Immunoregulatory effects of Lactococcus lactis‐derived extracellular vesicles in allergic asthma

BACKGROUND: Probiotics have been shown to prevent various allergic diseases by producing extracellular vesicles (EVs). However, the role of EVs in allergic asthma has not yet been completely determined. METHODS: Gut microbial composition, mainly genera related to probiotics, was investigated in allergic asthmatic mice. Moreover, EVs were isolated from Lactococcus lactis (L. lactis, a selected bacterium) and EV proteins were identified by peptide mass fingerprinting. EV functions in immune responses were evaluated in vivo or ex vivo. Furthermore, the levels of specific IgG antibodies (an alternative marker for EV quantification) to L. lactis‐EVs were measured by ELISA in the sera of 27 asthmatic patients and 26 healthy controls. RESULTS: Allergic asthmatic mice showed a lower proportion of Lactococcus compared to healthy mice. L. lactis was cultured and its EVs abundantly contained pyruvate kinase. When allergic asthmatic mice were intranasally treated with EVs, airway hyperresponsiveness, eosinophil number, cytokine secretion, and mucus production were significantly decreased. Moreover, L. lactis‐EV treatment shifted immune responses from Th2 to Th1 by stimulating dendritic cells to produce IL‐12. In addition, significantly lower levels of serum specific IgG4 (but not IgG1) to L. lactis‐EVs were noted in asthmatic patients than in healthy controls. A positive correlation between the levels of EV‐specific IgG4 and FEV(1) (%), but a negative correlation between the levels of EV‐specific IgG4 and IL‐13 were observed. CONCLUSION: These findings suggest that L. lactis‐EVs may have immune‐regulating effects on airway inflammation mediated by dendritic cell activation, providing a potential benefit for allergic asthma.