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

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.

Exploring functional metabolites in preterm infants.

AIM: Metabolomics is the study of small molecules that represent the functional end points of cellular reactions that can impact health. Necrotising enterocolitis (NEC) and late onset sepsis (LOS) are the main cause of death in preterm infants surviving the initial days of life. METHODS: This review will explore and summarise the current literature exploring metabolomics in preterm infants. RESULTS: There are a relatively limited number of studies investigating metabolomics in preterm infants with NEC and/or LOS and matched controls. Nonetheless, it is evident across longitudinally age-related metabolomic studies that there are significant changes in metabolite profiles post-partum and over the first year of life. Existing studies have reported associations between the metabolite profiles of serum, urine and stool in health and disease in preterm infants. Although some studies have found selected metabolites are associated with disease, the specific metabolites vary from study to study, and larger studies are required. Excitingly, recent work has also begun to untangle how microbially produced metabolites can impact immunoregulation of the infant. CONCLUSION: Metabolic exploration is an emerging research area with huge potential for developing novel biomarkers and better understanding disease processes in preterm infants.