Deciphering dynamic antibiotics-microbiome-metabolome interactions in preterm infants using systems biology

Preterm infants are frequently administered antibiotics to prevent infections, yet their impact on the developing gut microbiota and metabolome remains complex and clinically significant. To systematically assess these effects, we analyzed longitudinal stool samples from 54 extremely- and very-low-birthweight infants by integrating clinical data, 16S rRNA-based microbiome profiling, targeted metabolomics, and community-scale metabolic modeling. Antibiotic exposure disrupted microbial diversity, depleted beneficial taxa, and altered metabolites such as short-chain fatty acids (SCFAs) and bile acids. Class-specific antibiotic effects were observed, with cephalosporins promoting Staphylococcus dominance and potentially reducing bile acid diversity. Necrotizing enterocolitis (NEC) samples showed SCFAs depletion and enrichment of antibiotic-resistant genera. In silico models further identified microbial contributors to SCFAs production and recapitulated metabolite trends. These findings demonstrate how antibiotic regimens can perturb the neonatal gut ecosystem and highlight the need for precision antibiotic stewardship to preserve microbiome-derived metabolic functions and reduce disease risk in preterm infants.