Modulation Of Gut Microbiota In Type 2 Diabetic Patients By Drugs And Its Relationship With The Alleviation Of Diabetes

In the past few decades,metabolic diseases including type 2 diabetes have become one of the most prevalent diseases seriously threatening the lives of human beings.Accumulating studies showed that gut microbiota can causatively induce metabolic diseases in germ-free mice,indicating its role as a potential target in the prevention and treatment of metabolic diseases.Metformin was reported to improve glucose and lipid homeostasis through modulating gut microbiota in mice.However,different animals showed different responding bacteria to metformin treatment.Whether metformin can modulate gut microbiota in humans remains to be elucidated.Chinese herbal formula Gegen Qinlian Decoction(GQD)and CBC herbal formula showed profound clinical efficacy in treating type 2 diabetes.However,randomized clinical trials are needed for the systemic evaluation of their efficacy and safety.Besides,the complexities and unknown mechanisms of herbal formulas prevent the mechanisms from being elucidated.The major chemical components of many herbs such as berberine showed poor absorption into the bloodstream after oral administration and was mainly excreted via feces in its intact form.Moreover,berberine prevented high fat diet induced obesity and insulin resistance through increasing short chain fatty acid-producing bacteria in Wistar rats,which opens an avenue for studying the mechanisms of Chinese herbal formulas.Therefore,in this study,we conducted two randomized clinical trials to evaluate the efficacy of the two Chinese herbal formla and metformin,examine the effects of these drugs in modulating the gut microbiota and explore their relationships with anti-diabetic effects in humans.With a randomized,placebo-controlled clinical trial,we firstly examined the clinical efficacy of different doses of GQD,the structural changes of gut microbiota and their relationships with the alleviation of type 2 diabetes.Patients that received the high or median dosage showed significant reductions in adjusted mean changes from baseline of fasting blood glucose(FBG)and glycated hemoglobin(HbA1c)compared with the placebo and low dosage groups.Pyrosequencing of the V3 region of 16 S rRNA genes revealed a dose-dependent deviation of gut microbiota in response to GQD treatment.This deviation occurred before significant improvement of T2 D symptoms was observed.Redundancy analysis identified 47 GQD-enriched species level phylotypes,17 of which were negatively correlated with FBG and 9 with HbA1 c.Real-time qPCR confirmed that GQD significantly enriched Faecalibacterium prausnitzii,which was negatively correlated with FBG,HbA1 c and 2-h postprandial blood glucose levels and positively correlated with homeostasis model assessment of ?-cell function.Therefore,these data indicate that structural changes of gut microbiota are induced by Chinese herbal formula GQD.Specifically,GQD treatment may enrich the amounts of beneficial bacteria,such as Faecalibacterium spp.In conclusion,changes in the gut microbiota are associated with the anti-diabetic effects of GQD.Secondly,we compared the efficacies of metformin and CBC herbal formula in improving glucose and lipi homeostasis,their modulating effects on the gut microbiota and their relationships with the attenuations of hyperglycemia and hyperlipidemia.Both metformin and CBC herbal formula were efficacious in improving the glucose and lipid homeostasis in diabetic patients,with CBC showing better efficacy in lowering plasma triglyceride.Illumina sequencing of the V3-V4 regions of 16 S rRNA genes revealed that both drugs significantly changed the gut microbiota structure of T2 D patients.Moreover,CBC herbal formula exerted a larger effect on gut microbiota modulation than metformin.Both drugs significantly increased a co-abundance group represented by Blautia spp.,which showed significant correlations with the alleviation of dysglycemia and dyslipidemia.Taken together,these data suggest that both metformin and the CBC herbal formula can change the gut microbiota structure in T2 D patients.Specifically,they enriched the amounts of co-abundance groups containing beneficial bacteria,such as Blautia spp.,which might be associated with the improvements of glucose and lipid homeostasis by metformin and CBC herbal formula.In addition,we successfully isolated 15 different ERIC-patterns of Faecalibacterium spp.from a healthy man's gut by using M2 GSC medium.Then further studies can be performed to assess whether Faecalibacterium spp.can prevent or treat diabetes in the rodent models.In summary,our results showed that anti-diabetic drugs GQD,CBC and metformin can significantly change the gut microbiota during the alleviation of diabetes in clinical trials.They specifically increased benefical bacteria,such as Faecalibacterium and Blautia spp.,which were significantly associated with the improvement of glucose homeostasis.Our study suggest that pharmacological manipulation of the gut microbiota in favour of Faecalibacterium and Blautia spp.might be a potential treatment for T2 D.Moreover,TCMs may serve as a new source for drug leads in gut microbiota-targeted diabetes management.