Dynamics of early-life bacteriophage- bacteria interactions in very preterm infants and their implications in disease

Background Preterm infants, especially if born very premature (before week 32 of gestation), are characterised by having immature organs including the gastrointestinal tract, associated with a skewed gut microbiota maturation and increased risk of gastrointestinal disorders. Early life gut microbiota maturation is crucial for various biological functions, influencing host metabolism, immune response, and pathogen protection. While the maturation of the bacterial gut microbiota component in preterm infants is well studied, very little is known about the interplay between these bacteria and their viruses, i.e. bacteriophages. This study focuses on the faecal bacterial and bacteriophage communities of very preterm infants during their first 90 days of life. Methods A prospective cohort including 23 very preterm infants (28 weeks' gestation or birth weight under 1000 g) in a Neonatal Intensive Care Unit in Italy was recruited. The majority (20/23) received antibiotic therapy in this period. Faecal samples were collected at birth and at 15, 30, and 90 days of life for 16S rRNA gene amplicon and metavirome sequencing. Analyses were performed to assess bacterial and viral composition, their interactions and their correlation with clinical parameters. Results Caudoviricetes members were the dominant bacteriophages, while facultative anaerobes dominated the bacterial community in the preterm infants' gut. The bacterial diversity increased over time, whereas bacteriophage diversity decreased and trans-kingdom interaction analysis revealed distinct clusters of co-occurring bacteria and bacteriophages. Notably, twin pairs exhibited higher virome similarity compared to bacterial community similarity. Antibiotic treatment correlated strongly with bacterial community composition and modestly with virome composition. Bronchopulmonary dysplasia (BPD) incidence and predicted viral host composition significantly correlated, suggesting a potential role of bacteriophages in disease aetiology. Conclusion This study provides a view on the complex interplay between bacterial and viral components in the preterm infant gut. We find that of bacteriophages appear to have a pivotal role in shaping the bacterial community before a more stable microbiota is reached. Furthermore we show that BPD and viral host composition are linked, suggesting that the preterm gut virome might be an important factor to consider in managing premature birth complications.