Mulberry leaf improves type 2 diabetes in mice via gut microbiota-SCFAs-GPRs axis and AMPK signaling pathway

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-10 DOI:10.1016/j.phymed.2025.156970

Ying Zhang , Han Jiang , Xiao-han Peng , Yan-lin Zhao , Xian-jie Huang , Kang Yuan , Yi-fan Yang , Yan Du , Shuai Ji , Dao-quan Tang

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引用次数: 0

Abstract

Background

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.

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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桑叶通过肠道微生物- scfas - gprs轴和AMPK信号通路改善小鼠2型糖尿病

桑叶是临床上用于治疗2型糖尿病（T2DM）的中草药，已被证明通过调节肠道菌群失调来改善T2DM。然而，桑叶是否可以通过恢复肠道菌群，促进短链脂肪酸（SCFAs）水平，从而激活相关信号通路，从而改善肠道炎症和代谢功能障碍，目前尚不清楚。目的探讨微生物- scfas - g蛋白偶联受体（GPRs）信号通路在桑叶抗t2dm中的作用。方法高脂高糖饮食4周后，腹腔注射链脲佐菌素诱导的T2DM小鼠，随机分为桑叶水提取物（MLWE）和乙醇提取物（MLEE）、二甲双胍（Glucophage）、蒸馏水治疗，连续10周。检测代谢参数、促炎细胞因子、粪便微生物群和细菌代谢物（脂多糖（LPS）和SCFAs）的变化。此外，我们还进行了微生物群剥夺，以证实mlwe调节的T2DM伪无菌小鼠肠道微生物群的抗糖尿病作用。结果smlwe和/或MLEE可通过激活结肠GPR43/109A和肝脏腺苷5′-单磷酸活化蛋白激酶（AMPK）通路提高胰岛素敏感性，提高肝脏促炎因子如肿瘤坏死因子α、白细胞介素(IL)-1β、IL-6和IL-10的表达，通过提高紧密连接蛋白如occluden -1和Occludin的表达，提升肠道屏障降低环状LPS水平。通过抑制toll-like receptor 9- myeloid differentiation primary response protein 88- interferon-γ信号通路，降低肠道炎症反应，同时有益菌如Akkermansia、Bifidobacterium、Dubosiella、Muribaculaceae_unclassified等丰度增加，有害菌如Acetatifactor、Clostridiales_unclassified、Colidextribacter、Desulfovibrionaceae_unclassified、GCA-900066575等丰度降低。lachnospiraceae_unclassified、Lachnospiraceae_NK4A136_group、Oscillibacter、Murinomas和Tuzzerella，以及相应的T2DM小鼠粪便SCFAs水平升高。结论桑叶干预后，肠道微生物- scfas - gprs轴和AMPK通路可能参与T2DM小鼠炎症和胰岛素抵抗的缓解，为阐明桑叶治疗T2DM的潜在机制提供了新的思路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.