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-rDNA sequencing was performed to analyse 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 diabetes patients to germ-free mice was performed to investigate the contribution of the altered microbiome to antidiabetic effects of the drugs. Fecal metabolomics was also analysed 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 colonized mice, while acarbose did not. Moreover, DPP-4i increased the abundance of Bacteroidetes, and also promoted a functional shift in the gut microbiome, especially increasing the production of succinate. Interpretation Our findings demonstrate an important effect of DPP-4i on the gut microbiota, revealing a new hypoglycemic mechanism and an additional benefit of it. Furthermore, modulating the microbial composition, and the functional shift arising from changes in the microbiome, might be a potential strategy for improving glucose homeostasis. Fund 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 of Chongqing (No. cstc2014jcyjjq10006, No. cstc2016jcyjA0093 and No. cstc2016jcyjA0518).

Patients with diabetes often experience multiple disease complications. Hypoglycemic agents can have both positive and negative effects on diabetic complications, which should be carefully assessed when personalized treatment strategies are developed. In this study we report that dipeptidyl peptidase 4 inhibitors (DPP-4is), a group of widely used antihyperglycemic agents, can improve diabetic wound healing, independent of their beneficial effects on glycemic control. In particular, DPP-4is promoted the migration and epithelial-mesenchymal transition of keratinocytes, directly and indirectly, by inducing stromal cell-derived factor 1α production of fibroblasts in vitro and in diabetic mice. In addition, DPP-4is attenuated collagen synthesis and deposition, which may diminish scar formation. Furthermore, the results of a randomized clinical trial (NCT02742233) involving 67 patients with type 2 diabetes supported the role of DPP-4i treatment in diabetic wound healing. Our findings support the application of DPP-4i as a preferred option for treating ulcers in patients with diabetes.

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