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Mechanisms affecting the gut of preterm infants in enteral feeding trials: A nested cohort within a randomised controlled trial of lactoferrin

Young, Gregory R.; Berrington, Janet E.; Cummings, Stephen; Dorling, Jon; Ewer, Andrew K.; Frau, Alessandra; Lett, Lauren; Probert, Christopher; Juszczak, Edmund; Kirby, John; Beck, Lauren C.; Renwick, Victoria L.; Lamb, Christopher A.; Lanyon, Clare; McGuire, William; Stewart, Christopher J.; Embleton, Nicholas D.


Gregory R. Young

Janet E. Berrington

Stephen Cummings

Jon Dorling

Andrew K. Ewer

Alessandra Frau

Lauren Lett

Christopher Probert

John Kirby

Lauren C. Beck

Victoria L. Renwick

Christopher A. Lamb

Clare Lanyon

William McGuire

Christopher J. Stewart

Nicholas D. Embleton


Objective: To determine the impact of supplemental bovine lactoferrin on the gut microbiome and metabolome of preterm infants.

Design: Cohort study nested within a randomised controlled trial (RCT). Infants across different trial arms were matched on several clinical variables. Bacteria and metabolite compositions of longitudinal stool and urine samples were analysed to investigate the impact of lactoferrin supplementation.

Setting: Thirteen UK hospitals participating in a RCT of lactoferrin.

Patients: 479 infants born <32 weeks’ gestation between June 2016 and September 2017.

Results: 10 990 stool and 22 341 urine samples were collected. Analyses of gut microbiome (1304 stools, 201 infants), metabolites (171 stools, 83 infants; 225 urines, 90 infants) and volatile organic compounds (314 stools, 117 infants) were performed. Gut microbiome Shannon diversity at 34 weeks corrected age was not significantly different between infants in the lactoferrin (mean=1.24) or placebo (mean=1.06) groups (p=0.11). Lactoferrin receipt explained less than 1% variance in microbiome compositions between groups. Metabolomic analysis identified six discriminative features between trial groups. Hospital site (16%) and postnatal age (6%) explained the greatest variation in microbiome composition.

Conclusions: This multiomic study identified minimal impacts of lactoferrin but much larger impacts of hospital site and postnatal age. This may be due to the specific lactoferrin product used, but more likely supports the findings of the RCT in which this study was nested, which showed no impact of lactoferrin on reducing rates of sepsis. Multisite mechanistic studies nested within RCTs are feasible and help inform trial interpretation and future trial design.


Young, G. R., Berrington, J. E., Cummings, S., Dorling, J., Ewer, A. K., Frau, A., …Embleton, N. D. (2023). Mechanisms affecting the gut of preterm infants in enteral feeding trials: A nested cohort within a randomised controlled trial of lactoferrin. Archives of Disease in Childhood. Fetal and Neonatal Edition, 108(3), 272-279.

Journal Article Type Article
Acceptance Date Oct 26, 2022
Online Publication Date Nov 17, 2022
Publication Date 2023-05
Deposit Date Nov 2, 2022
Publicly Available Date Nov 17, 2022
Journal Archives of Disease in Childhood. Fetal and Neonatal Edition
Electronic ISSN 1468-2052
Peer Reviewed Peer Reviewed
Volume 108
Issue 3
Pages 272-279
Public URL
Publisher URL


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