Integrative Metagenomic Approaches to Study Antibiotic Resistance Genes and Microbial Functions in the Preterm Infant Gut Microbiome
The widespread use of antibiotics has substantially improved clinical outcomes, particularly the survival of preterm infants. In neonatal intensive care units, antibiotics are frequently administered because these infants are at high risk of severe bacterial infections. However, early-life antibiotic exposure can alter the developing gut microbiome and promote the enrichment and persistence of antibiotic resistance genes (ARGs). As microbial colonization during this period shapes the resistome, understanding the factors driving ARG distribution and persistence are essential. This thesis investigated the distribution and genomic context of ARGs in the gut microbiome of preterm infants during the first six month of life. The two main studies are based on metagenomic datasets from nine preterm infant cohorts comprising 6,343 stool samples analyzed using in silico approaches. The first study characterized the neonatal gut resistome across cohorts and linked ARGs to bacterial hosts and mobile genetic elements. The second study focused on Staphylococcus epidermidis, Staphylococcus haemolyticus and Staphylococcus aureus, which commonly colonize the preterm gut and are major causes of neonatal infections. It examined the genomic context of ARGs and their associations with other bacterial traits, such as virulence factors and metabolic capabilities. Resistance determinants often co-occurred within individual genomes. Resistance and virulence factors were often detected in the same genomic backgrounds but were not linked to the same mobile genetic elements. Several ARGs were significantly associated with metabolic pathways, suggesting functional integration of resistance determinants within bacterial hosts. In a third study, comparable analytical workflows are applied in conjunction with experimental methods to study antibiotic resistance in soil microbiomes. Overall, this dissertation provides new insights into factors shaping the early-life gut resistome and demonstrates that the analytical workflows developed here are transferable to other microbial systems, including soil microbiomes. These findings advance the understanding of genomic mechanisms underlying ARG persistence and spread across microbial communities.
metagenomics, antibiotic resistance, preterm infants, gut microbiome
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