Alteration of Gut Microbiota Induced by DPP-4i Treatment Improves Glucose Homeostasis

Background: Increasing evidence indicates that the gut microbiota contributes to the occurrence and development of metabolic diseases. However, little is known about the effects of commonly used antidiabetic agents on the gut microbiota. In this study, we investigated the roles of dipeptidyl peptidase-4 inhibitors (DPP-4i) and α-glucosidase inhibitor in modulating the gut microbiota. Methods: 16S rRNA sequencing was performed to analyze the effects of DPP-4i and acarbose on the gut microbiota in mice fed a high fat diet (HFD). Fecal microbiota transplantation (FMT) from type 2 diabetic patients to germ-free mice was conducted to investigate the contribution of the altered microbiome to antidiabetic effects of the drugs. Fecal metabolomics were also analyzed by untargeted and targeted GC-MS systems. Findings: Although DPP-4i and α-glucosidase inhibitor both altered the gut microbial composition, only the microbiome modulation of DPP-4i contributed to its hypoglycemic effect. Specifically, the changes of 68.6% genera induced by HFD were rescued by DPP-4i. FMT showed that the DPP-4i-altered microbiome improved glucose tolerance in conventionalized mice, while acarbose did not. Moreover, DPP-4i reduced the ratio of Firmicutes to Bacteroidetes, predominantly by increasing the abundance of Bacteroidetes. It also promoted the functional shift in the gut microbiome, especially the increased production of succinate. Interpretation: Our findings demonstrate a novel effect of DPP-4i on the gut microbiota, revealing a new hypoglycemic mechanism and additional benefit for it. Furthermore, modulating the ratio of Firmicutes to Bacteroidetes, and the functional shift arising from changes in the microbiome, might be a potential strategy for improving glucose homeostasis. Clinical Trial Number: Complete clinical trial registration is deposited in the Chinese Clinical Trials Registry (http://www.chictr.org.cn/index.aspx), and the registration number is ChiCTR-OPC-17010757. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (No.81700757, No.81471039, No.81700714 and No.81770434), the National Key R&D Program of China (No.2017YFC1309602, No.2016YFC1101100, No.2017YFD0500503 and No.2017YFD0501001), and the Natural Science Foundation Project of Chongqing (No. cstc2014jcyjjq10006, No. cstc2016jcyjA0093 and No. cstc2016jcyjA0518). Declaration of Interests: The authors disclose no conflicts interest. Ethics Approval Statement: Informed written consent was obtained from all participants. The experiment was approved by the Ethics Committee of Xinqiao Hospital of the Third Military Medical University.