Extracellular Vesicles from Escherichia coli Strains of the Gut Microbiota Trigger Hepatic Antioxidant and Anti-Lipogenic Effects via the Gut-Liver Axis in Healthy Neonatal Rats

<b>Background</b>: The gut-liver axis is essential for maintaining liver physiology, with the gut microbiota playing a central role in this bidirectional communication. Recent studies have identified microbiota-derived extracellular vesicles (EVs) as key mediators of inter-organ signaling. This study explored the impact of EVs from two beneficial <i>Escherichia coli</i> strains, the probiotic EcN and the commensal EcoR12, on hepatic metabolism and oxidative stress in healthy neonatal rats. <b>Methods</b>: EVs were administered orally during the first 16 days of life, and blood and liver samples were collected on days 8 and 16. <b>Results</b>: The results demonstrated that EVs significantly reduced intestinal permeability, as evidenced by decreased plasma zonulin levels. In the liver, EVs enhanced redox homeostasis by downregulating <i>CYP2E1</i> and upregulating key antioxidant genes (<i>SOD1</i>, <i>CAT</i>, <i>GPX</i>). Furthermore, the treatment shifted liver metabolism toward an anti-lipogenic profile by inducing fatty acid oxidation genes (<i>PPARA</i>, <i>CPT1A</i>) and suppressing genes involved in de novo lipogenesis (<i>SREBP1C</i>, <i>ACC1</i>, <i>FASN</i>, <i>CNR1</i>). Importantly, markers of hepatic inflammation remained unchanged, indicating the safety of the intervention. In vitro experiments using human HepG2 cells supported these findings, further validating the antioxidant and metabolic effects of the EVs. <b>Conclusions</b>: Our results underscore the role of microbiota-derived EVs as important mediators of hepatic metabolic programming in healthy individuals via the gut-liver axis and highlight their potential as therapeutic postbiotic agents for management of fatty liver diseases.