Most microbiome differences associated with delayed full enteral feeding were not independent of gestational age, suggesting that time to full enteral feeding may reflect maturity and illness severity rather than act as an independent determinant of the gut microbiome.
Key Findings
Results
Gut microbiome composition at first stool did not differ between Early FEF and Delayed FEF groups.
Infants were classified as Early FEF (achieving full enteral feeding in <14 days, n = 293) or Delayed FEF (≥14 days, n = 35)
694 stool samples from 328 NICU infants were profiled using 16S rRNA gene sequencing
Samples were collected at first stool, discharge, and 4- and 6-month corrected age (CA)
No significant differences in community composition were detected at the first stool timepoint between the two groups
Results
At discharge, the Delayed FEF group had higher Proteobacteria, lower Firmicutes, lower Streptococcus, and a different community structure compared to Early FEF, but only in unadjusted analyses.
Lower Streptococcus was statistically significant at q = 0.028 in unadjusted analysis
Community structure differences were detected by PERMANOVA in unadjusted analyses
None of these differences remained statistically significant after adjustment for gestational age (GA)
Linear mixed models and PERMANOVA analyses were both adjusted for GA
Results
No phylum-level microbiome trajectory differences between Early FEF and Delayed FEF groups were significant after adjustment for gestational age.
Longitudinal trajectories from birth to 6 months corrected age were examined
No phylum showed a GA-adjusted trajectory difference between the two groups
Alpha diversity did not differ between Early and Delayed FEF groups at any timepoint after GA adjustment
Analyses covered four timepoints: first stool, discharge, 4-month CA, and 6-month CA
Results
In a continuous analysis, longer time to full enteral feeding was associated with higher Bacteroidetes at discharge and 4-month corrected age.
This was described as an 'exploratory continuous analysis' where time to FEF was analyzed as a continuous variable rather than a binary classification
The association with higher Bacteroidetes was observed at discharge and at 4-month CA
This finding was identified as exploratory in nature
The association was not described as persisting to 6-month CA
Background
Delayed achievement of full enteral feeding is common in NICU infants and is closely linked to gestational age.
The study enrolled 328 NICU infants with 694 stool samples collected longitudinally
35 infants (approximately 10.7% of the cohort) were classified as Delayed FEF (≥14 days)
293 infants (approximately 89.3%) were classified as Early FEF (<14 days)
Gestational age was identified as a key confounding variable requiring adjustment in all primary analyses
Discussion
Time to full enteral feeding appears to reflect neonatal maturity and illness severity rather than independently determining gut microbiome development.
After adjusting for gestational age, the majority of microbiome differences associated with delayed FEF disappeared
The authors concluded that time to FEF 'may reflect maturity and illness severity rather than act as an independent determinant of the gut microbiome'
GA adjustment was applied to both compositional (PERMANOVA) and abundance (linear mixed models) analyses
The findings suggest GA is the primary driver of observed microbiome differences rather than feeding timing per se
What This Means
This research examined whether the timing of when premature or sick newborns in the neonatal intensive care unit (NICU) achieve full feeding through the gut — rather than through intravenous lines — affects how their gut bacterial communities develop over the first six months of life. Researchers collected stool samples from 328 NICU babies at four timepoints (shortly after birth, at hospital discharge, and at 4 and 6 months of corrected age) and used genetic sequencing to identify the bacteria present. Babies who took 14 days or more to reach full gut feeding were compared to those who achieved it sooner.
The study found that while delayed feeding was associated with differences in gut bacterial composition at hospital discharge — including more potentially harmful Proteobacteria and less Firmicutes — these differences disappeared once the babies' gestational age (how premature they were) was taken into account. In other words, it appeared to be the babies' prematurity itself, rather than the delay in feeding, that explained the microbiome differences. A separate analysis treating feeding timing as a continuous measure did find that longer time to full feeding was linked to more Bacteroidetes bacteria at discharge and at 4 months, but this was considered exploratory.
This research suggests that efforts to improve gut bacterial development in NICU infants should focus on understanding the role of prematurity and overall illness severity, rather than targeting feeding timing alone as an independent factor. The findings highlight how difficult it is to separate the effects of feeding practices from the underlying biology of premature birth when studying the neonatal gut microbiome.
Shin J, Kim H, Kim S, Kang H, Youn Y. (2026). Timing of Full Enteral Feeding and Longitudinal Gut Microbiome Development in Infants Admitted to the Neonatal Intensive Care Unit.. Nutrients. https://doi.org/10.3390/nu18193262