Role of microbe-derived extracellular vesicles in glucose metabolism

Abstract

Gut microbiota interact with their host and affect its homeostatic functions. This interaction and the composition of the microbiota are implicated in the pathogenesis of type 2 diabetes (T2D), which is characterized by chronic inflammation and insulin resistance. Recently, extracellular vesicles (EVs) have been shown to play roles in intracellular communication in some pathological and physiological conditions including tumors and immune response, but the precise role of these EVs in host metabolism is not clear. To identify diabetes-related EVs, metagenomic data analysis of stool EVs derived from regular diet (RD)- and high-fat diet (HFD)-fed mice was performed. Interestingly, 16S ribosomal DNA sequencing indicated that several EVs exhibited changes in composition after the mice were administered with HFD. These EVs were used to treat myotubes to evaluate effects of EVs on metabolic cells. Specifically, Pseudomonas panacis-derived EVs (PpEVs) inhibited insulin function, which is responsible for increasing glucose uptake into cells. In addition, PpEVs were administered to mice via the oral route to investigate their effect on host glucose metabolism. It was observed that PpEV-treated mice, when fed with a regular diet, showed a diabetic phenotype including impaired glucose tolerance and insulin resistance. The insulin resistance was due to inhibition of Akt phosphorylation, which has been shown to be involved in the insulin signaling pathway. Thus, these data suggest that microbe-derived EVs may play a role in the development of insulin resistance in diabetes. To further investigate the diverse effects of EVs on glucose homeostasis, Akkermansia muciniphila-derived EVs (AmEVs) were isolated and compared with Escherichia coli-derived EVs (EcEVs) that are known to be pathogenic. These EVs had similar physical characteristics such as shape and size, but exhibited distinct protein contents and functions. AmEVs increased GLUT4 translocation on the cell surface by activation of AMP-activated protein kinase (AMPK), which is responsible for glucose uptake in myotubes, whereas EcEVs did not stimulate the myotubes. Moreover, AmEV treatment improved body weight gain, glucose tolerance, and hyperinsulinemia in HFD-induced diabetic mice in an AMPK-dependent manner. Thus, AmEVs had a protective effect on improvement of insulin sensitivity. Taken together, these results suggest that EVs from gut microbioita can affect host cells by controlling phosphorylation of intracellular signaling molecules involved in glucose uptake. Therefore, gut microbe-derived EVs play a significant role in regulation of host glucose metabolism.