The gut microbiome of extremely preterm infants randomized to the early progression of enteral feeding

Ariel A Salas, Kent A Willis, Waldemar A Carlo, Nengjun Yi, Li Zhang, William J Van Der Pol, Noelle E Younge, Elliot J Lefkowitz, Charitharth V Lal, Ariel A Salas, Kent A Willis, Waldemar A Carlo, Nengjun Yi, Li Zhang, William J Van Der Pol, Noelle E Younge, Elliot J Lefkowitz, Charitharth V Lal

Abstract

Background: Early progression of feeding could influence the development of the gut microbiome.

Methods: We collected fecal samples from extremely preterm infants randomized to receive either early (feeding day 2) or delayed (feeding day 5) feeding progression. After study completion, we compared samples obtained at three different time points (week 1, week 2, and week 3) to determine longitudinal differences in specific taxa between the study groups using unadjusted and adjusted negative binomial and zero-inflated mixed models. Analyses were adjusted for a mode of delivery, breastmilk intake, and exposure to antibiotics.

Results: We analyzed 137 fecal samples from 51 infants. In unadjusted and adjusted analyses, we did not observe an early transition to higher microbial diversity within samples (i.e., alpha diversity) or significant differences in microbial diversity between samples (i.e., beta diversity) in the early feeding group. Our longitudinal, single-taxon analysis found consistent differences in the genera Lactococcus, Veillonella, and Bilophila between groups.

Conclusions: Differences in single-taxon analyses independent of the mode of delivery, exposure to antibiotics, and breastmilk feeding suggest potential benefits of early progression of enteral feeding volumes. However, this dietary intervention does not appear to increase the diversity of the gut microbiome in the first 28 days after birth.

Trial registration: ClinicalTrials.gov identifier: NCT02915549.

Impact: Early progression of enteral feeding volumes with human milk reduces the duration of parenteral nutrition and the need for central venous access among extremely preterm infants. Early progression of enteral feeding leads to single-taxon differences in longitudinal analyses of the gut microbiome, but it does not appear to increase the diversity of the gut microbiome in the first 28 days after birth. Randomization in enteral feeding trials creates appealing opportunities to evaluate the effects of human milk diets on the gut microbiome.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1. Feeding protocol to advance volumes…
Fig. 1. Feeding protocol to advance volumes according to feeding day.
Feeding volumes were advanced on either feeding day 2 or feeding day 5. Rates of feeding advancement were similar in both groups.
Fig. 2. Differences in microbial diversity between…
Fig. 2. Differences in microbial diversity between groups.
Differences in beta diversity according to advancing weeks of life were statistically significant in PERMANOVA and RDA analyses (a). Differences in beta diversity according to study group were not statistically significant by principal coordinate analysis (PCoA) of Bray–Curtis dissimilarity (PERMANOVA, R2 = 0.01, p = 0.09) or redundancy analysis (RDA, f = 1.41, p = 0.13). PERMANOVA permutational multivariate ANOVA, RDA redundancy analysis.
Fig. 3. Differences in microbial diversity between…
Fig. 3. Differences in microbial diversity between groups by week of life.
Significant differences in beta diversity between early and late feeding progression groups at three different time points (n = 57 at week 1, n = 42 at week 2, n = 38 at week 3) were not detected by principal coordinate analysis (PCoA) of Bray–Curtis dissimilarity. PERMANOVA permutational multivariate ANOVA.
Fig. 4. Taxonomic differences at the genus…
Fig. 4. Taxonomic differences at the genus level between groups according to week of life.
For the top 10 most common taxa at the genus level, there were no significant differences between groups at week 1 (n = 57). At week 2 (n = 42), the total read counts of Staphylococcus were higher in the late feeding group (p = 0.02). During week 3 (n = 38), no significant differences in the total read counts were found.
Fig. 5. Unadjusted and adjusted longitudinal analysis…
Fig. 5. Unadjusted and adjusted longitudinal analysis with negative binomial and zero-inflated mixed models to account for individual variability in the gut microbiome.
An unadjusted single-taxon analysis showed that Veillonella spp. counts were significantly higher in the early feeding group (a). An adjusted single-taxon analysis showed that Bilophila, Veillonella, and Lactococcus spp. were significantly higher in the early feeding group (b). The right labels denote statistically significant p values.

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