Abstract Peripheral neuropathy is one of the major complications of diabetes that greatly contribute to morbidity and mortality. Currently, there is no effective treatment for diabetic peripheral neuropathy (DPN). Diabetes at an early stage affects the intestinal microbial composition that promotes the manifestation of metabolic syndrome. However, how gut dysbiosis contributes to the diabetic complications including DPN, is unknown. Extracellular vesicles (EVs) mediate intercellular communication and bacterial EVs retain bacterial genetic and biomaterials. Recent studies show that gut bacterial EVs participate in immune signaling pathways and host metabolic homeostasis that are associated with many disorders. The impact of microbiota derived EVs on DPN has not been investigated. Our preliminary studies demonstrate that gut bacterial EVs participate in the DPN progression. Importantly, our preliminary data also indicate that Lactobacillus-derived EVs alleviate the systemic inflammatory response, protect peripheral nerve damage, and improve neurorecovery in diabetic mice with peripheral neuropathy. In this application, we propose to investigate the effect of gut bacteria-EVs on the development of DPN and to examine the therapeutic potential of Lactobacillus-derived EVs and molecular mechanisms underlying this therapy on neuroinflammation and peripheral nerve damage. These studies will not only significantly expand our understanding of molecular mechanisms underlying gut microbiota-peripheral nerve communication and progression of DPN, but also provide a novel and potentially useful treatment strategy for patients with DPN. .