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Background: Probiotics species appear to differentially regulate the intestinal immune response. Moreover, we have shown that different immune-modulatory abilities can be found among probiotic strains belonging to the same species. In this study, we further addressed this issue while studying L. gasseri, a species that induces relevant immune activities in human patients. Results: We determined the ability of two strains of L. gasseri, OLL2809 and L13-Ia, to alter cell surface antigen expression, cytokine production and nuclear erythroid 2-related factor 2 (Nrf2)-mediated cytoprotection in murine bone marrow-derived dendritic cells (DCs) and MODE-K cells, which represent an enterocyte model. Differential effects of L. gasseri strains were observed on the expression of surface markers in mature DCs; nevertheless, both strains dramatically induced production of IL-12, TNF- and IL-10. Distinctive responses to OLL2809 and L13-Ia were also shown in MODE-K cells by analyzing the expression of MHC II molecules and the secretion of IL-6; however, both L. gasseri strains raised intracellular glutathione. Treatment of immature DCs with culture medium from MODE-K monolayers improved cytoprotection and modified the process of DC maturation by down-regulating the expression of co-stimulatory markers and by altering the cytokine profile. Notably, bacteria-conditioned MODE-K cell medium suppressed the expression of the examined cytokines, whereas cytoprotective defenses were significantly enhanced only in DCs exposed to OLL2809-conditioned medium. These effects were essentially mediated by secreted bacterial metabolites. Conclusions: We have demonstrated that L. gasseri strains possess distinctive abilities to modulate in vitro DCs and enterocytes. In particular, our results highlight the potential of metabolites secreted by L. gasseri to influence enterocyte-DC crosstalk. Regulation of cellular mechanisms of innate immunity by selected probiotic strains may contribute to the beneficial effects of these bacteria in gut homeostasis. © 2013 Luongo et al.; licensee BioMed Central Ltd.