The Pulmonary Microbiome after Lung Transplantation is Associated with Gastroesophageal Reflux Disease, Inflammation, and Allograft Dysfunction

Abstract

<h3>Purpose</h3> The pulmonary microbiome modulates the immune milieu in the lung allograft and is in turn influenced by gastroesophageal reflux disease (GERD). Although GERD has been linked to a higher risk of chronic lung allograft dysfunction (CLAD), the underlying role of the allograft microbiome is unknown. We assessed the relationships between the post-transplant pulmonary microbiome, GERD, inflammation, and allograft dysfunction. <h3>Methods</h3> 24 GERD and 51 no-GERD patients, defined by pH-impedance probe, had bronchoalveolar lavage (BAL) obtained at 3, 6, 9, and 12 months post-transplant. A separate cohort of 18 patients who underwent Nissen fundoplication for GERD within the first year post-transplant had BAL obtained before and after surgery. BAL were analysed for microbial communities and inflammatory cytokines using 16S rRNA sequencing and immunoassays, respectively. <h3>Results</h3> Hierarchical clustering of all GERD and no-GERD samples by Bray-Curtis dissimilarity identified three distinct community state types (CST) (Figure A). CST1 was positively associated with GERD and enriched in <i>Prevotella</i> and <i>Veillonella</i>. CST2 was negatively associated with GERD and enriched in <i>Streptococcus</i>. CST3 was independent of GERD and enriched in <i>Pseudomonas</i> and <i>Staphylococcus</i>. Compared to other CSTs, CST3 was associated with a greater proportion of patients with BAL inflammation, concurrent acute decline in lung function at 3 months, and earlier CLAD onset. Patients with the greatest decrease in BAL inflammation post-Nissen also had decreases in bacterial load and density of <i>Prevotella</i> (Figure B). <h3>Conclusion</h3> Pulmonary microbiota after lung transplantation cluster into three CSTs which differ by their associations with GERD. CST3 may represent a GERD-independent state of microbial dysbiosis which promotes inflammation and allograft rejection. Anti-GERD surgery appears to decrease GERD-associated microbiota.