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Effect of metformin either alone or in combination with HCE on the in vitro insulin secretion, insulin sensitivity, and glucose uptake. (A) Insulin secretion, (B) insulin sensitivity and (C) glucose uptake were measured using INS-1 (an insulin-secreting cell line), C2C12 (an immortalized mouse myoblast cell line), and HepG2 (a human liver cancer cell line) cells, respectively as mentioned in the Materials and Methods section. Data with different letters are significantly different (p < 0.05) according to one way ANOVA analysis.
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Metformin and Houttuynia cordata are representative anti-diabetic therapeutics in western and oriental medicine, respectively. The current study examined the synergistic anti-diabetic effect of Houttuynia cordata extraction (HCE) and metformin combination in Otsuka Long–Evans Tokushima Fatty (OLETF) rats. Fecal microbiota were analyzed by denaturin...
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Context 1
... baseline corrected ipITT glucose AUC in the metformin + HCE group was found to be significantly lower than that in metformin group. In alignment, co-exposure to HCE caused marked enhancement in the insulin secretion, insulin sensitivity, and glucose uptake in a concentration-dependent manner in metformin-treated INS-1 (an insulin-secreting cell line, at high glucose level), C2C12 (glucosamine-induced), and HepG2 cells, respectively ( Figure 3A-C). ...
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Citations
... For the determination of total flavonoid content in the three drug samples, a previously established method was followed [20]. Initially, 10 µL of each sample was dissolved in 30 µL of 5% NaNO 2 and allowed to stand for 5 min. ...
Helicobacter pylori has been implicated in various gastrointestinal disorders, including functional dyspepsia. This study aimed to compare the anti-H. pylori activity and gastroprotective effects of three typical herbal formulas used for gastrointestinal disorders in Korea: Shihosogan-tang (ST), Yijung-tang (YT), and Pyeongwi-san (PS). Firstly, we assessed the total phenolic and flavonoid contents, as well as the antioxidative capacity. Additionally, we evaluated the antibacterial effect on H. pylori using an ammonia assay, minimum inhibitory concentration (MIC) test, and the disk agar diffusion method. Furthermore, we examined alterations in the gene expression of tight junction proteins, pro-inflammatory cytokines, and cellular vacuolation using an AGS cell model infected with H. pylori. While ST exhibited a higher total phenolic content, superior free radical scavenging, and inhibition of H. pylori compared to YT and PS, YT more evidently inhibited gastric cellular morphological changes such as vacuolation. All formulations significantly ameliorated changes in inflammatory and gastric inflammation-related genes and cellular morphological alterations induced by H. pylori infection. Overall, the present in vitro study suggests that all three herbal formulas possess potential for ameliorating gastrointestinal disorders, with ST relatively excelling in inhibiting H. pylori infection and inflammation, while YT potentially shows greater efficacy in directly protecting the gastric mucosa.
... Zhang et al. [27] reported that using metformin for 8 weeks in highly fat-fed rats resulted in the enrichment of the genus Klebsiella. For E. coli, most of the experimental studies in mice or rats used metformin with a high-fat diet and reported a significant reduction of E. coli [28][29][30][31]. In humans, we could not find any data regarding the effect of metformin on gut microbiota in NAFLD or NSAH patients. ...
Ethanol-producing dysbiotic gut microbiota could accelerate the progress of non-alcoholic fatty liver disease (NAFLD). Metformin demonstrated some benefits in NAFLD. In the present study, we tested the ability of metformin to modify ethanol-producing gut bacterial strains and, consequently, retard the progress of NAFLD. This 12-week study included forty mice divided into four groups (n = 10); normal diet, Western diet, Western diet with intraperitoneal metformin, and Western diet with oral metformin. Oral metformin has a slight advantage over intraperitoneal metformin in ameliorating the Western diet–induced changes in liver function tests and serum levels of different cytokines (IL-1β, IL-6, IL-17, and TNF-α). Changes in liver histology, fibrosis, lipid content, Ki67, and TNF-α were all corrected as well. Faecal ethanol contents were increased by the Western diet but did not improve after treatment with metformin although the numbers of ethanol-producing Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli) were decreased by oral metformin. Metformin did not affect bacterial ethanol production. It does not seem that modification of ethanol-producing K. pneumoniae and E. coli bacterial strains by metformin could have a significant impact on the therapeutic potentials of metformin in this experimental model of NAFLD.
... Para as dosagens de concentração sérica de glicose (Gold Analisa Diagnóstica Ltda, cat nº 434), triglicérides (TG -Gold Analisa Diagnóstica Ltda cat nº 459), colesterol total (Gold Analisa Diagnóstica Ltda cat nº 460), lipoproteína de alta densidade (HDL -Gold Analisa Diagnóstica Ltda cat nº 413), utilizou-se kits enzimático-colorimétricos. Os níveis de lipoproteína de baixa densidade (LDL) e lipoproteína de muito baixa densidade (VLDL) foram obtidos como descrito anteriormente (VON DENTZ et al., 2020). A razão TG/HDL, apontada como um possível marcador de resistência à insulina, foi calculada (WANG et al., 2017). ...
O tecido adiposo produz e secreta uma série adipocinas que participam no controle de processos fisiológicos e fisiopatológicos. Compostos ativos foram descritos no óleo-resina de copaíba, o qual apresenta efeitos terapêuticos. Contudo, não há dados sobre os efeitos do óleo-resina de copaíba sobre o tecido adiposo. Assim, a ação do óleo-resina de copaíba sobre marcadores inflamatórios e sistema redox, no tecido adiposo de animais saudáveis, foi avaliada. Ratos Wistar machos foram casualmente divididos para receber dieta padrão (C, n=7) ou dieta padrão e óleo-resina de copaíba (OC, n=7), por 8 semanas. O óleo-resina de copaíba foi administrado via gavagem na dose de 200 mg/kg/dia. Animais do grupo C receberam veículo, via gavagem, em volume equivalente ao oferecido ao grupo OC. Os dados mostram que a suplementação com óleo-resina de copaíba foi eficiente em diminuir o ganho de peso e a adiposidade sem alterar parâmetros metabólicos, marcadores inflamatórios ou marcadores do sistema antioxidante e de danos oxidativos no tecido adiposo. Concluindo, assim, que a suplementação com óleo-resina de copaíba atenua ganho de peso e não apresenta efeitos indesejáveis ao tecido adiposo em animais saudáveis.
... It is known that adipose tissue dysfunction leads to lipolysis and insulin resistance, resulting in increased hepatic lipogenesis and decreased free fatty acids oxidation, which promotes ectopic liver fat accumulation, leading to the onset of steatosis (Jung and Choi 2014). The TG/HDL ratio is considered a potential biomarker of insulin resistance (Murguía-Romero et al. 2013;Wang et al. 2017), and its behavior was altered by high sucrose, suggesting insulin resistance in the S group. Copaiba oleoresin supplementation was associated with improvement of the lipid profile and fasting glucose levels. ...
Obesogenic diets lead to fat accumulation and dysfunctional adipose tissue. Active compounds were described in copaiba oleoresin, which presents anti-inflammatory, antimicrobial, and antioxidant properties. However, there are no data regarding the effects of copaiba oleoresin in adipose tissue. Therefore, we tested the hypothesis that the copaiba oleoresin could prevent or minimize obesity and adipose tissue inflammation and oxidative stress in response to a high sucrose diet. Male Wistar rats were randomly assigned to receiving commercial chow (C, n = 8), commercial chow and 30% sucrose added to the drinking water (S, n = 8), or commercial chow and 30% sucrose added to the drinking water + copaiba oleoresin (S+CO, n = 8). Copaiba oleoresin was given at a dose of 200 mg kg⁻¹ day⁻¹ by gavage for eight weeks. C and S animals received vehicle, at equivalent volume, by gavage. At the end of the experiment, blood samples and epididymal adipose tissue were collected for biochemical, inflammatory, and oxidative stress analyses. Copaiba oleoresin supplementation prevented weight gain, adiposity, insulin resistance, and increased IL-1β levels. Additionally, copaiba oleoresin partially attenuated the increase in fasting glucose levels, lipids, and IL-6 levels, and improved the redox status in adipose tissue. Our results suggest that the use of copaiba oleoresin could be a good strategy for prevention of obesity and its complications.
KEYWORDS:
natural products; high sucrose diet; obesity; Copaifera
... Most of these are different plant extracts with high phenolic and flavonoid concentrations, that act as anti-inflammatory and antioxidant agents [97]. One such herb extract from Houttuynia cordata (HC) has been added to metformin and compared with metformin-therapy alone in Otsuka Long-Evans Tokushima Fatty (OLETF) rats [98]. While both interventions changed the intestinal microbial profile and the production of SCFA, the combination-therapy had significantly stronger insulinsensitizing and anti-inflammatory effects than metformin alone, lowering both serum and fecal LPS and cytokines like TNF-α and IL-1β, though glucose tolerance was similar in both groups at the end of the experiment. ...
Obesity is a systemic disease and represents one of the leading causes of death worldwide by constitutingthe main risk factor for a series of non-communicable diseases such as type 2 diabetes mellitus (T2DM),cardiovascular diseases and dyslipidemia. Lifestyle interventions have been attempting to prevent T2DM andobesity but are difficult to maintain by most patients. However, the recent focus on the intestinal microbiotaand its important role in the host’s metabolism provides a new key for improving metabolic health. Modulatingthe composition of the gut microbiota was proposed as a method to manage these metabolic diseases andmost frequently this is undertaken by using probiotics, prebiotics or synbiotics. Furthermore, the action ofmetformin, the most commonly prescribed drug for treating T2DM, is mediated in part by the gut microbiota,although this interplay may also be responsible for the frequent gastrointestinal adverse effects of metformin.Thus, adding a gut microbiota modulator (GMM), such as probiotics or prebiotics, to metformin therapy couldamplify its anti-diabetic effects, while decreasing its adverse reactions. This review summarizes the varioustherapies that are used to shift the composition of the microbiome and their efficacy in alleviating metabolicparameters, it assesses the interaction between metformin and the gut microbiota, and it evaluates the existingclinical and preclinical studies that analyze the potential synergy of a combined metformin-GMM therapy.
... For H&E and AB/PAS staining of the desired tissues, the sections were placed on positively charged silicon-coated glass slides, deparaffinized with xylene and then rehydrated using a graded series of decreasing alcohol concentrations. Finally, the liver and epididymal adipose tissue sections were stained with H&E solution (Sigma-Aldrich) and the intestinal sections were stained with an alcian blue/PAS staining kit (Abcam, Cambridge, MA, USA), in accordance with previous reports [40,41]. For Oil Red O staining of the liver, the hepatic tissues were embedded in FSC 22 Frozen Section Compound (mounting medium) (Leica Biosystems, Buffalo Grove, IL, USA) and frozen at −30 • C. The tissues were then sectioned at a 12 µm thickness using a Leica CM1860 Cryostat microtome (Leica Microsystems, Nussloch, Germany). ...
Akkermansia muciniphila (A. muciniphila) is a promising probiotic candidate owing to its health-promoting properties. A previous study reported that the pasteurized form of A. muciniphila strains isolated from human stool samples had a beneficial impact on high-fat diet-induced obese mice. On the other hand, the differences in the probiotic effects between live and pasteurized A. muciniphila on the metabolism and immune system of the host are still inconclusive. This study examines the differences between the live and pasteurized forms of A. muciniphila strains on the lipid and glucose metabolism and on regulating the inflammatory immune responses using a HFD-fed obese mouse model. The animals were administered the live and pasteurized forms of two A. muciniphila strains five times per week for the entire study period of 12 weeks. Both forms of the bacterial strains improved the HFD-induced obesity and metabolic dysregulation in the mice by preventing body-weight gains after one week. In addition, they cause a decrease in the weights of the major adipose tissues, adipogenesis/lipogenesis and serum TC levels, improvement in glucose homeostasis and suppression of inflammatory insults. Furthermore, these treatments restored the damaged gut architecture and integrity and improved the hepatic structure and function in HFD-induced animals. On the other hand, for both bacterial strains, the pasteurized form was more potent in improving glucose tolerance than the live form. Moreover, specific A. muciniphila preparations with either live or pasteurized bacteria decreased the number and population (%) of splenic Treg cells (CD4+ Foxp3+) significantly in the HFD-fed animals, further supporting the anti-inflammatory properties of these bacteria.
... In the mouse model of non-alcoholic steatohepatitis (NASH) induced by methionine choline deficiency diet (MCD), supplement of butyrate reduced the abundance of Bilophila and Rikenellaceae, and significantly increased the content of Akkermansia, Roseburia, Coprococcus, Coprobacillus, Delftia, Sutterella, and Coriobacteriaceae [136]. Some of these Bilophila have been shown to damage intestinal mucosa and produce LPS [137], while Akkermansia and Roseburia have the function of improving gut barrier and preventing immune system diseases [138,139]. Therefore, butyrate can induce the protective transfer of intestinal microbiome to repair mice' gut barrier, and effectively prevent the liver damage related to NASH caused by MCD diet [136]. Sodium butyrate supplementation can also protect gut barrier, limit endotoxin displacement, and slow down NAFLD development in mice induced by fluid diet rich in fat, fructose, and cholesterol, which was achieved by increasing the expression of tight junction protein in the duodenum directly [140]. ...
Purpose
In previous studies, short-chain fatty acids (SCFAs) have been found to regulate gut microbiota and change gut barrier status, and the potential positive effects of SCFAs on inflammatory bowel disease (IBD), type 1 diabetes mellitus (T1D), and non-alcoholic fatty liver disease (NAFLD) have also been found, but the role of SCFAs in these three diseases is not clear. This review aims to summarize existing evidence on the effects of SCFAs on IBD, T1D, and NHFLD, and correlates them with gut barrier and gut microbiota (gut microbiota barrier).
Methods
A literature search in PubMed, Web of Science, Springer, and Wiley Online Library up to October 2020 was conducted for all relevant studies published.
Results
This is a retrospective review of 150 applied research articles or reviews. The destruction of gut barrier may promote the development of IBD, T1D, and NAFLD. SCFAs seem to maintain the gut barrier by promoting the growth of intestinal epithelial cells, strengthening the intestinal tight connection, and regulating the activities of gut microbiota and immune cells, which might result possible beneficial effects on the above three diseases at a certain dose.
Conclusions
Influencing gut barrier health may be a bridge for SCFAs (especially butyrate) to have positive effects on IBD, T1D, and NAFLD. It is expected that this article can provide new ideas for the subsequent research on the treatment of diseases by SCFAs and help SCFAs be better applied to precise and personalized treatment.
... In addition, Lee et al. [89] showed that the expression of IL-1β, which is related to insulin resistance, decreased while the abundance of Bacteroides and Butyricimonas was increased. The tendency to decrease the expression of IL-6, IL-1β and TNF-α was also observed in other studies, but the types of bacteria that correlated with the expression of inflammatory cytokines were different [92,94,128,130]. With the inhibition of pro-inflammatory cytokines, modulation of the inflammatory signaling pathway is a potential mechanism to attenuate inflammation. ...
... In addition, abundance of other gut bacteria increased in the metformin-treated group and were known to interact with the host immune response. For example, Roseburia is more abundant in the metformintreated group and is known to inhibit the activity of NF-κB [92,94,124,130,152,153]. In addition, the genus Lactobacillus and several Lactobacillus species have been shown to modulate inflammation, as reported in previous studies [154][155][156][157]. Thus, future studies should be warranted to unveil how metformin prevents the host inflammatory response related to the alteration of gut bacteria. ...
Metformin is the first-line pharmacotherapy for treating type 2 diabetes mellitus (T2DM); however, its mechanism of modulating glucose metabolism is elusive. Recent advances have identified the gut as a potential target of metformin. As patients with metabolic disorders exhibit dysbiosis, the gut microbiome has garnered interest as a potential target for metabolic disease. Henceforth, studies have focused on unraveling the relationship of metabolic disorders with the human gut microbiome. According to various metagenome studies, gut dysbiosis is evident in T2DM patients. Besides this, alterations in the gut microbiome were also observed in the metformin-treated T2DM patients compared to the non-treated T2DM patients. Thus, several studies on rodents have suggested potential mechanisms interacting with the gut microbiome, including regulation of glucose metabolism, an increase in short-chain fatty acids, strengthening intestinal permeability against lipopolysaccharides, modulating the immune response, and interaction with bile acids. Furthermore, human studies have demonstrated evidence substantiating the hypotheses based on rodent studies. This review discusses the current knowledge of how metformin modulates T2DM with respect to the gut microbiome and discusses the prospect of harnessing this mechanism in treating T2DM.
... Two studies gave the rats HFD for 2 or 10 weeks to induce an obese rat model, 41,42 five studies treated rats with HFD for 2-12 weeks followed by injection of streptozotocin (STZ) to induce diabetes, [43][44][45][46][47] and two studies used spontaneously diabetic rat models. 48,49 The dose of metformin ranged from 30 to 215.12 mg/kg/d, and the treatment period ranged from 4 weeks to 12 weeks. Similar to the results in mice, Verrucomicrobia was significantly increased in HFD-induced Wistar obese rats after treatment with metformin. ...
... Through summarizing and comparing the results in patients and rodent models, we found that metformin significantly increases the abundance of the phylum Verrucomicrobia, genus Akkermansia, and species Akkermansia muciniphila. 26,27,31,41,42,45,48,53,54 Zhang et al found that Akkermansia muciniphila was reduced in patients with prediabetes (impaired glucose tolerance and/ or impaired fasting glucose) and newly diagnosed T2DM patients, suggesting that a low abundance of this bacterium might be a biomarker of glucose intolerance. 71 Lee et al found that Akkermansia muciniphila was negatively correlated with serum glucose level in HFD-fed mice treated with metformin. ...
Metformin is a first-line treatment for type 2 diabetes mellitus (T2DM); however, its underlying mechanism is not fully understood. Gut microbiota affect the development and progression of T2DM. In recent years, an increasing number of studies has focused on the relationship between metformin and gut microbiota, suggesting that metformin might exert part of its hypoglycemic effect through these microbes. However, most of these results were not consistent due to the complex composition of the microbiota, the differences between species, the large variation between individuals, and the differences in experimental design, bringing great obstacle for our better understanding of the effects of metformin on the gut microbiota. Here, we reviewed the published papers concerning about the impacts of metformin on the gut microbiota of mice, rats, and humans with obesity or T2DM, and summarized the changes of gut microbiota composition caused by metformin and the possible underlying hypoglycemic mechanism which is related to gut microbiota. It was found that the proportions of some microbiota, such as phyla Bacteroidetes and Verrucomicrobia and genera Akkermansia, Bacteroides and Escherichia, were significantly affected by metformin in several studies. Metformin may exert part of hypoglycemic effects by altering the gut microbiota in ways that maintain the integrity of the intestinal barrier, promote the production of short-chain fatty acids (SCFAs), regulate bile acid metabolism, and improve glucose homeostasis.
... These examples include Daesiho-Tang (DSHT) that attenuated obesity and significantly increased the relative abundance of Bacteroidetes, B/F ratio, Akkermansia, Bifidobacterium, Lactobacillus, and decreased the level of Firmicutes (Hussain et al., 2016), Gegen Qinlian Decoction (GQD) alleviated Type 2 diabetes and significantly increased Faecalibacterium prausnitzii (Xu et al., 2015), while Qushi Huayu Decoction (QHD) reduced HFD-induced non-alcoholic fatty liver disease (NAFLD), and significantly increased the abundance of Parabacteroides and decreased the abundance of Odoribacter, Rikenella, Tyzzerella, Intestinibacter, Romboutsia and 2 members in Lachnospiraceae (Leng et al., 2020). Other examples related to gut microbiota changes included (Table 1): 20% Folium Mori amelioration of diabetes , Xiexin Tang-mediated improvement of type 2 diabetes (Wei et al., 2018), amelioration of human type 2 diabetes by metformin and a traditional Chinese herbal formula, AMC (Tong et al., 2018), Huang-Lian-Jie-Du decoction-mediated treatment of hyperglycemia and insulin resistance , improvement of type 2 diabetes by treatment with Qijian (Gao et al., 2018), Banxia Xiexin decoction on diabetic gastroparesis rats , Houttuynia cordata facilitation of metformin on reducing insulin resistance (Wang et al., 2017b), berberine, the main bioactive alkaloid of Coptis chinensis, on glucolipid metabolism and insulin resistance in diabetic mice Liu et al., 2018a), and rhein's role in antidiabetic effects . Evidently, efficacy of TCM herbal treatment is closely related to their influence on gut microbiota composition. ...
Traditional Chinese Medicine (TCM) has been extensively used to ameliorate diseases in Asia for over thousands of years. However, owing to a lack of formal scientific validation, the absence of information regarding the mechanisms underlying TCMs restricts their application. After oral administration, TCM herbal ingredients frequently are not directly absorbed by the host, but rather enter the intestine to be transformed by gut microbiota. The gut microbiota is a microbial community living in animal intestines, and functions to maintain host homeostasis and health. Increasing evidences indicate that TCM herbs closely affect gut microbiota composition, which is associated with the conversion of herbal components into active metabolites. These may significantly affect the therapeutic activity of TCMs. Microbiota analyses, in conjunction with modern multiomics platforms, can together identify novel functional metabolites and form the basis of future TCM research.
