PMID- 33935735 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210504 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 12 DP - 2021 TI - Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice. PG - 642400 LID - 10.3389/fphar.2021.642400 [doi] LID - 642400 AB - The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation. CI - Copyright (c) 2021 Liu, Liu, Cao, Ji, Li, Huan, Lei, Fu, Gao, Liu and Shen. FAU - Liu, Quan AU - Liu Q AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Liu, Shuainan AU - Liu S AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Cao, Hui AU - Cao H AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Ji, Wenming AU - Ji W AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Li, Caina AU - Li C AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Huan, Yi AU - Huan Y AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Lei, Lei AU - Lei L AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Fu, Yaxin AU - Fu Y AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Gao, Xuefeng AU - Gao X AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Liu, Yuling AU - Liu Y AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Shen, Zhufang AU - Shen Z AD - Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Key Laboratory of Polymorphic Drugs of Beijing, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. LA - eng PT - Journal Article DEP - 20210415 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC8082153 OTO - NOTNLM OT - gut microbiome OT - ileal damage OT - inflammation OT - ramulus mori (sangzhi) alkaloids OT - type 2 diabetes COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/05/04 06:00 MHDA- 2021/05/04 06:01 PMCR- 2021/04/15 CRDT- 2021/05/03 06:10 PHST- 2020/12/16 00:00 [received] PHST- 2021/03/10 00:00 [accepted] PHST- 2021/05/03 06:10 [entrez] PHST- 2021/05/04 06:00 [pubmed] PHST- 2021/05/04 06:01 [medline] PHST- 2021/04/15 00:00 [pmc-release] AID - 642400 [pii] AID - 10.3389/fphar.2021.642400 [doi] PST - epublish SO - Front Pharmacol. 2021 Apr 15;12:642400. doi: 10.3389/fphar.2021.642400. eCollection 2021.