Targeting bacterial quorum sensing shows promise in improving intestinal barrier function following burn-site infection

摘要

Burn-site infections, commonly due to Pseudomonas aeruginosa, have been associated with deranged intestinal integrity, allowing bacteria and their products to translocate from the gut to the circulatory system. The P. aeruginosa quorum sensing (QS) transcription factor MvfR (PqsR) controls the expression of numerous virulence factors, and the synthesis of several toxic products. However, the role of QS in intestinal integrity alterations, to the best of our knowledge, has not been previously investigated. Using a proven anti-MvfR, anti-virulence agent, the in vivo results of the present study revealed that inhibition of MvfR function significantly decreased Fluorescein Isothiocyanate-Dextran (FITC-Dextran) flow from the intestine to the systemic circulation, diminished bacterial translocation from the intestine to mesenteric lymph nodes (MLNs), and improved tight junction integrity in thermally injured and infected mice. In addition, the MvfR antagonist administration alleviates the intestinal inflammation, as demonstrated by reduced ileal TNF-α and fecal lipocalin-2 concentrations. In addition, it is associated with lower levels of circulating endotoxin and decreased P. aeruginosa dissemination from the burn wound to the ileum. Collectively, these results hold great promise that the inhibition of this QS system mitigates gut hyperpermeability by attenuating the derangement of morphological and immune aspects of the intestinal barrier, suggesting that MvfR function is crucial in the deterioration of intestinal integrity following P. aeruginosa burn-site infection. Therefore, an anti-virulence approach targeting MvfR, could potentially offer a novel therapeutic approach against multi-drug resistant P. aeruginosa infections following thermal injuries. Since this approach is targeting virulence pathways that are non-essential for growth or viability, our strategy is hypothesized to minimize the development of bacterial resistance, and preserve the beneficial enteric microbes, while improving intestinal integrity that is deranged as a result of burn and infection.