The aerial parts of Salvia miltiorrhiza Bge. strengthen intestinal barrier and modulate gut microbiota imbalance in streptozocin-induced diabetic mice
Introduction
Salvia species were used as food and celebrated traditional Chinese materia medica all around the world for its antimicrobial, toxicity, antioxidant, and enzyme inhibitory activity (Bahadori et al., 2017). The rhizome of S. miltiorrhiza Bge. has recently been listed as a health-care food which can soothe the nerves. Traditionally, it was widely used for cardiovascular diseases, diabetes, and its complications around the world (Lei and Chiou, 1986, Ren et al., 2016, Xie and Du, 2011). Total salvianolic acids, the abundant bioactive components of S. miltiorrhiza, has received a considerable attention in studies on DM by lowing the blood glucose, triglyceride levels, and increasing insulin sensitivity (Huang et al., 2012). As our study clearly demonstrated that the content of total salvianolic acids in the aerial parts is about the same as that in roots. The aerial parts of S. miltiorrhiza Bge. (DJ) have been developed as a “Danshen Tea” (Sichuan Tongxing natural plant Pharmaceutical Co. Ltd., Sichuan, China) for treatment and prevention of coronary artery disease and dilation of blood vessels, often used for daily health care about regulating blood lipids and hypoxia tolerance. Blood-activating and stasis-dissolving drugs could ameliorate intestinal epithelial barrier damage induced by high glucose through regulating syndecan-1 and heparanase expression (Qiang et al., 2014, Raoufi et al., 2015). Moreover, salvianolic acid B and rosmarinic acid, the two main phenolic acids of DJ, could attenuate vascular dysfunction of aorta induced by diabetes and modulate intestinal SGLT1 levels by working on blood glucose (Qing et al., 2015). According to the literature, salvianolic acid B possesses a certain protective effect on blood glycemic, insulin resistance and glycogen synthesis in diabetes (Mackie, Rigby, Harvey, & Bajka, 2016).
Diabetes mellitus (DM) is a chronic and progressive disease that without medical curable method (Qing et al., 2015, Sanyal, 2013). It requires lifelong medical treatment and has with a rapidly rising incidence worldwide. Besides, cardiovascular diseases, cancers, and infectious diseases, and gastrointestinal complications also frequently come along with the diabetes (de Ferranti et al., 2014, Qu and Jiang, 2014, Sharma et al., 2014). Gastrointestinal complications, known as gastroparesis and diabetic enteropathy (DE), significantly reduce the quality of individuals with DM. Indeed, intestinal symptoms have up to 80% of individuals with Type 1 diabetes (T1D) (Fiorina et al., 2001). Previous studies on DE mainly concentrated on the dysfunction of gastrointestinal motility especially the changes in intestinal smooth muscle cells and the enteric nervous system. It has been demonstrated that colon morphological and biomechanical remodeling could be induced in experimental diabetes (Zhao, Nakaguchi, & Gregersen, 2009). Simultaneously, in diabetic rodents, intestinal mucosa morphology was deranged significantly, suggesting that intestinal homeostasis may be altered in T1D (Domènech et al., 2011). In recent years, the associations between common chronic human disorders and gut microbiome composition dysfunction have been reported (Aguirre & Venema, 2015). Accumulating studies have indicated that an abnormal gut microbiota is responsible for human obesity and DM by influencing energy extraction, inflammation, and neuroendocrine secretions (Musso et al., 2011, Qin et al., 2012).
However, the functional and health-care effects of the aerial parts of S. miltiorrhiza and their potential use as functional food resources have not been explored clearly. The current study was conducted to investigate the protective effect of DJ on DE mice, especially emphasizing the impact on ameliorating the intestinal epithelial barrier and gut microbiota dysfunction induced by diabetes.
Section snippets
Herbal extraction and component analysis
The aerial parts of S. miltiorrhiza (DJ) were collected from the medicine court of Nanjing University of Chinese Medicine. All DJ were crushed into powder after having been dried until the water content was 9.01%. For extraction of DJ, 1 kg chopped herbs were weighed and then extracted with 10 L 60% ethanol for 2 h each time. A reflux extraction device was used to extract twice. LABCONCO Freezone1 lyophilizer (Kansas City, MO) was used to lyophilize the extraction. The dry powder was then stored
Component analysis of DJ
Eleven components were identified in DJ, containing danshensu, protocatechualdehyden, caffeic acid, rutin, isoquercitrin, astragalin, rosmarinic acid, lithospermic acid, salvianolic acid B, salvianolic acid A, and salvianolic acid C (Fig. 1). The content of total salvianolic acids was probably 5.28% while that of flavonoids was 0.37%.
DJ improves the general histological changes of intestine in STZ-induced diabetic mice
The layer and mucosa thickness in the diabetic duodenum did not differ from the normal group (Fig. 2A). Whereas, the intestinal mucosa was altered in the ileum and
Discussion
Salvia miltiorrhiza Bge. has been widely used to cure many diseases for a long time. It is a celebrated traditional Chinese herbal medicine, having been recorded in many classics like Sheng Nong's herbal classic, Compendium of Materia Medica, etc. And now it is also used as a kind of health-care food (Chen, Shu, Chuang, & Wang, 2016). The wild Salvia sources in China have almost been exhausted with the increasing demands of rhizomes of Salvia miltiorrhiza. It is notable that the contents of
Conclusion
In conclusion, the present study is the first attempt to investigate the protective effects of the aerial parts of S. miltiorrhiza, a novel and valuable food or medical supplement, on the intestinal symptoms of DM mice. We obtained evidence showing an obvious effect of DJ on strengthening the intestinal barrier and modulating gut microbiota in streptozotocin-induced diabetic mice. In addition, DJ had no enterotoxicity on normal mice. Thus, it is reasonable to take the aerial parts of S.
Conflict of interest
The authors have declared that there is no conflict of interest.
Author contribution
Jun-fei Gu, analysis and interpretation of data, conception and design; Shu-lan Su, acquisition of data and writing of the manuscript; Jian-Ming Guo, acquisition of data, analysis and interpretation of data; Yue Zhu, experimental design; Jin-Ao Duan, conception and design, study supervision, revision of the manuscript.
Acknowledgements
The authors gratefully acknowledge the financial support of the Key Project from National Natural Science Foundation of China (81673533) and the Key Project of Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization (ZDXM-2-5).
References (51)
- et al.
Salvia nemorosa L.: A novel source of bioactive agents with functional connections
LWT-Food Science and Technology
(2017) - et al.
Huangqi-Honghua combination and its main components ameliorate cerebral infarction with Qi deficiency and blood stasis syndrome by antioxidant action in rats
Journal of Ethnopharmacology
(2014) - et al.
Increasing dietary oat fibre decreases the permeability of intestinal mucus
Journal of Functional Foods
(2016) - et al.
Clostridium difficile infection in diabetes
Diabetes Research and Clinical Practice
(2014) - et al.
Salvianolic acid B improves vascular endothelial function in diabetic rats with blood glucose fluctuations via suppression of endothelial cell apoptosis
European Journal of Pharmacology
(2016) - et al.
Colorectal cancer: Histopathologic differences in tumor characteristics between patients with and without diabetes
Clinical Colorectal Cancer
(2014) - et al.
Overexpression of miR-21 in patients with ulcerative colitis impairs intestinal epithelial barrier function through targeting the Rho GTPase RhoB
Biochemical and Biophysical Research Communications
(2013) - et al.
The art of targeting gut microbiota for tackling human obesity
Genes and Nutrition
(2015) The use of animal models in the study of diabetes mellitus
British Journal of Pharmacology
(2012)- et al.
Occludin regulates macromolecule flux across the intestinal epithelial tight junction barrier
American Journal of Physiology. Gastrointestinal and Liver Physiology
(2011)
Vinpocetine and vasoactive intestinal peptide attenuate manganese-induced toxicity in NE-4C cells
Biological Trace Element Research
QIIME allows analysis of high-throughput community sequencing data
Nature Methods
Advanced glycation end-product expression is upregulated in the gastrointestinal tract of type 2 diabetic rats
World Journal of Diabetes
Inflammatory and apoptotic regulatory activity of tanshinone IIA in helicobacter pylori-infected cells
American Journal of Chinese Medicine
Qualitative analysis and simultaneous quantification of phenolic compounds in the aerial parts of Salvia miltiorrhiza by HPLC-DAD and ESI/MS(n)
Phytochemical Analysis
Type 1 diabetes mellitus and cardiovascular disease: A scientific statement from the American Heart Association and American Diabetes Association
Diabetes Care
Morphofunctional changes underlying intestinal dysmotility in diabetic RIP-I/hIFNβ transgenic mice
International Journal of Experimental Pathology
Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes
Diabetes
Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota
Nature
CD-HIT: Accelerated for clustering the next-generation sequencing data
Bioinformatics
Streptozotocin-induced diabetic models in mice and rats
Current Protocols in Pharmacology
Vasoactive intestinal peptide induces an immunosuppressant microenvironment in the maternal-fetal interface of non-obese diabetic, mice and improves early pregnancy outcome
American Journal of Reproductive Immunology
Antidiabetic effect of the total polyphenolic acids fraction from Salvia miltiorrhiza Bunge in diabetic rats
Phytotherapy Research
Frequency of Firmicutes and Bacteroidetes in gut microbiota in obese and normal weight Egyptian children and adults
Archives of Medical Science
Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy
Biomolecular Concepts
Cited by (40)
Two new constituents from the aerial parts of Salvia miltiorrhiza Bge
2023, Natural Product ResearchMitigation mechanisms of Hizikia fusifarme polysaccharide consumption on type 2 diabetes in rats
2020, International Journal of Biological MacromoleculesCitation Excerpt :On the other hand, the lipopolysaccharide (LPS) and peptidoglycan predominantly derived from partial intestinal microbial metabolism might cause inflammation and insulin resistance in peripheral tissues [37]. In our research, diabetic rats in DC group exhibited a noticeable change of Firmicutes/Bacteroidetes when compared with non-diabetic rats, which is consistent with the connection of gut flora with the occurrence and development of diabetes as reported previously [13,38,39]. However, HFP administration significantly reversed the changes of gut microbiota composition of diabetic rats, restoring the Firmicutes/Bacteroidetes ratio close to that of non-diabetic rats.
Cocoa diet modulates gut microbiota composition and improves intestinal health in Zucker diabetic rats
2020, Food Research InternationalCitation Excerpt :These results suggest that cocoa diet may improve the barrier function and integrity of diabetic animals through enhancing the protein expressions of mucin and ZO-1. Supporting this it has been shown that the intake of Salvia miltiorrhiza, a natural source of phenolic acids, ameliorates the damaged barrier function of diabetic mice through enhancing the expressions of tight junction proteins decreased by streptozotocin (STZ) (Gu et al., 2017). Likewise, it has been proved that long term intake of anthocyanims promoted intestinal integrity in healthy mouse (Peng et al., 2019).
Prevention and treatment of chronic heart failure through traditional Chinese medicine: Role of the gut microbiota
2020, Pharmacological ResearchCitation Excerpt :Cordyceps polysaccharide can improve gut microbiota and intestinal integrity, reduce metabolic endotoxin, and inflammation [78]. Salvia miltiorrhiza stem and leaf can also enhance intestinal barrier function by up-regulating the expression of tight junction protein ZO-1, closed protein, and tight junction donor protein-5 in ileum and colon [79]. Berberine can drastically reduce the levels of serum lipopolysaccharide (LPS), IL-1β, TNF-α, and IL-6 in mice.
Polysaccharide from tuberous roots of Ophiopogon japonicus regulates gut microbiota and its metabolites during alleviation of high-fat diet-induced type-2 diabetes in mice
2019, Journal of Functional FoodsCitation Excerpt :Gut microbiota dysbiosis was found during the onset and progression of type-2 diabetes, characterized especially by increased and/or decreased of Firmicutes-to-Bacteroidetes ratio (Larsen et al., 2010; Sircana et al., 2018), reduced abundance of butyrate-producing bacteria, e.g. Faecalibacterium prausnitzii, Clostridiales sp. and Roseburia intestinalis, and increased of opportunistic pathogens, e.g. Desulfovibrio sp. and Clostridium (Qin et al., 2012). These parameters are varied according to different factors (Gu et al., 2017; Sircana et al., 2018). Short-chain fatty acids (SCFAs, fatty acids with an aliphatic tail less than six carbons) are major metabolites produced from bacterial fermentation of non-digestible fibers in the colon, which comprise mainly acetate, propionate and butyrate.
Gut microbiota modulation with traditional Chinese medicine: A system biology-driven approach
2019, Pharmacological Research