Abstract
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.
| Original language | English |
|---|---|
| Article number | 324477 |
| Journal | Archives of Disease in Childhood: Fetal and Neonatal Edition |
| DOIs | |
| Publication status | Accepted/In press - 2022 |
| Externally published | Yes |
Bibliographical note
Funding Information:JEB, NE and CS report grants to their institutions from Prolacta Biosciences US (Duarte, CA, USA), grants from Danone Early Life Nutrition (Paris, France) and personal fees from Nestlé Nutrition Institute (La Tour-de-Peilz, Switzerland). JD reports grants from the National Institute for Health Research (NIHR) during the conduct of the study and has been a member of the Health Technology Assessment (HTA) Efficient Study Designs; HTA Maternity, Newborn and Child Health (MNCH) Panel (2013-18); HTA General Board (2017-18); and HTA Post-Funding Committee teleconference. JD also reports grants from NIHR and Nutricia. Professor Juszczak reports grants from the National Institute for Health Research (NIHR) during the conduct of the study and was a member of the NIHR HTA General Board from (2016-17) and the HTA commissioning Board (2013-16). AKE reports grants from the NIHR.
Funding Information:
The MAGPIE study was funded by the Efficacy and Mechanistic Evaluation programme (EME) (Project Reference Number 13/122/02). The EME Programme is funded by the Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR). The Speed of Increases in Feeds Trial (SIFT) and the Enteral Lactoferrin in Neonates trial (ELFIN) were funded by the Health Technology Assessment programme of the UK NIHR. VLR also received PhD support from NECUK (registered charity 1181026). CL was an Academic Clinical Lecturer supported by the NIHR. The other authors received no additional funding. All funders did not participate in the work or have any influence on study design or conduct, data collection, management, interpretation of results, manuscript review or preparation.
Funding Information:
We gratefully acknowledge the research teams at individual recruiting sites (detailed online: https://doi.org/10.3310/eme08140 ), support from Chris Price and all the R&D department at Newcastle Hospitals NHS Trust, and all the parents who agreed for their baby to join the study. We acknowledge support from the NIHR Newcastle Biomedical Research Centre. We also gratefully acknowledge the members of the Trials Steering Committee: Professor Ben Stenson (chair), Professor Jonathan Wyllie, Dr Anne Dale and Ms Sharon McLeod (parent representative). Dr Anne Dale sadly died before this paper was published, and we would like to especially acknowledge her generosity in supporting our work. Mark Shirley and Steve Rushton (SNES, Newcastle University) aided in study design. Warwick Dunn and team (Phenome Centre, University of Birmingham) provided LCMS data of stool and urine. Darren Smith and Andrew Nelson (NUOMICS, Northumbria University) provided 16S rRNA sequencing data.
Publisher Copyright:
© 2022 Author(s). Published by BMJ.
ASJC Scopus Subject Areas
- Pediatrics, Perinatology, and Child Health
- Obstetrics and Gynaecology
PubMed: MeSH publication types
- Journal Article