INTRODUCTION: Obesity and diabetes are common chronic metabolic disorders which can cause an imbalance of the intestinal flora and gut-liver metabolism. Several studies have shown that probiotics, including Nissle 1917 (EcN), promote microbial balance and metabolic health. However, there are no studies on how EcN outer membrane vesicles (EcN-OMVs) influence the intestinal microflora and affect the metabolic disorders of obesity and diabetes. METHODS: In this study, we evaluated the effects of EcN-OMVs on high-fat diet (HFD)-induced obesity and HFD + streptozotocin (STZ)-induced diabetes. RESULTS: EcN-OMVs could reduce body weight, decrease blood glucose, and increase plasma insulin in obese mice. Similarly, EcN-OMVs treatment could modify the ratio of / in the gut, elevate intestinal short-chain fatty acid (SCFA)-producing flora, and influence the SCFA content of the intestine. Furthermore, the intestinal metabolites ornithine and fumaric acid, hepatic ω-6 unsaturated fatty acids, and SCFAs were significantly increased after administering EcN-OMVs. DISCUSSION: Overall, this study showed that EcN-OMVs might act as post-biotic agents that could modulate gut-liver metabolism and ameliorate the pathophysiology of obesity and diabetes.