Microbial extracellular vesicles from min pigs remodel macrophage polarization via STING to sustain intestinal immune homeostasis

Intestinal immune homeostasis is crucial for intestinal function and health. Increasing evidence suggests that certain gut microbiota can enhance the host's intestinal immune regulatory capacity. However, the mechanisms by which the microbiota confers beneficial traits and robust immunity to the host, as well as the cross-species reproducibility of these effects, remain unclear. This study, through multi-omics integration comparison and functional validation, revealed that Streptococcus hyointestinalis from Min pigs regulates macrophage polarization homeostasis by targeting and inhibiting the excessive activation of the STING signaling pathway and its downstream pro-inflammatory cascade reactions through its extracellular vesicles (EVs), thereby shifting them toward the M2 phenotype. This process ensures the integrity of the intestinal barrier and alleviates colitis induced by the combined effects of low temperature and sodium sulfate-induced colitis (DSS). Notably, in Sting-/- mice, the EV-mediated intestinal protective effect was eliminated, confirming its targeted efficacy. Our data reveal a microbial EV‒STING‒macrophage axis in which symbiotic bacterial exosomes promote reparative macrophage programs by regulating STING signaling and maintaining intestinal integrity under environmental stress. These findings reveal a novel host–microbiota communication pathway with therapeutic potential for the treatment of inflammation-driven intestinal diseases.