Timing of Full Enteral Feeding and Longitudinal Gut Microbiome Development in Infants Admitted to the Neonatal Intensive Care Unit

Abstract

Background/Objectives: Delayed achievement of full enteral feeding (FEF) is common in neonatal intensive care unit (NICU) infants but is closely linked to gestational age (GA). We examined whether time to FEF is associated with gut microbiome development from birth to 6 months of corrected age (CA) beyond GA. Methods: We profiled 694 stool samples from 328 NICU infants, collected at first stool, discharge, and 4- and 6-month CA, by 16S rRNA gene sequencing. Infants were classified as Early FEF (<14 days, n = 293) or Delayed FEF (≥14 days, n = 35), and time to FEF was also analyzed continuously. Linear mixed models and PERMANOVA were adjusted for GA. Results: Composition at first stool did not differ between groups. At discharge, the Delayed group had higher Proteobacteria, lower Firmicutes, lower Streptococcus (q = 0.028), and a different community structure in unadjusted analyses, but none of these differences remained after GA adjustment. No phylum showed a GA-adjusted trajectory difference, and alpha diversity did not differ. In an exploratory continuous analysis, longer time to FEF was associated with higher Bacteroidetes at discharge and 4-month CA. Conclusions: Most microbiome differences associated with delayed FEF were not independent of GA. Time to FEF may reflect maturity and illness severity rather than act as an independent determinant of the gut microbiome.