The DPP-4 inhibitor sitagliptin alters the gut microbiota and prevents neuronal damage of hippocampus in STZ induced type 2 diabetic rats

Abstract Background : Type 2 Diabetes mellitus is characterized by impaired glucose metabolism and insulin resistance with increasing risk of specific complication, including central neuropathy. Dipeptidyl peptidase 4 (DPP-4) inhibitors are agents designed to regulate hyperglicemia through increasing the half-life of incretins. Although they are administered orally, their effects on central neuropathy and gut microbiota remain unclear. Our objective was aimed to identify the impact of the DPP-4 inhibitor sitagliptin on gut microbiota and central neuropathy in a rat model of streptozotocin (STZ)-induced diabetes Methods: Diabetic rats were induced by a high-fat diet and streptozotocin injection. Diabetic rats were orally administered a dose of sitagliptin (10mg/kd/d), and normal diet for 12 weeks. Fecal DNA extraction and sequencing based on analysis of 16S rRNA genes was used to determine the overall structure of microbiota in fecal samples. Then rats were killed, of which the brain tissue sections were observed for changes of neurons in the hippocampus by HE staining. Results: Sequencing of the V3-V4 regions of 16S rRNA genes revealed that sitagliptin significantly altered the gut microbiota. Compared to the diabetic group, Shannon index and the abundance of phylum Bacteroidetes decreased significantly, whereas the proportion of phylum Firmicutes increased significantly in the sitagliptin-treated rats. Moreover, higher abundance of a few putative short-chain fatty acid-producing bacteria, including Clostridium and Fusobacterium was observed remarkably after sitaglitin treatment. Genera Lactobacillus , Streptococcus and Clostridium, which could produce some neurotransmitters, were also found increased substantially in the sitagliptin-treated rats. Notably, we found that sitagliptin treatment could ameliorate the abnormal changes of pyramidal neurons in hippocampus with HE staining. Conclusions: Our study demonstrated that sitagliptin prevented the neuronal damage of hippocampus in type 2 diabetic rats, accompanied by changes of gut microbiome. It indicated that sitagliptin might alleviate diabetic central neuropathy through triggering “microbiota-gut-brain” axis.