Although previous observational research has found that type 2 diabetes (T2D) is related to gut dybsiosis, a causal link between gut microbial dysbiosis and T2D development has not yet been proven. Besides this, it has been reported that treatment with Metformin-a commonly prescribed drug for the treatment of individuals with T2D- may confer metabolic benefits through alteration of the gut microbiota. To what extent other anti-diabetic drugs acts via modulating the gut microbiota is still unknown.
A new multicentre, randomised controlled clinical trial, led by Prof. Weiqing Wang from the Shanghai National Research Centre for Endocrine and Metabolic Diseases at the Shanghai Jiaotong University School of Medicine in Shanghai (China), has found that gut microbiota may help predict which patients with T2D respond to treatment with Acarbose.
The aim of this intervention study was to elucidate the extent to which oral antidiabetic drugs exert their therapeutic action via altering the gut microbiota and whether such changes may be discriminated from T2D-dependent alterations. The researchers assigned treatment-naïve T2D patients from 5 centres in Shanghai (China) to treatment with one of two oral antidiabetic drugs used to achieve targeted glycaemic control: Acarbose (n = 51) or Glipizide (n = 43). Acarbose is an alpha-glucosidase inhibitor that exerts its hypoglycaemic effects by inhibiting the hydrolysis and absorption of carbohydrates in the small intestine, which changes the abundances of substrates for fermentation by the gut microbiota in the distal intestine. Glipizide is a second-generation sulfonylurea that improves insulin sensitivity, glucose-mediated insulin secretion and glucose utilization.
Effects of Acarbose and Glipizide on several metabolic parameters and the gut microbiota were studied. Faecal and plasma samples were collected at baseline and after 3 months of treatment.
Although both treatment groups reached the targeted level of glycaemic control (levels of glycated haemoglobin -HbA1c- below 7.0%) at the end of the 3-month treatment, without differing significantly between the drugs, the reductions in body weight and body mass index (BMI) were more pronounced in the Acarbose arm. Besides this, subjects receiving Acarbose but not Glipizide showed a significant improvement in the homeostasis model assessment of insulin resistance, total cholesterol, and triglycerides.
The researchers identified drug-dependent alterations in the gut microbiota and plasma bile acids (BAs). Acarbose, but not Glipizide, altered plasma BA composition by decreasing the levels of plasma secondary bile acids -mainly conjugated deoxycholic acids- and increasing overall levels of unconjugated primary BAs -cholic acid and chenodeoxycholic acid. This led to an increased ratio of primary BAs to secondary BAs and unconjugated to conjugated BAs, which are key steps of bacterial BA biotransformation, in treatment-naïve T2D patients. Statistical analysis showed that changes in plasma BAs correlated with improvements of clinical outcomes including BMI, blood glucose, HbA1C, lipid profiles, insulin secretion and resistance status. These results show that the microbial transformation of BAs may be modulated by the interaction between host BAs and the gut microbiome. Thus, Acarbose-induced changes in the gut microbiota could explain the observed additional metabolic effects besides the hypoglycaemic effect.
The two types of antidiabetic treatment led to differential responses of the gut microbiome. Acarbose elicited a stronger impact on the gut microbiota than Glipizide. Specifically, Acarbose increased the relative abundances of saccharolytic Lactobacillus and Bifidobacterium in the distal intestine and depleted the original distal gut-residing putrefactive species of Bacteroides, Alistipes and Clostridium.
BA metabolism alteration led by Acarbose treatment together with alteration of other genes associated with host-gut barrier integrity and lipopolysaccharide synthesis suggest the existence of certain common routes in the response of the gut microbiome to antidiabetic treatments.
Finally, treatment-naïve T2D patients were stratified into 2 groups based on their individual baseline gut microbiomes. Patients were classified into 2 groups according to which bacteria dominated their gut microbiota: one enterotype-like cluster driven by Prevotella and the other one driven by Bacteroides. Those patients that harboured a baseline gut microbiota profile enriched in Bacteroides had lower levels of secondary BAs and exhibited more beneficial therapeutic responses to Acarbose treatment -consisting of reduced BMI and improved insulin resistance status and lipid profile. These results suggest that baseline gut microbiota composition may be used to stratify T2D patients prior to treatment and thus could be a useful biomarker to predict the response to Acarbose.
To sum up, this study highlights that Acarbose-induced changes in the gut microbiota may contribute to its beneficial metabolic effects besides its classical mechanism of action. Besides this, baseline composition of the gut microbiota could be used for stratification of patients prior to initiation of the antidiabetic treatment.
Gu Y, Wang X, Li J, et al. Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment. Nat Commun. 2017; 8(1):1785. doi: 10.1038/s41467-017-01682-2.