Bacterial Extracellular Vesicles as Regulators of the Gut Microbiome-Circadian Axis in Inflammatory and Metabolic Diseases.

Bacteria-derived extracellular vesicles (BEVs) have emerged as key mediators of intercellular and interkingdom communication. These nanoscales, lipid bilayer-enclosed particles are secreted by both Gram-positive and Gram-negative bacteria and carry diverse bioactive cargoes, including proteins, lipids, nucleic acids, and metabolites. Through the delivery of these molecules, BEVs regulate host physiology by modulating immune responses, epithelial barrier integrity, and gut microbial community composition. Accumulating evidence indicates that BEVs derived from probiotics or commensal bacteria promote gut homeostasis, whereas vesicles released by pathogenic bacteria exacerbate dysbiosis, inflammation, and disease progression. The gut microbiome plays a central role in maintaining immune and metabolic homeostasis, and its disruption contributes to the development of inflammatory and metabolic diseases, including inflammatory bowel disease, atopic dermatitis, and metabolic dysfunction-associated steatohepatitis. In parallel, circadian rhythms orchestrate host metabolism, immunity, and microbial interactions, and emerging evidence highlights a bidirectional relationship between the gut microbiome and the circadian clock. Disruption of this microbiome-circadian axis further exacerbates inflammation and metabolic dysfunction. This review integrates current knowledge of the structural and functional characteristics of BEVs, their roles in regulating the gut microbiome, and their emerging involvement in circadian biology. We further discuss how BEVs may mediate communication within the gut microbiome-circadian axis and contribute to the pathogenesis or resolution of inflammatory and metabolic diseases. Understanding the BEV-gut microbiome-circadian axis provides new mechanistic insights into host-microbe communication and highlights BEVs as promising postbiotic candidates for restoring immune-metabolic homeostasis and developing next-generation microbiome-targeted therapeutics.