The Gut-Lung Axis During Ethanol Exposure and a Pseudomonas aeruginosa Bacterial Challenge

Background: Susceptibility to and severity of pulmonary infections increase with ethanol consumption. We have previously shown that ethanol-induced changes in the gut microbiome disrupt gut homeostasis, allowing for the translocation of proinflammatory mediators into the circulation and eliciting an immune response in the lung. Additionally, targeting the gut with butyrate supplementation not only rescues ethanol-induced disruptions to gut health but also reverses aspects of immune dysregulation in the lungs. Here, we assessed the impact of this connection on a subsequent infectious challenge. Methods: To assess if ethanol-induced alterations to the gut microbiome could also impact the host response to a pulmonary infectious challenge, we employed a chronic-binge ethanol-feeding mouse model followed by a nasal instillation of Pseudomonas aeruginosa. Results: In addition to altering gut microbiome composition and metabolism, ethanol consumption also disrupted the local immune response as demonstrated by suppressed cecal SIgA levels, a decreased presence of CD3⁺CD8a⁺ cytotoxic T cells in the proximal colon mucosa, and depleted CD3⁺CD8a⁺ T cells and CD11c⁺CD8a⁺ dendritic cells in the mesenteric lymph nodes. Circulatory Ly6G⁺CD11b⁺ neutrophils increased, indicating a systemic change in immune-cell presence with ethanol exposure. Ethanol exposure increased CD11c⁺CD64⁺ macrophages and Ly6G⁺CD11b⁺ neutrophils in the lungs, with neutrophil populations being further exacerbated during a bacterial challenge with Pseudomonas aeruginosa. Lipocalin 2, a marker of oxidative stress, was also elevated with ethanol consumption, though not with infection. Conclusions: These data suggest that ethanol-induced changes in the gut microbiome and immune environment are linked to dysfunctional immune responses in the intestine, blood, and the lungs, compromising the pulmonary immune response during an infectious challenge in mice.