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Dapagliflozin Modulates the Fecal Microbiota in a Type 2 Diabetic Rat Model.

ABSTRACT: Background: The gut microbiota is recognized as a major modulator of metabolic disorders such as type 2 diabetes. Dapagliflozin, sodium glucose cotransporter 2 inhibitors (SGLT2i), enhances renal glucose excretion, and lowers blood glucose levels. The study aimed to determine the effects of dapagliflozin on fecal microbiota in a type 2 diabetic rat model. Methods: Four-week-old male Sprague Dawley rats (n = 24) were fed a high-fat diet (HFD) for 8 weeks and then given a single dose of STZ injection (30 mg/kg, i.p). They were randomly divided into three groups (n = 8). Each group received intragastric infusion of normal saline (2 ml, 0.9%) or metformin (215.15 mg/kg/day) or dapagliflozin (1 mg/kg/day) for 4 weeks. Blood glucose levels and plasma insulin levels were detected during intragastric glucose tolerance. Fecal samples were collected to access microbiome by 16S ribosomal RNA gene sequencing. Results: Dapagliflozin significantly decreased fasting and postprandial blood glucose levels as metformin in type 2 diabetic rats (P < 0.001). Enterotype was composed of Ruminococcaceae after treatment of dapagliflozin, whereas Ruminococcaceae and Muribaculaceae were the main enterotypes following metformin treatment. Dapagliflozin did not increase the abundance of beneficial bacteria including Lactobacillaceae and Bifidobacteriaceae. However, these were increased in the metformin group. It is surprising to find that Proteobacteria (especially Desulfovibrionaceae) were enriched in the dapagliflozin group. Conclusion: Dapagliflozin and metformin exerted complementary effects on the main beneficial bacteria. A combination of these two drugs might be beneficial to improve the structure of fecal microbiota in the treatment of type 2 diabetes.

SUBMITTER: Yang M

PROVIDER: S-EPMC7707060 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dapagliflozin Modulates the Fecal Microbiota in a Type 2 Diabetic Rat Model.

Yang Mei M Shi Fang-Hong FH Liu Wen W Zhang Min-Chun MC Feng Ri-Lu RL Qian Cheng C Liu Wei W Ma Jing J

Frontiers in endocrinology 20201117

Background: The gut microbiota is recognized as a major modulator of metabolic disorders such as type 2 diabetes. Dapagliflozin, sodium glucose cotransporter 2 inhibitors (SGLT2i), enhances renal glucose excretion, and lowers blood glucose levels. The study aimed to determine the effects of dapagliflozin on fecal microbiota in a type 2 diabetic rat model. Methods: Four-week-old male Sprague Dawley rats (n = 24) were fed a high-fat diet (HFD) for 8 weeks and then given a sing ...[more]

PMID: 33312157

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Project description:BackgroundNucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is associated with metabolic disorder and cell death, which are important triggers in diabetic cardiomyopathy (DCM). We aimed to explore whether NLRP3 inflammasome activation contributes to DCM and the mechanism involved.MethodsType 2 diabetic rat model was induced by high fat diet and low dose streptozotocin. The characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. Gene silencing therapy was used to investigate the role of NLRP3 in the pathogenesis of DCM. High glucose treated H9c2 cardiomyocytes were used to determine the mechanism by which NLRP3 modulated the DCM. The cell death in vitro was detected by TUNEL and EthD-III staining. TXNIP-siRNA and pharmacological inhibitors of ROS and NF-kB were used to explore the mechanism of NLRP3 inflammasome activation.ResultsDiabetic rats showed severe metabolic disorder, cardiac inflammation, cell death, disorganized ultrastructure, fibrosis and excessive activation of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), pro-caspase-1, activated caspase-1 and mature interleukin-1? (IL-1?). Evidence for pyroptosis was found in vivo, and the caspase-1 dependent pyroptosis was found in vitro. Silencing of NLRP3 in vivo did not attenuate systemic metabolic disturbances. However, NLRP3 gene silencing therapy ameliorated cardiac inflammation, pyroptosis, fibrosis and cardiac function. Silencing of NLRP3 in H9c2 cardiomyocytes suppressed pyroptosis under high glucose. ROS inhibition markedly decreased nuclear factor-kB (NF-kB) phosphorylation, thioredoxin interacting/inhibiting protein (TXNIP), NLRP3 inflammasome, and mature IL-1? in high glucose treated H9c2 cells. Inhibition of NF-kB reduced the activation of NLRP3 inflammasome. TXNIP-siRNA decreased the activation of caspase-1 and IL-1?.ConclusionNLRP3 inflammasome contributed to the development of DCM. NF-?B and TXNIP mediated the ROS-induced caspase-1 and IL-1? activation, which are the effectors of NLRP3 inflammasome. NLRP3 gene silencing may exert a protective effect on DCM.

Dataset Information

Dapagliflozin Modulates the Fecal Microbiota in a Type 2 Diabetic Rat Model.

Publications

Dapagliflozin Modulates the Fecal Microbiota in a Type 2 Diabetic Rat Model.

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