Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung

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Background:Homeostatic turnover of the extracellular matrix conditions the structure and function of the healthy lung. In lung transplantation, long-term management remains limited by chronic lung allograft dysfunction, an umbrella term used for a heterogeneous entity ultimately associated with pathological airway and/or parenchyma remodeling.Objective:This study assessed whether the local cross-talk between the pulmonary microbiota and host cells is a key determinant in the control of lower airway remodeling posttransplantation.Methods:Microbiota DNA and host total RNA were isolated from 189 bronchoalveolar lavages obtained from 116 patients post lung transplantation. Expression of a set of 11 genes encoding either matrix components or factors involved in matrix synthesis or degradation (anabolic and catabolic remodeling, respectively) was quantified by real-time quantitative PCR. Microbiota composition was characterized using 16S ribosomal RNA gene sequencing and culture.Results:We identified 4 host gene expression profiles, among which catabolic remodeling, associated with high expression of metallopeptidase-7, -9, and -12, diverged from anabolic remodeling linked to maximal thrombospondin and platelet-derived growth factor D expression. While catabolic remodeling aligned with a microbiota dominated by proinflammatory bacteria (eg,Staphylococcus,Pseudomonas,andCorynebacterium), anabolic remodeling was linked to typical members of the healthy steady state (eg,Prevotella,Streptococcus,andVeillonella). Mechanistic assays provided direct evidence that these bacteria can impact host macrophage-fibroblast activation and matrix deposition.Conclusions:Host-microbes interplay potentially determines remodeling activities in the transplanted lung, highlighting new therapeutic opportunities to ultimately improve long-term lung transplant outcome.Graphical abstract

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