RATIONALE: Bronchopulmonary dysplasia (BPD) is the most common morbidity affecting very preterm infants. Gut microbial communities contribute to multiple lung diseases and gut microbiome alterations may be a factor in BPD pathogenesis. OBJECTIVE: To determine if features of the multikingdom gut microbiome predict the development of BPD in very low birthweight newborns. METHODS: We performed a prospective, observational cohort study comparing the multikingdom fecal microbiota of 147 preterm infants with BPD or post-prematurity respiratory disease (PPRD) by sequencing the bacterial 16S and fungal ITS2 ribosomal RNA gene. To address the potential causative relationship between gut dysbiosis and BPD, we used fecal microbiota transplant in an antibiotic-pseudohumanized mouse model. Comparisons were made using RNA sequencing, confocal microscopy, lung morphometry, and oscillometry. MEASUREMENTS AND MAIN RESULTS: We analyzed 100 fecal microbiome samples collected during the second week of life. Infants who later developed BPD showed an obvious fungal dysbiosis as compared to infants with PPRD ( P = 0.0209). Instead of fungal communities dominated by Candida and Saccharomyces , the microbiota of infants who developed BPD were characterized by the abundance of Aureobasidium and a greater diversity of rarer fungi in less interconnected community architectures. On successful colonization, the gut microbiota from infants with BPD augmented lung injury in the offspring of recipient animals. We identified alterations in the murine lung and intestinal microbiomes and transcriptional alterations associated with augmented lung injury. CONCLUSIONS: The gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis. TRIAL REGISTRATION: NCT03229967.
