Multi-Omics Correlations Reveal Lipid Species Involved in Lung Allograft Adaptation

Purpose Allograft adaptation after lung transplantation is a multi-factor process. We hypothesized that early adaptation can influence the risk of matrix remodeling and CLAD development by shaping the inflammatory state of the lung environment. In a longitudinal study, we followed a defined patient cohort in year 1 p.t. and detected ordered cell composition changes with repercussions in the microbiome, small molecular composition and lipidome in BAL samples. We delimited clusters of pro-inflammatory factors and identified long-chain lipid species from the lung environment that modulated inflammatory response in vitro. Methods We used FACS to identify cell populations and 16S sequencing, metabolomics, lipidomics to characterize the lung environment. With correlations and hierarchical clustering we extracted pro- and anti-inflammatory clusters around well-characterized cell populations. For detection of inflammation drivers, we quantified feature differential abundances in samples with more or less neutrophilia. Predicted candidates were tested to modify inflammatory responses in vitro by screening IL-6 production of LPS-triggered macrophages. Results Early after surgery, the allograft experienced neutrophilia, a lack of resident macrophages and a gradual influx of host-derived macrophage-precursors directly resonating with changes in the pulmonary microenvironment. The computational analysis revealed features that clustered either with neutrophils or alveolar macrophages. From these, 30% showed significant abundance differences in high and low neutrophilia conditions. Consistently, certain ceramide species displayed antagonistic behavior to several phosphatidylcholines. We tested their capability of modifying macrophage response and found the ceramide to enhance, and PCs to reduce IL-6 production. Conclusion Our study suggests that the lung microenvironment plays a key role in allograft adaptation and specific lipid species are capable of modulating cellular inflammatory response in a differentiated manner early after transplantation. Our results provide first fundamental concepts for developing concrete precision therapies based on reprogramming tissue homoeostasis and inflammation management.