWE）和乙醇提取物（MLEE）、二甲双胍（格华止）或蒸馏水。检测代谢参数、促炎细胞因子、粪便微生物群和细菌代谢产物（脂多糖（LPS）和SCFAs）的变化。此外，进行微生物群剥夺以证实MLWE调节的肠道微生物群在无菌T2DM小鼠中的抗糖尿病作用。
MLWE和/或MLEE可通过激活结肠中的GPR43/109A和肝脏中的5'-单磷酸腺苷激活蛋白激酶（AMPK）途径增强胰岛素敏感性，改善肝脏中肿瘤坏死因子α、白细胞介素（IL）-1β、IL-6和IL-10等促炎因子的表达，通过增强紧密连接蛋白如闭合蛋白-1和闭合蛋白的表达提高肠道屏障以降低循环LPS水平，并通过抑制结肠中的Toll样受体9-髓样分化初级反应蛋白88-干扰素-γ信号通路减轻肠道炎症，同时有益菌如阿克曼氏菌、双歧杆菌、杜氏菌和未分类的毛螺菌科丰度增加，有害菌如乙酸杆菌属、未分类的梭菌目、结肠杆菌属、未分类的脱硫弧菌科、GCA-900066575、未分类的毛螺菌科、毛螺菌科_NK4A136组、颤杆菌属、鼠瘤菌属和土佐菌属丰度降低，T2DM小鼠粪便SCFAs水平相应升高。
肠道微生物群-SCFAs-GPRs轴和AMPK途径可能参与了桑叶干预的T2DM小鼠炎症和胰岛素抵抗的缓解，这为阐明桑叶治疗T2DM的潜在机制提供了新的见解。
