Probiotic extracellular vesicles reprogram macrophage immunometabolism: From gut crosstalk to host health

Probiotic-derived extracellular vesicles (PEVs) are functional nanovesicles secreted by various microbiota. As a novel class of microbial signals, they encapsulate proteins, nucleic acids, lipids, and microbial-associated molecular patterns, emerging as potent modulators of communication between gut microbiota and host immune cells, such as macrophages. Macrophages, as a crucial component of the innate immune system, rely heavily on specific metabolic reprogramming to execute their immune functions effectively. Recent evidence demonstrates the pivotal role of macrophage immunometabolism in orchestrating inflammatory responses and regulating systemic metabolic health. This review provides the first comprehensive synthesis of current evidence linking PEVs to the function and metabolic reprogramming of macrophages. We first conducted a detailed exploration of the release rationale, biosynthesis, composition, uptake by macrophages, and biological activity of PEVs. Subsequently, we elucidated how these vesicles and their cargo influence macrophage polarization through several metabolic pathways, including glycolysis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and amino acid metabolism. We further explore the implications of macrophage immunometabolism in chronic inflammation and metabolic disorders, including inflammatory bowel disease (IBD), neurodegenerative diseases, and atherosclerosis. Additionally, emerging evidence indicates that PEVs may be influenced by various factors, which in turn can affect host immunity and metabolism. Finally, we briefly discuss the limitations and future challenges in this field. This review highlights new research targets concerning the impact of gut microbiota on host immunity and metabolism.