Anti-diabetic effects of natural and modified 'Ganzhou' navel orange peel pectin on type 2 diabetic mice via gut microbiota.

Pectin, a kind of dietary fiber, has attracted much attention owing to its beneficial effect on human health in recent years. In this study, the effects of both 'Ganzhou' navel orange peel pectin (GOP) and modified GOP (MGOP) on type 2 diabetes (T2DM) were investigated. The results indicated that GOP and MGOP intervention had positive effects on T2DM in C57BL/6 mice. After modification, pectin can be changed into low methoxy pectin (LMP) and the content of GalA can increase, which endow MGOP with significant effects on improving lipid metabolism (TC, TG, and LDL-C decreased by 30.46%, 50%, and 37.56%, respectively, and HDL-C increased by 56%) and OGTT, further reducing insulin resistance (insulin decreased by 74.35%). In addition, MGOP was superior to GOP in improving oxidative stress (GSH and GSH-Px increased by 52.05% and 29.08% respectively, and MDA decreased by 84.02%), inhibiting inflammation and promoting SCFA synthesis. 16S rRNA analysis showed that MGOP changed the composition of intestinal microbiota in diabetic mice, decreased the abundance of Alistipes, Helicobacter and Oscillibacter, and increased the relative abundance of Dubosiella, Akkermansiaceae, and Atopobiaceae. The phenotypes of the gut microbiome also changed accordingly, which showed that MGOP significantly inhibited the growth of Gram-negative bacteria and potential pathogenic bacteria and reversed the related complications. Taken together, our findings revealed that MGOP intake regulated lipid metabolism and oxidative stress and improved the gut health of mice, with promising effects against T2DM and related complications.

Exploring Active Ingredients, Beneficial Effects, and Potential Mechanism of Allium tenuissimum L. Flower for Treating T2DM Mice Based on Network Pharmacology and Gut Microbiota.

Forty compounds were isolated and characterized from A. tenuissimum flower. Among them, twelve flavonoids showed higher α-glucosidase inhibition activities in vitro than acarbose, especially kaempferol. The molecular docking results showed that the binding of kaempferol to α-glucosidase (GAA) could reduce the hydrolysis of substrates by GAA and reduce the glucose produced by hydrolysis, thus exhibiting α-glucosidase inhibition activities. The in vivo experiment results showed that flavonoids-rich A. tenuissimum flower could decrease blood glucose and reduce lipid accumulation. The protein expression levels of RAC-alpha serine/threonine-protein kinase (AKT1), peroxisome proliferator activated receptor gamma (PPARG), and prostaglandin G/H synthase 2 (PTGS2) in liver tissue were increased. In addition, the Firmicutes/Bacteroidetes (F/B) ratio was increased, the level of gut probiotics Bifidobacterium was increased, and the levels of Enterobacteriaceae and Staphylococcus were decreased. The carbohydrate metabolism, lipid metabolism, and other pathways related to type 2 diabetes mellitus were activated. This study indicating flavonoids-rich A. tenuissimum flower could improve glycolipid metabolic disorders and inflammation in diabetic mice by modulating the protein expression and gut microbiota.

Diosmetin ameliorate type 2 diabetic mellitus by up-regulating Corynebacterium glutamicum to regulate IRS/PI3K/AKT-mediated glucose metabolism disorder in KK-Ay mice.

BACKGROUND AND PURPOSE: Diosmetin (Dios), a flavonoid compound with multiple pharmacological activities. However, fewer studies have reported its effects on type 2 diabetic mellitus (T2DM). Here, we address the effect of Dios on glucose metabolism and gut microbiota in KK-Ay diabetic mice. METHOD: Wild type C57BL/6 J mice or diabetic KK-Ay mice were treated with vehicle or Dios for one month. The ELISA kit and fluorescence microscope system were respectively employed to the evaluation of serum biochemical indicators and histopathological changes. Liver RNA-Seq and western blot were used to reveal the key signaling pathway. The effects of Dios on gut microbiota was investigated by the 16S rRNA gene sequencing, as well as the relationship between Dios and C. glu on glucose metabolism was explored with the C. glu transplantation. RESULTS: Dios treatment significantly decreased blood glucose and increased serum insulin concentrations. RNA-Seq analysis found that the underlying action mechanism of Dios on T2DM was via modulating glucose metabolism, which was proved by up-regulating IRS/PI3K/AKT signaling pathway to promote glycogen synthesis and GLUT4 translocation. Besides, Dios treatment reshaped the unbalanced gut microbiota by suppressing the ratio of Firmicutes/Bacteroidetes and markedly increasing the richness of C. glu. Moreover, treatment with C. glu and Dios together could markedly ameliorate glucose metabolism by up-regulating IRS/PI3K/AKT signaling pathway to promote glycogen synthesis and GLUT4 translocation. CONCLUSIONS: Dios treatment remarkably ameliorated glucose metabolism in KK-Ay diabetic mice by the regulation of C. glu via IRS/PI3K/AKT signaling pathway and reshaped the unbalanced gut microbiota. Our study provided evidence for the application of Dios to the treatment of T2DM.

Regulating the gut microbiota and SCFAs in the faeces of T2DM rats should be one of antidiabetic mechanisms of mogrosides in the fruits of Siraitia grosvenorii.

ETHNOPHARMACOLOGICAL RELEVANCE: The Siraitia grosvenorii fruits extract (SG, in which mogrosides are the main components), considered as a non-nutritional sweetener, has an antidiabetic effect. Our previous studies have confirmed that an extract of mogrosides being rich in triterpene glycosides with 1-3 glucosyl residues, designated as low-polar S. grosvenorii glycosides (L-SGgly), had a significant antidiabetic effect. However, whether the mechanism through impacting on gut microbiota to exert the antidiabetic effect of mogrosides remains unclear. AIMS OF THE STUDY: To explore the potential mechanism of mogrosides (SG and L-SGgly) on gut microbiota and faecal metabolites in the treatment of diabetes. STUDY DESIGN AND METHODS: In this study, the effects of SG and L-SGgly on gut microbiota and faecal endogenous metabolites were explored by sequencing the 16S rRNA V3-V4 region of gut microbiota, and detecting with gas chromatography-mass spectrometry (GC-MS) and liquid chromatography quadrupole time-of-flight MS (LC-Q-TOF/MS), respectively. In particular, correlation analyses revealed how these influences affect the anti-hyperglycaemic effect, to give the underlying antidiabetic mechanisms of the mogrosides in S. grosvenorii fruits. RESULTS: After a 14-day treatment with SG and L-SGgly for type 2 diabetes mellitus (T2DM) rats induced by a high-fat diet (HFD) and streptozotocin (STZ), the disordered gut microbiota in the faeces of T2DM rats were recovered. At the same time, the short-chain fatty acids (SCFAs) concentration significantly increased and the deoxycholic acid and 1ß-hydroxycholic acid content decreased in the faeces of T2DM rats. Moreover, correlation analyses provided the evidences that gut microbiota and its metabolites could be the target for exerting the anti-hyperglycaemic effects of SG and L-SGgly. Especially, Elusimicrobium, Lachnospiraceae_UCG-004, acetate, butyrate, and 1ß-hydroxycholic acid would be the potential dominant bacteria and biomarkers for SG and L-SGgly in reducing the blood glucose and insulin resistance of T2DM rats. CONCLUSION: It is the first time that a mechanism of targeting on gut microbiota for the antidiabetic effect of mogrosides in S. grosvenorii fruits has been proposed.

Anemarrhena asphodeloides modulates gut microbiota and restores pancreatic function in diabetic rats.

Anemarrhena asphodeloides is an herb widely used to treat symptoms associated with diabetes in traditional Chinese medicine. However, its key components and metabolites have low bioavailability and poor host absorption. To clarify the anti-diabetic mechanism of A. asphodeloides extract (AAE), we examined the anti-diabetic effects of AAE in rats with diabetes induced by a high-fat diet and streptozotocin. Faeces levels of the main components and metabolites of AAE were significantly higher than levels in plasma, which indicated that gut microbiota might play important roles in its anti-diabetic effect. Microbiological studies showed that unabsorbed components increased the diversity of the gut microbiota, enriched potentially beneficial bacteria, and suppressed potentially harmful bacteria. In vitro studies showed that AAE promoted the proliferation of Blautia coccoides, a bacterium with positive implication for diabetes, in a dose-dependent manner. AAE also promoted pancreatic cell regeneration and restored the function of pancreatic islet cells via peroxiredoxin 4 overexpression. Overall, these results suggest that AAE alleviates diabetes via modulating gut microbiota and protein expression.

Cyclocarya paliurus polysaccharides alleviate type 2 diabetic symptoms by modulating gut microbiota and short-chain fatty acids.

BACKGROUND: Cyclocarya paliurus polysaccharide (CCPP), a primary active component in the leaves of Cyclocarya paliurus (Batal.) Iljinsk (C. paliurus), has the ability to treat type 2 diabetes mellitus (T2DM), but cannot be digested by our digestive system. Therefore, mechanisms of regulating the gut microbiota and intestinal metabolites might exist. PURPOSE: To reveal the potential mechanism of CCPP treatment, this study aimed to investigate the alterations of the gut microbiota and intestinal metabolites especially short chain fatty acids (SCFAs) in type 2 diabetic rats. STUDY DESIGN AND METHODS: Type 2 diabetic rat models were developed, and the therapeutic effects of CCPP were evaluated. Metagenomics analysis was utilized to analyze the alterations to the gut microbiota, and UHPLC-QTOF/MS-based untargeted metabolomics analysis of colon contents was used to identify the differential intestinal metabolites. GC/MS was used to measure the SCFAs in rat's colon contents and human fecal inoculums. Furthermore, the expression of SCFA receptors including GPR41, GPR43 and GPR109a was verified by qRT-PCR and the concentration of glucagon-like peptide-1(GLP-1) and peptide tyrosinetyrosine (PYY) was measured by Elisa. RESULTS: Inhibition of the blood glucose levels and improvements in glucose tolerance and serum lipid parameters were observed after CCPP treatment. Eleven SCFA-producing species including Ruminococcus_bromii, Anaerotruncus_colihominis, Clostridium_methylpentosum, Roseburia_intestinalis, Roseburia_hominis, Clostridium_asparagiforme, Pseudoflavonifractor_capillosus, Intestinimonas_butyriciproducens, Intestinimonas_sp._GD2, Oscillibacter_valericigenes and Oscillibacter_ruminantium were clearly increased in the CCPP group. Furthermore, our study indicated that CCPP increases the production of SCFAs both in vivo and in vitro, and the gut microbiota are the key factor of this process. The SCFA receptors including GPR41, GPR43 and GPR109a, were significantly stimulated in the CCPP treated rats, which was accompanied by the upregulated expression of GLP-1 and PYY. CONCLUSION: These results demonstrated that CCPP could alleviate type 2 diabetic symptoms by increasing the SCFA-producing bacteria, promoting the production of SCFAs and upregulating SCFA-GLP1/PYY associated sensory mediators.

A specific gut microbiota and metabolomic profiles shifts related to antidiabetic action: The similar and complementary antidiabetic properties of type 3 resistant starch from Canna edulis and metformin.

The relationship between gut microbiota and type 2 diabetes mellitus (T2DM) has drawn increasing attention, and the benefits of various treatment strategies, including nutrition, medication and physical exercise, maybe microbially-mediated. Metformin is a widely used hypoglycemic agent, while resistant starch (RS) is a novel dietary fiber that emerges as a nutritional strategy for metabolic disease. However, it remains unclear as to the potential degree and interactions among gut microbial communities, metabolic landscape, and the anti-diabetic effects of metformin and RS, especially for a novel type 3 resistant starch from Canna edulis (Ce-RS3). In the present study, T2DM rats were administered metformin or Ce-RS3, and the changes in gut microbiota and serum metabolic profiles were characterized using 16S-rRNA gene sequencing and metabolomics, respectively. After 11 weeks of treatment, Ce-RS3 exhibited similar anti-diabetic effects to those of metformin, including dramatically reducing blood glucose, ameliorating the response to insulin resistance and glucose tolerance test, and relieving the pathological damage in T2DM rats. Interestingly, the microbial and systemic metabolic dysbiosis in T2DM rats was effectively modulated by both Ce-RS3 and, to a lesser extent, metformin. The two treatments increased the gut bacterial diversity, and supported the restoration of SCFA-producing bacteria, thereby significantly increasing SCFAs levels. Both treatments simultaneously corrected 16 abnormal metabolites in the metabolism of lipids and amino acids, many of which are microbiome-related. PICRUSt analysis and correlation of SCFAs levels with metabolomics data revealed a strong association between gut microbial and host metabolic changes. Strikingly, Ce-RS3 exhibited better efficacy in increasing gut microbiota diversity with a peculiar enrichment of Prevotella genera. The gut microbial properties of Ce-RS3 were tightly associated with the T2DM-related indexes, showing the potential to alleviate diabetic phenotype dysbioses, and possibly explaining the greater efficiency in improving metabolic control. The beneficial effects of Ce-RS3 and metformin might derive from changes in gut microbiota through altering host-microbiota interactions with impact on the host metabolome. Given the complementarity of Ce-RS3 and metformin in regulation of gut microbiota and metabolites, this study also prompted us to suggest possible "Drug-Dietary fiber" combinations for managing T2DM.

Changes in Intestinal Microbiota of Type 2 Diabetes in Mice in Response to Dietary Supplementation With Instant Tea or Matcha.

OBJECTIVE: Gut microbiota plays a key role in metabolism and health in diabetes patients with gastrointestinal microbiota dysbiosis. Thus, regulating the ecological balance of gut microbiota may provide a pathway toward improvement for these patients. Our previous study showed that functional ingredients in tea may inhibit cornstarch digestion in vitro. METHODS: A cornstarch-tea diet was developed, and in this study we investigated the effects of such a diet on blood glucose and gut microbiota in diabetic mice. RESULTS: Diabetes resulted in significant weight loss, hyperphagia and hyperglycemia. 16S rDNA sequencing revealed that in diabetes there is significantly increased Bacteroidaceae, Helicobacteraceae, Ruminococcaceae, Enterobacteriaceae, Rikenellaceae and Saccharibacteria_genera_incertae_sedis, and significantly decreased Lactobacillaceae, Prevotellaceae, Coriobacteriaceae, Verrucomicrobiaceae and Bifidobacteriaceae. The cornstarch‒tea diet resulted in a trend toward reduced blood glucose, with particularly increased levels of Coriobacteriaceae, Lactobacillaceae, Prevotellaceae and Bifidobacteriaceae, and decreased Bacteroidaceae, Ruminococcaceae, Helicobacteraceae and Enterobacteriaceae. CONCLUSIONS: Instant tea and matcha supplementation had beneficial effects on regulation of blood glucose and gut microbiota, reversing the changes in microbiota caused by alloxan injection. The cornstarch‒tea regulation pathway is involved in bacterium group regulation rather than single-species regulation, which suggests that cornstarch combined with tea may be used as a functional food supplement for diabetes patients.

BuZangTongLuo decoction improved hindlimb ischemia by activating angiogenesis and regulating gut microbiota in diabetic mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Seven traditional medicinal plants (including Astragalus membranaceus, Dioscorea hemsleyi, Salvia miltiorrhiza, Scrophularia ningpoensis, Ophiopogon japonicus, Panax ginseng and Fritillariae cirrhosae) and one insect leech (Whitmania pigra Whitman) were combined into BuZangTongLuo formula (BZTLF) under the guidance of traditional Chinese medicine. BZTLF is potentially effective against diabetic vascular complications. AIM OF THE STUDY: Previous studies failed to clarify the molecular mechanism through which BZTLF suppressed diabetic ischemia. In this study, we aimed to explore whether BZTLF treatment could prevent the occurrence of type 2 diabetic (T2D) hindlimb ischemia in mice. Further, we investigated the regulatory effect of BZTLF on angiogenesis-related VEGF signaling pathway and gut microbiota dysfunction in diabetic ischemia mice. MATERIALS AND METHODS: C57BL/6J mice fed with high-fat diet (HFD) received STZ injection and femoral artery ligation to build T2D diabetic hindlimb ischemia model. Mice were gavaged with BZTLF (5 g [raw materials]/kg/d) or with metformin plus atorvastatin for three weeks. Laser doppler imaging system was utilized for the visualization of blood flow. Histochemistry analysis was performed for microvascular vessel staining. Western blot was applied to detect the protein changes of signaling molecules responsible for VEGF pathway. Finally, 16S rDNA gene sequencing was conducted for analysis of gut microbiota structure. RESULTS: BZTLF treatment remarkably restored blood flow and capillary density of diabetic hindlimb ischemia. And the protein changes of VEGF signaling molecules were reversed in BZTLF-treated diabetic ischemia mice, including the decreased VEGF and HIF-1α, and the increased NO, eNOS and p-ERK1/2. The gut microbiota analysis suggests that BZTLF treatment increased the abundances of several beneficial bacteria (Akkermansia, Bifidobacterium and Bacteroides), while decreased the populations of some harmful bacteria(Blautia, Weissella, Escherichia Shigella and Kurthia). By using Spearman's correlation analysis, these changed gut flora were positively/negatively correlated with VEGF signaling pathway or glycometabolic parameters. CONCLUSION: BZTLF displayed beneficial effects on diabetic hindlimb ischemia by reshaping the gut microbiota structure and stunning the VEGF/HIF-1α pathway.

Polyphenol-Rich Extracts from Brown Macroalgae Lessonia trabeculate Attenuate Hyperglycemia and Modulate Gut Microbiota in High-Fat Diet and Streptozotocin-Induced Diabetic Rats.

Brown macroalgae are an important source of polyphenols with multiple health functions. In this work, polyphenol extracts from Lessonia trabeculate were purified and investigated for the antidiabetic activity in vitro and in vivo. The purified polyphenol extracts exhibited good antioxidant activities, α-glucosidase and lipase inhibition activities (IC50 < 0.25 mg/mL). The HPLC-DAD-ESI-MS/MS analysis indicated that the compounds in polyphenol extracts were mainly phlorotannin derivatives, phenolic acid derivatives, and gallocatechin derivatives. In vivo, C57BL/6J rats treated with polyphenol extracts for 4 weeks had lower fasting blood glucose levels, insulin levels, as well as better serum lipid profiles and antioxidant stress parameters, compared with the diabetic control (DC) group. Histopathology revealed that polyphenol extracts preserved the architecture and function of the liver. Short-chain fatty acid contents in rats' fecal samples with polyphenols administration were significantly recovered as compared with the DC group. Furthermore, the gut microflora of rats was investigated with high-throughput 16S rRNA gene sequencing and results indicated that polyphenol extracts had a positive effect on regulating the dysbiosis of the microbial ecology in diabetic rats. All of the results from the study provided a scientific reference of the potentially beneficial effects of L. trabeculate polyphenols on diabetes management.

Propolis modulates the gut microbiota and improves the intestinal mucosal barrier function in diabetic rats.

OBJECTIVE: Diabetes mellitus is associated with gut microbiota disturbance and intestinal mucosal injuries. This study investigated the influence of propolis on the gut microbiota and intestinal mucosa in rats with diabetes. METHODS: Sprague-Dawley (SD) rats were randomly assigned to the control group, model group, and three propolis groups (supplemented with 80, 160, and 240 mg/kg·bw propolis, respectively). A high-fat diet combined with a streptozotocin (STZ) abdominal injection were used to induce diabetes in the rats. After 4 weeks, the intestinal histopathological analysis of the ileum was observed by transmission electron microscopy. The fasting blood glucose (FBG), plasma insulin, glucose tolerance (OGTT) and glycosylated hemoglobin (HbA1c) levels were measured. The expression of tight junction (TJ) proteins in the ileum was measured using western blotting. The molecular ecology of the fecal gut microbiota was analyzed by 16S rDNA high-throughput sequencing. The contents of the short-chain fatty acids (SCFAs) in feces were measured using high-performance liquid chromatography (HPLC). RESULTS: After propolis treatment, compared to the model group, FBG and HbA1c levels declined, while the glucose tolerance and insulin sensitivity index (ISI) increased. The levels of TJ proteins in the ileum increased in the propolis groups. The tight junctions and gap junctions of the intestinal epithelium were also improved in the propolis groups. The contents of the feces acetic acid, propionic acid and butyrate were increased in the propolis groups. 16S rDNA high-throughput sequencing revealed that the composition of the gut microbiota of rats in the propolis supplement group was significantly improved. CONCLUSIONS: Compared to the model group, propolis exerted hypoglycemic effects in diabetic rats, and it repaired intestinal mucosal damage, benefited the communities of the gut microbiota and increased SCFA levels in diabetic rats.

Modulation of Gut Microbiota by Low Methoxyl Pectin Attenuates Type 1 Diabetes in Non-obese Diabetic Mice.

Intestinal homeostasis underpins the development of type 1 diabetes (T1D), and dietary manipulations to enhance intestinal homeostasis have been proposed to prevent T1D. The current study aimed to investigate the efficacy of supplementing a novel specific low-methoxyl pectin (LMP) dietary fiber in preventing T1D development. Female NOD mice were weaned onto control or 5% (wt/wt) LMP supplemented diets for up to 40 weeks of age, overt diabetes incidence and blood glucose were monitored. Then broad-spectrum antibiotics (ABX) treatment per os for 7 days followed by gut microbiota transfer was performed to demonstrate gut microbiota-dependent effects. Next-generation sequencing was used for analyzing the composition of microbiota in caecum. Concentration of short chain fatty acids were determined by GC-MS. The barrier reinforcing tight junction proteins zonula occludens-2 (ZO-2), claudin-1 and NOD like receptor protein 3 (NLRP3) inflammasome activation were determined by Western blot. The proportion of CD25+Foxp3+CD4+ regulatory T cell (Foxp3+ Treg) in the pancreas, pancreatic and mesenteric lymph nodes was analyzed by flow cytometry. We found that LMP supplementation ameliorated T1D development in non-obese diabetic (NOD) mice, as evidenced by decreasing diabetes incidence and fasting glucose levels in LMP fed NOD mice. Further microbiota analysis revealed that LMP supplementation prevented T1D-associated caecal dysbiosis and selectively enriched caecal bacterial species to produce more SCFAs. The LMP-mediated microbial balance further enhanced caecal barrier function and shaped gut-pancreatic immune environment, as characterized by higher expression of tight junction proteins claudin-1, ZO-2 in caecum, increased Foxp3+ Treg population and decreased NLRP3 inflammasome activation in both caecum and pancreas. The microbiota-dependent beneficial effect of LMP on T1D was further proven by the fact that aberration of caecal microbiota by ABX treatment worsened T1D autoimmunity and could be restored with transfer of feces of LMP-fed NOD mice. These data demonstrate that this novel LMP limits T1D development by inducing caecal homeostasis to shape pancreatic immune environment. This finding opens a realistic option for gut microbiota manipulation and prevention of T1D in humans.

Liupao tea extract alleviates diabetes mellitus and modulates gut microbiota in rats induced by streptozotocin and high-fat, high-sugar diet.

Liupao tea, a popular dark tea, exhibited anti-diabetic activity in Chinese tea culture. However, the bioavailability of the main active components is low. Therefore, the relationship between the anti-diabetic activity and the modulation of gut microbiota was investigated in this study for the first time. Liupao tea extract (LTE) could significantly alleviate hyperglycemia, insulin-resistance, and plasma lipid profiles. The hypoglycemic effect of high-dose LTE was comparable to that of metformin. Importantly, LTE exhibited beneficial effect on modulating the diabetic-induced disorder of gut microbiota, such as increasing Bacteroidetes/Firmicutes ratio and up-regulating putative short-chain fatty acid (SCFA)-producing bacteria, including Prevotella and Bacteroides. Moreover, 29 key phylotypes were significantly correlated with at least one diabetic index. In conclusion, LTE could be developed into an anti-diabetic functional beverage and its beneficial effects is likely to be associated with the prebiotic effects for increasing the level of SCFAs and the relative abundance of SCFA-producing bacteria.

Extract of ice plant (Mesembryanthemum crystallinum) ameliorates hyperglycemia and modulates the gut microbiota composition in type 2 diabetic Goto-Kakizaki rats.

Ice plant (Mesembryanthemum crystallinum) extract (IPE) is a rich source of d-pinitol, which is widely known to have potential anti-diabetic effects. In the present study, response surface methodology (RSM) was used to optimize d-pinitol extraction conditions with the Box-Behnken design. We then evaluated the anti-diabetic effects properties of IPE that was extracted under optimized conditions (53 °C, 119 min extraction time, and 1 : 11 dilution) in type 2 diabetic Goto-Kakizaki (GK) rats. IPE (400 mg kg-1 day-1) effectively controlled the increased fasting blood glucose level (decreased by 45% vs. GK-control rats) and impaired glucose tolerance (decreased area under curve (AUC) of glucose values by 24%, p < 0.05 vs. GK-control rats) after eight weeks of treatment. Furthermore, IPE significantly improved pancreatic islet morphology, ß-cell survival, and insulin secretion in diabetic rats, thus contributing to the antihyperglycemic effect. Finally, prebiotic effects of IPE on gut microbiota were observed and included increased abundance of the beneficial bacteria Bacteroidales_S24-7 and Ruminococcaceae_UCG-014 and decreased abundance of Treponema_2 and Lactobacillus. Overall, IPE has a substantial effect on attenuating hyperglycemia and modulating gut microbiota composition in diabetic GK rats. Therefore, IPE might be a promising functional food for the prevention of diabetes.

Edgeworthia gardneri (Wall.) Meisn. water extract improves diabetes and modulates gut microbiota.

ETHNOPHARMACOLOGICAL RELEVANCE: In Chinese folk medicine, the flower of Edgeworthia gardneri (Wall.) Meisn. is used to treat various metabolic diseases, such as hyperglycemia, hypertension, and hyperlipidemia. AIM OF THE STUDY: This study aimed to explore the antidiabetes potential of the flower of E. gardneri and investigate whether it can benefit the entire gut bacteria community. MATERIALS AND METHODS: Chemical constituents of the extract were analyzed by UHPLC-Q Exactive Mass Spectrometer (UHPLC-QE-MS). The antidiabetes effect of the water extract (WAE) of the flower of E. gardneri was evaluated in diabetic mice induced by high-fat diet (HFD) and streptozotocin (STZ) (six groups, n = 8) daily at doses of 1, 2, and 3 g/kg for 4 weeks. The gut microbiota was analyzed using high-throughput 16S rRNA gene sequencing. Short-chain fatty acids (SCFAs) in the fecal were also investigated. RESULTS: UHPLC-QE-MS analysis identified 29 compounds, including five alkaloids, six coumarins, four flavonoids, 11 organic acids, and three additional compounds, in the WAE. Results showed that the high dose of WAE considerably decreased the blood glucose level by 30.0%. Furthermore, E. gardneri significantly ameliorated insulin resistance and lipid metabolism dysfunction and repaired islet, hepatic, and white fat and colon histology in diabetic mice. Diabetic mice treated with WAE showed apparent changes in the structure and composition of the gut microbiota. WAE reversed the changes in Clostridiales, Lachnospiraceae, S24-7, Rikenellaceae, and Dorea in diabetic mice. The correlation analysis indicated that key OTUs were related to diabetes indices. The amounts of SCFAs, including acetic, propionic, and valeric acids, were significantly high in WAE-treated diabetic groups. CONCLUSIONS: E. gardneri treatment improved the glucose metabolism and reshaped the unbalanced gut microbiota of diabetic mice. Our study provides evidence for application of E. gardneri to treatment of diabetes mellitus.

Dietary supplementation with strawberry induces marked changes in the composition and functional potential of the gut microbiome in diabetic mice.

Gut microbiota contributes to the biological activities of berry anthocyanins by transforming them into bioactive metabolites, and anthocyanins support the growth of specific bacteria, indicating a two-way relationship between anthocyanins and microbiota. In the present study, we tested the hypothesis that strawberry supplementation alters gut microbial ecology in diabetic db/db mice. Control (db/+) and diabetic (db/db) mice (7 weeks old) consumed standard diet or diet supplemented with 2.35% freeze-dried strawberry (db/db + SB) for 10 weeks. Colon contents were used to isolate bacterial DNA. V4 variable region of 16S rRNA gene was amplified. Data analyses were performed using standardized pipelines (QIIME 1.9 and R packages). Differences in predictive metagenomics function were identified by PICRUSt. Principal coordinate analyses confirmed that the microbial composition was significantly influenced by both host genotype and strawberry consumption. Further, α-diversity indices and ß-diversity were different at the phylum and genus levels, and genus and operational taxonomical units levels, respectively (P<.05). At the phylum level, strawberry supplementation decreased the abundance of Verrucomicrobia in db/db + SB vs. db/db mice (P<.05). At the genus level, db/db mice exhibited a decrease in the abundance of Bifidobacterium, and strawberry supplementation increased Bifidobacterium in db/db + SB vs. db/db mice (P<.05). PICRUSt revealed significant differences in 45 predicted metabolic functions among the 3 groups. Our study provides evidence for marked changes in the composition and functional potential of the gut microbiome with strawberry supplementation in diabetic mice. Importantly, strawberry supplementation increased the abundance of beneficial bacteria Bifidobacterium which play a pivotal role in the metabolism of anthocyanins.

JinQi Jiangtang Tablet Regulates Gut Microbiota and Improve Insulin Sensitivity in Type 2 Diabetes Mice.

BACKGROUND: Gut microbiota modulates the barrier function and host inflammatory state in metabolic disease. JinQi Jiangtang (JQJT) tablets are a traditional Chinese medicine for the treatment of diabetes. However, the low bioavailability of its chemical compositions makes it hard to explain the pharmacological mechanisms. METHOD: Diabetic mice were orally treated with JQJT tablets for 5 weeks. Fasting blood glucose and the level of HbA1c were measured, and ITT were conducted to determine the insulin improvement effect of JQJT tablets. The regulation effect on gut microbiota was assessed by 16S rRNA gene sequencing on an Illumina HiSeq platform. The concentration of short-chain fatty acids was measured by HS-GC/MS. D-LA leakage experiment and PAS staining were used to check the function of the gut barrier. The levels of the inflammatory cytokines were determined by using an ELISA kit. RESULTS: This study showed that JQJT tablets downregulated fasting blood glucose and HbA1c and regulated gut microbiota. JQJT tablet-treated groups exhibited a more sensitive reaction after a small-dose injection of short-acting insulin. T2DM mice treated with JQJT tablets showed a higher abundance of Akkermansia spp. and lower abundance of Desulfovibrio. JQJT tablets increased the concentration of acetic acid, propionic acid, and butyric acid; in particular, butyric acid was significantly increased with respect to the MOD group. Gut mucosal barrier function experiment showed that the level of D-LA was obviously decreased in JQJT tablet-treated groups compared with the model group and the number of goblet cells was significantly increased by JQJT tablet treatment. JQJT tablets could also reduce the levels of TNF-α, IL-6, and MCP-1, which were related to insulin resistance. CONCLUSION: We demonstrated that JQJT tablets could improve T2DM insulin resistance, regulating the gut microbiota and promoting the production of SCFAs. The mechanism was related to increasing the gut barrier function and reducing the host inflammatory reaction.

The anti-diabetic activities, gut microbiota composition, the anti-inflammatory effects of Scutellaria-coptis herb couple against insulin resistance-model of diabetes involving the toll-like receptor 4 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria-coptis herb couple (SC) is one of the well-known herb couples in many traditional Chinese compound formulas used for the treatment of diabetes mellitus (DM), which has been used to treat DM for thousands of years in China. AIM OF THE STUDY: Few studies have confirmed in detail the anti-diabetic activities of SC in vivo and in vitro. The present investigations aimed to evaluate the anti-diabetic activity of SC in type 2 diabetic KK-Ay mice and in RAW264.7 macrophages to understand its possible mechanism. MATERIALS AND METHODS: High-performance liquid chromatography with ultraviolet detection (HPLC-UV) and LC-LTQ-Orbitrap Pro mass spectrometry were used to analyze the active ingredients of SC extracts and control the quality. A type 2 diabetic KK-Ay mice model was established by high-fat diet. Body weight, fasting blood glucose levels, fasting blood insulin levels, glycosylated hemoglobin and glycosylated serum protein were measured. The effects of SC on total cholesterol (TC), high-density lipoprotein (HDL) and triglyceride (TG) levels were examined. The lipopolysaccharide (LPS), interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) levels were measured. Gut microbial communities were assayed by polymerase chain reaction (PCR) and PCR-denaturing gradient gel electrophoresis (PCR-DGGE) methods. The expressions of Toll-like receptor 4 (TLR4) and MyD88 protein in the colons were measured by western blot. In RAW264.7 macrophages, IL-6, TNF-α, TLR4 and MyD88 protein levels were measured by enzyme-linked immunosorbent assay (ELISA) kits or western blot, and the mRNA expression of IL-6, TNF-α and TLR4 was examined by the real time PCR. RESULTS: The present results showed that the SC significantly increased blood HDL and significantly reduced fasting blood glucose, fasting blood insulin, glycosylated hemoglobin, glycosylated serum protein, TC, TG, LPS, IL-6 and TNF-α levels (P < 0.05 or P < 0.01) in type-2 diabetic KK-Ay mice. Furthermore, SC could regulate the structure of intestinal flora. Additionally, the expressions of TLR4 and MyD88 protein in the colons were significantly decreased in the model group (P < 0.05 or P < 0.01). However, SC had no significant effect on weight gain. In RAW264.7 macrophages, SC containing serum (SC-CS) (5%, 10% and 20%) significantly decreased IL-6, TNF-α, TLR4 and MyD88 protein levels and the mRNA expression of IL-6, TNF-α and TLR4 (P < 0.05 or P < 0.01). CONCLUSIONS: The anti-diabetic effects of SC were attributed to its regulation of intestinal flora and anti-inflammation involving the TLR4 signaling pathway. These findings provide a new insight into the anti-diabetic application for SC in clinical settings and display the potential of SC in the treatment of DM.

Improvement in infected wound healing in type 1 diabetic rat by the synergistic effect of photobiomodulation therapy and conditioned medium.

We investigated the effects of photobiomodulation therapy (PBMT) and conditioned medium (CM) of human bone marrow mesenchymal stem cells (hBM-MSC) individually and/or in combination on the stereological parameters and the expression of basic fibroblast growth factor (bFGF), hypoxia-inducible factor (HIF-1α), and stromal cell-derived factor-1α (SDF-1α) in a wound model infected with methicillin-resistant Staphylococcus aureus (MRSA) in diabetic rats. CM was provided by culturing hBM-MSCs. Type 1 diabetes mellitus (T1DM) was induced in 72 rats, divided into four groups, harboring 18 rats each: group 1 served as a control group, group 2 received PBMT, group 3 received CM, and group 4 received CM + PBMT. On days 4, 7, and 15, six animals from each group were euthanized and the skin samples were separated for stereology examination and gene expression analysis by real-time polymerase chain reaction. In the CM + PBMT, CM, and PBMT groups, significant decreases were induced in the number of neutrophils (1460 ± 93, 1854 ± 138, 1719 ± 248) and macrophages (539 ± 69, 804 ± 63, 912 ± 41), and significant increases in the number of fibroblasts (1073 ± 116, 836 ± 75, 912 ± 41) and angiogenesis (15 230 ± 516, 13 318 ± 1116, 14 041 ± 867), compared with those of the control group (2690 ± 371, 1139 ± 145, 566 ± 90, 12 585 ± 1219). Interestingly, the findings of the stereological examination in the CM + PBMT group were statistically more significant than those in the other groups. In the PBMT group, in most cases, the expression of bFGF, HIF-1α, and SDF-1α, on day 4 (27.7 ± 0.14, 28.8 ± 0.52, 27.5 ± 0.54) and day 7 (26.8 ± 1.4, 29.6 ± 1.4, 28.3 ± 1.2) were more significant than those in the control (day 4, 19.3 ± 0.42, 25.5 ± 0.08, 22.6 ± 0.04; day 7, 22.3 ± 0.22, 28.3 ± 0.59, 24.3 ± 0.19) and other treatment groups. The application of PBMT + CM induced anti-inflammatory and angiogenic activities, and hastened wound healing process in a T1 DM model of MRSA infected wound.

Effects of Rich-Polyphenols Extract of Dendrobium loddigesii on Anti-Diabetic, Anti-Inflammatory, Anti-Oxidant, and Gut Microbiota Modulation in db/db Mice.

Dendrobium is a traditional Chinese herb with anti-diabetic effects and has diverse bibenzyls as well as phenanthrenes. Little is known about Dendrobium polyphenols anti-diabetic activities, so, a rich-polyphenols extract of D. loddigesii (DJP) was used for treatment of diabetic db/db mice; the serum biochemical index and tissue appearance were evaluated. In order to gain an insight into the anti-diabetic mechanism, the oxidative stress index, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and gut microbiota modulation were determined by ELISA, immunohistochemistry or high throughput sequencing 16S rRNA gene. The results revealed that DJP had the effects to decrease the blood glucose, body weight, low density lipoprotein cholesterol (LDL-C) levels and increase insulin (INS) level in the mice. DJP improved the mice fatty liver and diabetic nephropathy. DJP showed the anti-oxidative abilities to reduce the malondialdehyde (MDA) level and increase the contents of superoxide dismutase (SOD), catalase (CAT) as well as glutathione (GSH). DJP exerted the anti-inflammatory effects of decreasing expression of IL-6 and TNF-α. After treatment of DJP, the intestinal flora balance of the mice was ameliorated, increasing Bacteroidetes to Firmicutes ratios as well as the relative abundance of Prevotella/Akkermansia and reducing the relative abundance of S24-7/Rikenella/Escherichia coli. The function's prediction of gut microbiota indicated that the microbial compositions involved carbohydrate metabolism or lipid metabolism were changed. This study revealed for the first time that DJP improves the mice symptoms of diabetes and complications, which might be due to the effects that DJP induced the decrease of inflammation as well as oxidative stress and improvement of intestinal flora balance.