Factors influencing preterm infant microbiota and their role in wheezing development

Abstract

Background: This multicenter prospective study, conducted between 2019 and 2022 in two neonatal intensive care units (NICUs) in Madrid (H. Severo Ochoa and H. La Paz), investigated the relationship between nasopharyngeal and gut microbiota in very preterm infants born at <32 weeks of gestation age and the development of recurrent wheezing during the first year of life.

Methods: A total of 91 preterm neonates were enrolled, excluding those with major malformations, genetic disorders, or immunodeficiency. During hospitalization, weekly nasopharyngeal aspirates (NPAs) were collected, beginning in the first 7 days of life. Respiratory viruses were detected via PCR. Stool samples for microbiota were obtained only one time during the first week of life. Microbial composition was characterized through 16S rRNA gene sequencing. The analysis of associations with wheezing specifically included microbiota data from samples collected during the first week of life (stools and NPAs). Microbial profiles were analyzed using bioinformatic and statistical tools, including alpha and beta diversity metrics, redundancy analysis (RDA), and random forest predictive models. Wheezing was defined as ≥2 episodes of physician-confirmed wheezing requiring medical attention during the first year of life, as reported by caregivers and verified by clinical records.

Results: The results showed that clinical factors such as delivery mode, antibiotic use, type of feeding, and mechanical ventilation significantly influenced microbial profiles. Infants who developed wheezing had a higher abundance of pathogens such as Klebsiella, Escherichia/Shigella, and Stenotrophomonas, whereas Bifidobacterium and Staphylococcus were more frequent in non-wheezing infants. Both nasopharyngeal and gut microbiota were significantly associated with respiratory outcomes, including hospital admissions and chronic respiratory treatments. Early-life dysbiosis-shaped by antibiotics and artificial feeding-was linked to heightened inflammation and increased risk of respiratory morbidity.

Conclusions: This study suggests that microbial composition during the first week of life can serve as an early predictor of wheezing in preterm infants. Targeted interventions, such as promoting breastfeeding and reducing unnecessary antibiotic use, may help preserve microbial diversity and improve long-term respiratory health in this vulnerable population.

Impact: The microbiota of preterm neonates during the first week of life plays a pivotal role in determining the risk of respiratory diseases, such as wheezing, later in life. Clinical factors such as antibiotic use, delivery mode, and breastfeeding have a profound impact on microbiota composition, with specific genera such as Moraxella, Corynebacterium, and Bifidobacterium emerging as key biomarkers, making them important targets for interventions to promote long-term respiratory health in preterm infants. To recognize microbial predictors of recurrent wheezing in preterm infants could allow to explore potential microbiota-modulating strategies to mitigate respiratory complications in this high-risk population.