Acetate inhibits Pseudomonas aeruginosa growth and reduces inflammatory responses to infection in primary human lung tissue ex vivo

<italic>P. aeruginosa</italic> infections are associated with a decline in lung function and increased mortality in patients with chronic lung diseases. Short-chain fatty acids (SCFAs), produced by the microbiome, might protect the host from infection and associated inflammation. Here, we investigated the effect of acetate on <italic>P. aeruginosa</italic> growth and the local immune response in the human lung <italic>ex vivo</italic>. Human bronchial epithelial (BEAS-2B) cells and precision-cut lung slices (PCLS) were infected with PAO1 or exposed to LPS ± acetate (0.1-20 mg/ml) for 24 h. Gentamicin was added 2-3 h post infection (p.i.). Cytokines were quantified by ELISA, tissue viability by LIVE/DEAD staining, and CFUs by dilution plating. Acetate significantly reduced the release of IL-8 triggered by PAO1 and LPS in BEAS-2B cells. In PCLS, acetate reduced only the release of IL-8 caused by PAO1, not by LPS. This indicates that acetate directly affects the growth of PAO1 rather than just having anti-inflammatory effects. In PCLS treated with subinhibitory concentrations of gentamicin, PAO1 infection caused massive cell death at 24 h p.i.. Pretreatment of these slices with 5 mg/ml acetate inhibited PAO1 growth by 1-2 log steps, thereby rescuing tissue’s viability. <italic>In vitro</italic>, acetate reduced the minimum inhibitory concentration of gentamicin 8-fold. Our data show anti-bacterial and anti-inflammatory effects of acetate, highlighting postbiotics as supplementary treatment for patients infected with <italic>P. aeruginosa</italic>. Using a combination of SCFAs might further enhance these effects. Future studies will focus on comparing different SCFAs and antibiotics and the efficacy of local versus systemic administration.