Bacterial Extracellular Vesicles as Systemic Messengers: Integrating Their Roles in Gut-Liver-Brain Communication and Disease.

Bacterial extracellular vesicles (BEVs) are nanosized lipid bilayer structures released by both Gram-positive and Gram-negative bacteria. They transport proteins, lipids, metabolites, and nucleic acids. Increasing evidence indicates that BEVs function as active mediators of gut-organ communication rather than passive microbial byproducts. This review synthesizes current knowledge on BEV cargo composition, isolation strategies, and host interaction mechanisms with particular emphasis on gut-liver and gut-brain cross-talk. Within the intestinal environment, BEVs interact with pattern-recognition receptors, including Toll-like receptor (TLR) pathways, and influence epithelial barrier integrity and cytokine signaling. Under conditions of increased permeability, BEVs can reach systemic circulation and activate Kupffer cells (KCs) and hepatic stellate cells, contributing to inflammation and fibrosis. In contrast, vesicles derived from commensal species such as Akkermansia muciniphila enhance barrier function and improve metabolic signaling. In obesity and type 2 diabetes, BEVs modulate insulin signaling pathways, linking microbial activity to host glucose homeostasis. Moreover, certain BEVs can cross the blood-brain barrier and influence neuroinflammatory processes. Importantly, we propose a context-dependent framework in which BEV-mediated effects are determined by vesicular cargo composition, host cellular state, and exposure dynamics. This perspective helps reconcile the dual pathogenic and protective roles reported in the literature. Finally, we discuss current methodological limitations and outline key future directions. These include standardized isolation protocols, in vivo fate-tracking studies, and the development of engineered vesicle-based therapeutic strategies. A more precise understanding of BEV biology may enhance biomarker discovery and support targeted interventions in chronic metabolic and inflammatory diseases.