Subinhibitory concentrations of meropenem stimulate membrane vesicle production and modulate immune response in Bacteroides fragilis infection

Abstract

This study explores an adaptation mechanism of Bacteroides fragilis to subinhibitory concentrations of meropenem, characterized by an alteration in the production of membrane vesicles (MVs) and modulation of the host inflammatory response. Using a rat model of infection, we demonstrated a significant increase in the size of MVs accompanied by a nonsignificant increase in their number in the meropenem-treated group compared to the infected control. Both infected groups showed significantly altered hematological parameters and shifts in monocyte on day 8 (average increase of 21.5 %). At the same time, significant changes in neutrophils (decrease by 26 %) and eosinophils (increase by 3 %) were observed only in the infected group but not in the infected meropenem-treated group. On day 16, increased macrophage activation, neovascularization, and fibrosis were observed in the tissues of the antibiotic-treated group. Immunological profile analysis revealed a slight increase in the levels of pro-inflammatory cytokines (IL-5, IL-6, IFN-γ and G-CSF) on day 8 of the experiment, followed by a sharp decrease on day 16 in both infected groups compared to the negative control. At the same time, network analysis of correlations between these immunological factors showed complex changes in response to subinhibitory concentrations of meropenem. The bacterial load did not differ between the infected groups on days 8 and 16, but only in the meropenem-free group a significant decrease in the number of bacteria was observed on day 16 in all samples. These findings suggest that subinhibitory antibiotic concentrations can influence the pathophysiological progression of B. fragilis infection, modulating both the bacterial response and the host immune reaction, potentially leading to a more complex and chronic disease course.