PMID- 38163557 OWN - NLM STAT- MEDLINE DCOM- 20240129 LR - 20240131 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 323 DP - 2024 Apr 6 TI - Mulberry (Morus alba L.) leaf water extract attenuates type 2 diabetes mellitus by regulating gut microbiota dysbiosis, lipopolysaccharide elevation and endocannabinoid system disorder. PG - 117681 LID - S0378-8741(23)01551-9 [pii] LID - 10.1016/j.jep.2023.117681 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: 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). AIM OF STUDY: 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. MATERIALS AND METHODS: 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. RESULTS: MLWE reduced the serum levels of AEA, 2-AG and LPS, decreased the expressions of N-acylphophatidylethanolamine phospholipase D, diacylglycerol lipase-alpha 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. CONCLUSION: MLWE could ameliorate intestinal permeability, inflammation, and glucose and lipid metabolism imbalance of T2D by regulating gut microbiota, LPS and eCBs. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Du, Yan AU - Du Y AD - Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. FAU - Zhang, Ran AU - Zhang R AD - 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. FAU - Zheng, Xiao-Xiao AU - Zheng XX AD - Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China; Department of Pharmacy, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, 221116, China. FAU - Zhao, Yan-Lin AU - Zhao YL AD - Department of Pharmacy, Suining People's Hospital Affiliated to Xuzhou Medical University, Suining, 221202, China. FAU - Chen, Yu-Lang AU - Chen YL AD - Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. FAU - Ji, Shuai AU - Ji S AD - Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. FAU - Guo, Meng-Zhe AU - Guo MZ AD - Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China. FAU - Tang, Dao-Quan AU - Tang DQ AD - 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. Electronic address: tdq993@hotmail.com. LA - eng PT - Journal Article DEP - 20231230 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Endocannabinoids) RN - 0 (Lipopolysaccharides) RN - 0 (Occludin) RN - 0 (RNA, Ribosomal, 16S) RN - Morus alba SB - IM MH - Mice MH - Animals MH - *Diabetes Mellitus, Type 2/drug therapy MH - Endocannabinoids/metabolism MH - Lipopolysaccharides MH - *Morus/chemistry MH - *Gastrointestinal Microbiome/genetics MH - Dysbiosis/drug therapy MH - Occludin MH - RNA, Ribosomal, 16S MH - Plant Leaves/metabolism OTO - NOTNLM OT - Endocannabinoid system OT - Gut microbiota OT - Intestinal permeability OT - Mulberry leaf OT - Type 2 diabetes mellitus COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/01/02 11:43 MHDA- 2024/01/29 06:43 CRDT- 2024/01/01 19:13 PHST- 2023/07/19 00:00 [received] PHST- 2023/12/04 00:00 [revised] PHST- 2023/12/26 00:00 [accepted] PHST- 2024/01/29 06:43 [medline] PHST- 2024/01/02 11:43 [pubmed] PHST- 2024/01/01 19:13 [entrez] AID - S0378-8741(23)01551-9 [pii] AID - 10.1016/j.jep.2023.117681 [doi] PST - ppublish SO - J Ethnopharmacol. 2024 Apr 6;323:117681. doi: 10.1016/j.jep.2023.117681. Epub 2023 Dec 30.