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November 27, 2017, Researchers from BGI and Ruijin Hospital, reported their findings that analyses of gut microbiome and plasma bile acid levels can guide the treatment of type 2 diabetes (T2D). The corresponding authors are Professor Weiqing Wang, Academician Guang Ning from Ruijin Hospital, Medical School of Shanghai Jiao Tong University, and Professor Karsten Kristiansen from University of Copenhagen and BGI.
By integrated techniques of metagenomics and metabolomics, researchers uncovered that treatment with Acarbose, but not Glipizide could significantly alter the gut microbiota in treatment-naïve T2D patients by increasing the relative abundances of Lactobacillus and Bifidobacterium and depleting Bacteroides and thereby changing the relative abundance of microbial genes involved in bile acid (BA) metabolism.
Further, researchers reported that patients harbouring a gut microbiota with a higher baseline abundance of Bacteroides exhibited more beneficial therapeutic responses to Acarbose treatment, including reduced BMI, and improved insulin resistance status and lipid profile. This is the first report of the link between the gut microbiome and the clinical response of T2D patients after anti-diabetes medications treatment. This is also the first time to disclose the mechanism of the clinical beneficial therapeutic responses of Acarbose treatment, which highlights the potential for stratification of T2D patients based on their gut microbiota prior to treatment.
The latest findings were published in Nature Communications.
As we know, Acarbose, an alpha-glycosidase inhibitor, is widely prescribed in China and Asia countries for the first line treatment of T2D. Acarbose impedes the hydrolysis and absorption of carbohydrates in the small intestine, which in turn changes the abundances of substrates for fermentation by the microbiota in the distal intestine. In addition, compared other classic oral antidiabetic drugs (OADs) such as thiazolidinediones (TZDs) or sulfonylureas (SUs) targeting insulin resistance or secretion, Acarbose exhibited similar hypoglycaemic effects but more therapeutic metabolism merits including reduced BMI and improved lipedema.
Hence, this has attracted the great interest of researchers to explore the unsolved questions of Acarbose treatment, such as the potential mechanism of Acarbose for other therapeutic responses, why different people have different response to the drug, and the potential roles of gut microbiota during treatment.
To explore such unsolved potential mechanisms of Acarbose in T2D treatment, the researchers have launched a multi-centre, randomized, positively-controlled clinical trial. 106 treatment-naïve T2D patients were enrolled and 1:1 randomized into the two treatment arms——Glipizide and Acarbose.
Blood and fecal samples were collected before and after 3-month treatment. At the end of the 3-month treatment both arms reached the targeted level of glycaemic control that did not differ significantly.
By comparing the gut microbiota changes before and after treatment in the two arms, the researchers demonstrate that Acarbose could significantly change both the compositional and functional characteristics of gut microbiota. After Acarbose treatment, the probiotic bacteria including Lactobacillus and Bifidobacterium species were increased whereas the original distal gut-residing, putrefactive species of Bacteroides, Alistipes and Clostridium were reduced. The relative abundance of genes encoding enzymes involved in hydrophobic secondary bile acids (SBAs) biosynthesis, including baiE and baiI, were also significantly decreased after treatment, suggesting the reduction of toxic hydrophobic SBAs (LCA and DCA) and accumulation of UDCA, a hydrophilic SBA which show several beneficial therapeutic effects on liver diseases.
Further, the researchers conducted LC-MS/MS based targeted metabolomics on both blood and fecal samples before and after treatment in two arms. In line with the findings in functional metagenomics, researchers validated the BA changes in both fecal and blood samples after treatment. Moreover, many of the Acarbose-induced changes of probiotic species and plasma BAs were highly correlated with those metabolic improvements. These finding together suggest some of the therapeutic effects of Acarbose-induced modulation of the gut microbiota are related to bacterial BA metabolism and, therefore, host BA signaling.
Additionally, the researchers reported that the baseline microbiomes of T2D patients could be clearly separated into two enterotype-like clusters, one driven by Bacteroides (Cluster B) and the other driven by Prevotella (Cluster P). Moreover, the researchers observed the patients in Cluster B exhibited significantly greater improvements in fasting blood glucose, insulin, C peptide levels and HOMA-IR over baseline levels than patients in Cluster P. This suggests that gut microbiota might play important roles in drug response.
In conclusion, the researchers report the differential therapeutic responses are related to distinct abilities of the microbial communities of the two microbiome clusters to metabolize bile acids, and, more importantly, these findings demonstrate that stratification of patients according to baseline gut microbiota composition may provide a tool for selecting precision medication strategy for T2D patients and predicting antidiabetic metabolic benefits.