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Expression, Microbiome Features Provide Pre-Treatment Lung Function Clues for Pediatric Patients

NEW YORK – Microbial community and host gene expression features in lung samples may provide pre-treatment clues to risky lung function features in children receiving bone marrow transplants from healthy donor individuals, new research suggests.

"Impaired baseline lung function is associated with mortality after pediatric allogeneic hematopoietic cell transplantation (HCT), yet limited knowledge of the molecular pathways that characterize pre-transplant lung function has hindered the development of lung-targeted interventions," co-senior authors Joseph DeRisi, a researcher affiliated with the University of California at San Francisco and the Chan Zuckerberg Biohub, and Jaap Boelens, with Cornell University and Memorial Sloan Kettering Cancer Center, and their colleagues explained.

As they reported in Science Translational Medicine on Wednesday, the researchers used metatranscriptomic RNA sequencing to profile microbiome and host gene expression features in bronchoalveolar lavage samples collected from 104 children in the Netherlands in roughly the week or two leading up to their allogeneic HCT treatments, comparing those patterns with results from matched pulmonary function tests.

Among the 54 children showing signs of pulmonary restriction, impaired oxygen diffusion, lung capacity, or other altered pulmonary functions based on Global Lung Index cutoff scores, the team saw an overrepresentation of Staphylococcus and other skin or nasal passage-related microbes, but lower-than-usual levels of commensal microbes that are typically detected in the supraglottic region of the throat.

The presence of pre-treatment pulmonary changes also corresponded to poorer outcomes after HCT, the researchers reported, including an uptick in all-cause mortality and lung injury. By bringing in gene expression data from the bronchoalveolar lavage samples — together with available insights into cell type-specific markers from resources such as the Human Lung Cell Atlas — they tracked the cellular and molecular shifts found in the children with altered lung function.

"[W]e found that among children preparing to undergo allogenic HCT, [pulmonary function testing] abnormalities were common and consisted mostly of restriction and impaired diffusion," the authors wrote. "Abnormalities were associated with pulmonary microbiome depletion, profibrotic signaling, and post-HCT mortality."

In particular, the host gene expression data pointed to reduced immune activity, activation of alveolar epithelial pathways, and so-called epithelial-to-mesenchymal transition features, the team explained. Together, such findings point to potential ties between altered microbial community features, pulmonary fibrosis, and injury to alveoli that the lungs used to swap oxygen for carbon dioxide from blood moving through the lungs.

"Detection of microbial depletion and abnormal epithelial gene expression in [bronchoalveolar lavage] enhanced the prognostic utility of pre-HCT pulmonary function tests for the outcome of post-HCT mortality," the authors suggested. "These findings suggest a potentially actionable connection between microbiome depletion, alveolar injury, and pulmonary fibrosis in the pathogenesis of pre-HCT lung dysfunction."