Evaluating the impact of short-chain fatty acids on lung cell physiology and antibiotic susceptibility of respiratory pathogens in COPD

<bold>Introduction:</bold> Short-chain fatty acids (SCFAs) are found in higher concentrations in the airways of COPD patients compared to healthy controls. However, the role of these SCFAs in the pathophysiology of COPD remains unclear. Therefore, this study aims to evaluate the impact of SCFAs on both human lung epithelial cells, and bacterial pathogens that are frequently associated with acute COPD exacerbations. <bold>Methods:</bold> 3 SCFAs were included in this study: acetate, propionate and butyrate. Their impact on the activity of 4 relevant antibiotics was evaluated in biofilm inhibition experiments with <italic>Moraxella catarrhalis</italic> DSM 11994. The most interesting findings were validated with 2 additional strains. The effects of SCFAs on host cells were investigated using an <italic>in vivo</italic>-like 3-D lung epithelial cell model. Cytotoxicity was assessed by measuring LDH release and through microscopic evaluation, and immunomodulation was evaluated by quantifying the secretion of pro-inflammatory interleukin-8 (IL-8) via ELISA. <bold>Results:</bold> The effect of SCFAs on antibiotic activity depended on the used antibiotic, SCFA type and concentration, and bacterial strain. Interestingly, propionate attenuated the biofilm-inhibiting activity of doxycycline for all 3 strains of <italic>M. catarrhalis</italic>. Propionate and butyrate were cytotoxic to 3-D lung cells at high concentrations, whereas acetate was not. In addition, all 3 SCFAs showed a pro-inflammatory effect by stimulating IL-8 secretion in 3-D lung epithelial cells. <bold>Conclusion:</bold> SCFAs may influence the pathophysiology of COPD by decreasing doxycycline activity against pathogens and by exerting cytotoxic and pro-inflammatory effects towards host cells.