Effect Of Dapagliflozin On Intestinal Flora In MafA-deficient Mice

Background:Diabetes mellitus?DM?is known as the most prevalent metabolic disorder caused by the inability of the pancreas to produce insulin sufficiently or the body's lack of ability to use insulin effectively.The International Diabetes Federation Eighth Edition Diabetes Atlas shows that there are approximately 425 million people with diabetes worldwide.It is estimated that the number of people with diabetes will increase to 700million by 2045.At present,the drugs for treating DM have been widely accepted and applied,but the side effects and drug prices still need to be studied.On the other hand,probiotics can also be used for prophylactic protection in addition to medications and diet to control blood glucose.The importance of intestinal flora in the development of diabetes has been paid more and more attention.Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor.It has been widely accepted that the mechanism of improving the hyperglycemia of diabetic patients by lowering the renal threshold of glucose.However,whether dapagliflozin can affect the intestinal microflora and thus improve the mechanism of hyperglycaemia is unclear.In this experiment,the effect of dapagliflozin on the intestinal microflora in MafA-deficient mice was investigated by establishing an animal model of DM.Objective:To investigate the effect of dapagliflozin on intestinal microflora in MafA-deficient mice using an animal model of diabetes.Methods:Eight week-old SPF grade male ICR MafA-deficient mice and wild-type ICR mice were selected.The experimental animals were divided into3 groups of 5 mice:the experimental group was ICR MafA-deficient mice given dapagliflozin(1.0 mg/kg·d^-1)by gavage for 6 weeks.ICR MafA-deficient mice in the control group and ICR mice in the blank group were given normal saline(1.0 mg/kg·d^-1)by gavage for the same duration as the experimental group.During the experiment,the animals were housed in groups in polypropylene cages in a well ventilated small animal room with a 12-h light and 12-h dark environment and were allowed to free access to water and standard feed.After 6 weeks,mouse body weights and fasting blood glucose levels were measured,and intestinal short-chain fatty acids were measured by gas chromatography.Analysis of the number of harmful bacteria in mice feces by plate counting,and high-throughput sequencing was used to sequence the changes in intestinal flora.All animal care and experimental procedures in this study were implemented after approval by the Jilin University Institutional Animal Care and Use Committee?approved on 27 February 2015,Protocol No.2015047?.This study was carried out after it was examined and approved by The Tab of Animal Experimental Ethical Inspection,Jilin University?Number of permit:SY201909005?.Results:The weight of the experimental mice decreased after dapagliflozin gavage,and fasting blood glucose was significantly lower than that in the control group?P<0.001?.At the same time,acetic acid and butyric acid contents in the intestinal tracts of the experimental mice increased,and the growth of harmful microorganisms,such as Clostridium perfringens,Enterococci and Enterobacteriaceae was inhibited.Blautia is a species found in the experimental group and was significantly different from the control and blank groups as determined by the LDA score from high throughput sequencing.Conclusion:Dapagliflozin can reduce fasting blood glucose,decrease body weight,increase short-chain fatty acid content,regulate the intestinal microecological balance of the body and promote energy homeostasis.