Mechanisms Affecting the Gut of Preterm Infants in Enteral Feeding Trials

Abstract

Large randomized controlled trials (RCTs) in preterm infants offer unique opportunities for mechanistic evaluation of the risk factors leading to serious diseases, as well as the actions of interventions designed to prevent them. Necrotizing enterocolitis (NEC) a serious inflammatory gut condition and late-onset sepsis (LOS) are common feeding and nutrition-related problems that may cause death or serious long-term morbidity and are key outcomes in two current UK National Institutes for Health Research (NIHR) trials. Speed of increasing milk feeds trial (SIFT) randomized preterm infants to different rates of increases in milk feeds with a primary outcome of survival without disability at 2 years corrected age. Enteral lactoferrin in neonates (ELFIN) randomizes infants to supplemental enteral lactoferrin or placebo with a primary outcome of LOS. This is a protocol for the mechanisms affecting the gut of preterm infants in enteral feeding trials (MAGPIE) study and is funded by the UK NIHR Efficacy and Mechanistic Evaluation programme. MAGPIE will recruit ~480 preterm infants who were enrolled in SIFT or ELFIN. Participation in MAGPIE does not change the main trial protocols and uses non-invasive sampling of stool and urine, along with any residual resected gut tissue if infants required surgery. Trial interventions may involve effects on gut microbes, metabolites (e.g., short-chain fatty acids), and aspects of host immune function. Current hypotheses suggest that NEC and/or LOS are due to a dysregulated immune system in the context of gut dysbiosis, but mechanisms have not been systematically studied within large RCTs. Microbiomic analysis will use next-generation sequencing, and metabolites will be assessed by mass spectrometry to detect volatile organic and other compounds produced by microbes or the host. We will explore differences between disease cases and controls, as well as exploring the actions of trial interventions. Impacts of this research are multiple: translation of knowledge of mechanisms promoting gut health may explain outcomes or suggest alternate strategies to improve health. Results may identify new non-invasive diagnostic or monitoring techniques, preventative or treatment strategies for NEC or LOS, or provide data useful for risk stratification in future studies. Mechanistic evaluation might be especially informative where there are not clear effects on the primary outcome (ISRCTN 12554594).

Immunonutrition for Preterm Infants

“…These include harnessing the immunological benefits of maternal breast milk or its beneficial components; minimising exposure to invasive procedures such as intravascular access devices by optimising early enteral feeding strategies; exploring the role of particular micronutrients such as conditionally essential amino acids; and avoiding interventions that compromise innate immunity, such as use of gastric acid suppressants [10]. …”

“…Another option is instilling these small amounts (typically < 0.5 mL) into the infant’s oropharyngeal cavity [22]. The rationale for this approach is that the oral epithelium contains receptors for the immunological and trophic factors in colostrum and that oropharynx-associated lymphoid tissue is a key interface between the infant’s immune system and the enteric microbial flora [10]. Trial evidence of benefits is currently limited, but large, high-quality randomised controlled trials to evaluate more precisely and reliably the effects of oropharyngeal colostrum on outcomes for preterm infants are planned or in progress [22, 23].…”

“…The possibility that the immunonutritive benefits of human breast milk in preterm infants are mediated via factors such as secretory immunoglobulin A and lactoferrin has generated interest and research efforts to assess whether enteral supplementation with these individual components might protect very preterm infants against NEC and late-onset infection [10]. …”

“…Probiotic microorganisms predominate in the intestinal microbiome of breastfed term infants. Very preterm infants, however, tend to harbour fewer probiotic microorganisms and more potential pathogens, which might be due to dysbiotic effects of enteral fasting and antibiotic exposure [10]. Furthermore, the intestinal microbiome in preterm infants who develop NEC or late-onset infection is less diverse and contains fewer bifidobacteria than that in healthy preterm infants.…”

Enteral Lactoferrin Supplementation for Very Preterm Infants: A Randomised Controlled Trial

“…aspx possibility that the immunoprotective and prebiotic properties of lactoferrin might act synergistically with probiotic supplementation. 27 Although the ELFIN trial did not show any evidence of diferential efects depending upon whether infants had received probiotics during the trial period, the data are not suicient to exclude the possibility that such prebiotic-probiotic synergism exists. A 2017 large cluster RCT 28 in India has suggested that prophylactic administration of an oral synbiotic (prebiotic fructo-oligosaccharide combined with probiotic Lactobacillus plantarum) reduces infection and mortality in late-preterm or term newborn infants.…”