Abstract Rationale Short-chain fatty acids (SCFAs), metabolites produced by anaerobic bacteria of the lung microbiome, are found at higher concentrations in the airways of patients with chronic obstructive pulmonary disease (COPD) compared to healthy individuals. Although SCFAs are generally considered to have anti-inflammatory and beneficial properties in the context of gut inflammation, the role of these metabolites in the pathophysiology of COPD remains poorly understood. In this study, we comprehensively investigated the influence of SCFAs on host-pathogen dynamics by assessing their effects on lung epithelial cell viability and inflammatory responses during infection with Moraxella catarrhalis, a respiratory pathogen frequently associated with acute exacerbations. We also examined how SCFAs affect the antibiotic susceptibility of M. catarrhalis during the infection process. Methods We utilized an in vivo-like three-dimensional (3-D) alveolar epithelial cell model to evaluate host cell response (i.e. cell integrity, cytotoxicity, and immunomodulation) to propionate, presumably the SCFA exerting the most potent immunomodulatory effects on lung epithelial cells, in the presence and absence of M. catarrhalis infection. Next, we investigated how varying concentrations of propionate influence host-pathogen interactions in the presence of the antibiotic doxycycline. Host association of M. catarrhalis was studied through enumeration of the M. catarrhalis bacteria that adhered to or were internalized by 3-D lung cells. Cell integrity was evaluated microscopically, while cytotoxic effects were analyzed by measuring lactate dehydrogenase release. Secretion of pro-inflammatory cytokines IL-8, IL-6, and MCP-1 was quantified via ELISA to assess immunomodulation. Results Propionate decreased the activity of doxycycline against M. catarrhalis in the 3-D lung model. Furthermore, propionate compromised the integrity and viability of 3-D lung epithelial cells infected with M. catarrhalis at low concentrations, while exhibiting cytotoxic effects on uninfected cells only at higher concentrations. In addition, propionate stimulated the secretion of IL-8, IL-6 and MCP-1 in uninfected lung cells, suggesting a pro-inflammatory influence of the SCFA. Interestingly, a distinct pattern was observed in infected lung cells: whereas IL-8 production was significantly increased by cells exposed to both M. catarrhalis and propionate compared to M. catarrhalis alone, secretion of IL-6 and MCP-1 was surprisingly reduced in infected cells exposed to propionate. Conclusions The SCFA propionate can impact the behavior of host cells and their interactions with bacterial pathogens, by decreasing antibiotic activity against M. catarrhalis during infection and by exerting cytotoxic and immunomodulatory effects on lung epithelial cells. These findings suggest that SCFAs could potentially contribute to the pathophysiology of COPD. This abstract is funded by: None
Meester et al. (Fri,) studied this question.