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Prenatal Immunity and Influences on Necrotizing Enterocolitis and Associated Neonatal Disorders.
Sampah, MES, Hackam, DJ
Frontiers in immunology. 2021;:650709
Abstract
Prior to birth, the neonate has limited exposure to pathogens. The transition from the intra-uterine to the postnatal environment initiates a series of complex interactions between the newborn host and a variety of potential pathogens that persist over the first few weeks of life. This transition is particularly complex in the case of the premature and very low birth weight infant, who may be susceptible to many disorders as a result of an immature and underdeveloped immune system. Chief amongst these disorders is necrotizing enterocolitis (NEC), an acute inflammatory disorder that leads to necrosis of the intestine, and which can affect multiple systems and have the potential to result in long term effects if the infant is to survive. Here, we examine what is known about the interplay of the immune system with the maternal uterine environment, microbes, nutritional and other factors in the pathogenesis of neonatal pathologies such as NEC, while also taking into consideration the effects on the long-term health of affected children.
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A Review of the Immunomodulating Components of Maternal Breast Milk and Protection Against Necrotizing Enterocolitis.
Nolan, LS, Parks, OB, Good, M
Nutrients. 2019;(1)
Abstract
Breast milk contains immunomodulating components that are beneficial to newborns during maturation of their immune system. Human breast milk composition is influenced by an infant's gestational and chronological age, lactation stage, and the mother and infant's health status. Major immunologic components in human milk, such as secretory immunoglobulin A (IgA) and growth factors, have a known role in regulating gut barrier integrity and microbial colonization, which therefore protect against the development of a life-threatening gastrointestinal illness affecting newborn infants called necrotizing enterocolitis (NEC). Breast milk is a known protective factor in the prevention of NEC when compared with feeding with commercial formula. Breast milk supplements infants with human milk oligosaccharides, leukocytes, cytokines, nitric oxide, and growth factors that attenuate inflammatory responses and provide immunological defenses to reduce the incidence of NEC. This article aims to review the variety of immunomodulating components in breast milk that protect the infant from the development of NEC.
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Necrotizing Enterocolitis and the Preterm Infant Microbiome.
Baranowski, JR, Claud, EC
Advances in experimental medicine and biology. 2019;:25-36
Abstract
Bacterial colonization patterns in preterm infants differ from those of their term counterparts due to maternal microbial diversity, delivery mode, feeding methods, antibiotic use, and exposure to commensal microbiota and pathogens in the neonatal intensive care unit (NICU). Early gut microbiome dysbiosis predisposes neonates to necrotizing enterocolitis (NEC), a devastating intestinal disease with high morbidity and mortality. Though mechanisms of NEC pathogenesis are not fully understood, the microbiome is a promising therapy target for prevention and treatment. Direct administration of probiotics to preterm infants has been shown to reduce the incidence of NEC, but is not without risk. The immature immune systems of preterm infants leave them vulnerable to even beneficial bacteria. Further research is required to investigate both short-term and long-term effects of probiotic administration to preterm infants. Other methods of altering the preterm infant microbiome must also be considered, including breastfeeding, prebiotics, and targeting the maternal microbiome.
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Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis in preterm infants: A PRISMA-compliant systematic review and meta-analysis.
He, Y, Cao, L, Yu, J
Medicine. 2018;(35):e11976
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Abstract
BACKGROUND Currently, prophylactic use of drugs to promote a healthy gut microbiota and immune system in preterm infants is hot debated, among which lactoferrin is a promising supplementation. However, the effect and safety of lactoferrin to prevent late-onset sepsis (LOS) and necrotizing enterocolitis (NEC) in preterm infants remains controversial. METHODS Databases including Medline, Ovid-Embase, The Cochrane Library, CBM, CNKI, and VIP database of Chinese Journal were searched to collect randomized controlled trials (RCTs) about lactoferrin for preventing LOS and NEC in preterm infants. Languages of included RCTs were restricted to English and Chinese. Meta-analysis was conducted by Rev Man 5.3 software. The Mantel-Haenszel method with random-effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs). RESULTS A total of 9 RCTs, involving 1834 patients, were included. Pooled analysis showed that prophylactic lactoferrin could significantly reduce the incidence all culture-proven LOS (41/629 [6.5%] vs 96/659 [15.3%]; RR 0.47; 95% CI 0.33-0.67; P < .01) and NEC (stage II or more) (9/448 [2.0%] vs 26/462 [5.6%]; RR 0.40; 95% CI 0.18-0.86; P < .01). Lactoferrin was also associated with a significantly decreased hospital-acquired infection (16/139 [11.5%] vs 35/140 [25%]; RR 0.47; 95% CI 0.27-0.80; P < .01); and infection-related mortality (4/474 [0.8%] vs 25/505 [4.9%]; RR 0.24; 95% CI 0.04-1.32; P < .01, I = 53%). Lactoferrin could shorten time to reach full enteral feeding (weighted mean difference [WMD] = -2.11, 95% CI -3.12 to -1.10; P < .01) and showed a decreasing trend of duration of hospitalization (WMD = -1.69, 95% CI -6.87 to 3.50; P < .01; I = 95%). Lactoferrin did not have a significant effect on all-cause mortality (22/625 [3.5%] vs 35/647 [5.4%]; RR 0.70; 95% CI 0.38-1.30; P = .16; I = 13%). None of the included trials reported any confirmed adverse effects caused by the supplemented lactoferrin or probiotics. CONCLUSION Current evidence indicates that lactoferrin could significantly reduce the incidence of NEC and LOS, and decrease the risk of hospital-acquired infection and infection-related mortality in premature infants without obvious adverse effects.
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Probiotics, Prebiotics, and Synbiotics for the Prevention of Necrotizing Enterocolitis.
Johnson-Henry, KC, Abrahamsson, TR, Wu, RY, Sherman, PM
Advances in nutrition (Bethesda, Md.). 2016;(5):928-37
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Abstract
Necrotizing enterocolitis (NEC) is a devastating intestinal disease in preterm infants characterized by barrier disruption, intestinal microbial dysbiosis, and persistent inflammation of the colon, which results in high mortality rates. Current strategies used to manage this disease are not sufficient, although the use of human breast milk reduces the risk of NEC. Mother's milk is regarded as a fundamental nutritional source for neonates, but pasteurization of donor breast milk affects the composition of bioactive compounds. Current research is evaluating the benefits and potential pitfalls of adding probiotics and prebiotics to pasteurized milk so as to improve the functionality of the milk and thereby reduce the burden of illness caused by NEC. Probiotics (live micro-organisms that confer health to the host) and prebiotics (nondigestible oligosaccharides that stimulate the growth of healthy bacteria) are functional foods known to mediate immune responses and modulate microbial populations in the gut. Clinical research shows strain- and compound-specific responses when probiotics or prebiotics are administered in conjunction with donor breast milk for the prevention of NEC. Despite ongoing controversy surrounding optimal treatment strategies, randomized controlled studies are now investigating the use of synbiotics to reduce the incidence and severity of NEC. Synbiotics, a combination of probiotics and prebiotics, have been proposed to enhance beneficial health effects in the intestinal tract more than either agent administered alone. This review considers the implications of using probiotic-, prebiotic-, and synbiotic-supplemented breast milk as a strategy to prevent NEC and issues that could be encountered with the preparations.
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Oral lactoferrin to prevent nosocomial sepsis and necrotizing enterocolitis of premature neonates and effect on T-regulatory cells.
Akin, IM, Atasay, B, Dogu, F, Okulu, E, Arsan, S, Karatas, HD, Ikinciogullari, A, Turmen, T
American journal of perinatology. 2014;(12):1111-20
Abstract
OBJECTIVE Lactoferrin (LF) is effective in the prevention of sepsis in very low birth weight (VLBW) neonates. T-regulatory cells (Tregs) are important subsets of T lymphocytes that control pathogen-specific immune responses and are essential for intestinal immune homoeostasis. The aim of the present study is to determine whether oral LF at a dosage of 200 mg/d reduces nosocomial sepsis episodes and necrotizing enterocolitis (NEC) in premature infants and to evaluate the possible effects of LF on Treg levels. STUDY DESIGN In this prospective, placebo-controlled, double-blind, randomized trial, infants either VLBW or born before 32 weeks were assigned to receive either placebo (n = 25), or 200 mg LF (n = 25) daily throughout hospitalization. Episodes of culture proven nosocomial sepsis and NEC were recorded. The level of FOXP3 + CD4 + CD25hi lymphocytes was studied by flow cytometry at birth and discharge. A third comparison was made with healthy term neonates (n = 16). RESULTS Fewer sepsis episodes were observed in LF-treated infants (4.4 vs. 17.3/1,000 patient days, p = 0.007) with none developing NEC, without statistical significance. Treg levels at birth and discharge were similar, while preterm infants showed significantly lower levels than term controls. However, individual increases in Treg levels were higher in the LF group. CONCLUSION LF prophylaxis reduced nosocomial sepsis episodes. Treg levels in preterm infants were lower than in term infants and an increase of Treg levels under LF prophylaxis was observed. Increase in Treg levels can be the mechanism for protective effects of LF on nosocomial sepsis.
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Probiotics in the prevention of necrotizing enterocolitis.
Ganguli, K, Walker, WA
Journal of clinical gastroenterology. 2011;:S133-8
Abstract
Necrotizing enterocolitis (NEC) is a common gastrointestinal inflammatory necrosis affecting almost exclusively premature infants usually after oral nutrition has been started, for example, 10 day plus postpartum. Although the pathogenesis is incompletely understood, major risk factors include prematurity and incomplete bacterial colonization. Evidence has been shown that the premature infant because of rapid passage through the birth canal or because of delivery by cesarean section has an inadequate initial ingestion of maternal colonic and vaginal flora and therefore, an inadequate initial colonization with less diversity of bacteria phylla and fewer species of bacteria in the microbiota. As a result, they are more susceptible to environmental pathogens. In addition, prematures have immature intestinal defenses (glycocalyx, tight junctions, innate immune response, etc.) resulting in excessive inflammation in response to luminal stimuli. Recently, we reported that genes mediating the innate inflammatory immune response are developmentally expressed with an increase in toll-like receptors, signaling molecules and transgenic factors and decreased negative regulators of inflammation, which undoubtedly contribute to an excessive inflammatory response. Several clinical studies have suggested that the use of probiotics and ingestion of expressed maternal breast milk containing probiotics can help to stabilize colonization and to reduce the incidence and severity of NEC when given to premature infants at risk. Meta-analyses of multiple small studies strongly suggest a protective effect in the use of probiotics. A multicenter study in Taiwan suggests that Bifidobacteria infantis and Lactobacillus acidophilus in combination may prevent NEC. These meta-analyses suggest that these probiotics should be used in routine care of premature infants. Other clinicians, however, suggest caution, holding out for a single protocol multicenter trial before routine use can be suggested.
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Probiotics for prevention of necrotizing enterocolitis in preterm infants.
Alfaleh, K, Bassler, D
The Cochrane database of systematic reviews. 2008;(1):CD005496
Abstract
BACKGROUND Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and associated morbidity. OBJECTIVES To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and/or sepsis in preterm infants. SEARCH STRATEGY The standard search strategy for the Cochrane Neonatal Review Group was performed by two review authors. Searches were made of MEDLINE (1966 to December 2006), EMBASE (1980 to December 2006), Cochrane Library Controlled Trials Register (CENTRAL, The Cochrane Library Issue 3, 2006), and abstracts of annual meetings of the Society for Pediatric Research (1995 - 2006). The authors of published articles were contacted. SELECTION CRITERIA Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age and/or < 2500 g birth weight were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome. DATA COLLECTION AND ANALYSIS Standard methods of the Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials. Retrieved articles were assessed for eligibility and data abstracted independently by two review authors. Where data were incomplete, the primary investigator were contacted for further information and clarification. Where appropriate, data of individual trials were combined using meta-analytic techniques to provide a pooled estimate of effect assuming a fixed effect model. MAIN RESULTS Nine eligible trials randomizing 1425 infants were included. Included trials were highly variable with regard to enrollment criteria (i.e. birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) [typical RR 0.32 (95% CI 0.17, 0.60)] and mortality [typical RR 0.43 (95% CI 0.25, 0.75]. There was no evidence of significant reduction of nosocomial sepsis [typical RR 0.93 (95% CI 0.73, 1.19)] or days on total parenteral nutrition (TPN) [WMD -1.9 (95% CI -4.6, 0.77)]. The included trials reported no systemic infection with the probiotics supplemental organism. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant. AUTHORS' CONCLUSIONS Enteral supplementation of probiotics reduced the risk of severe NEC and mortality in preterm infants. This analysis supports a change in practice in premature infants > 1000 g at birth. Data regarding outcome of ELBW infants could not be extracted from the available studies; therefore, a reliable estimate of the safety and efficacy of administration of probiotic supplements cannot be made in this high risk group. A large randomized controlled trial is required to investigate the potential benefits and safety profile of probiotics supplementation in ELBW infants.
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Addressing the "New" NEC: Part I: rediscovering the basics.
Simmonds, A, LaGamma, EF
Indian journal of pediatrics. 2006;(11):1011-8
Abstract
Epithelial cell functions ultimately define the ability of the extremely low birth weight human fetus to survive outside of the uterus. These specialized epithelial cell capacities manage all human interactions with the ex utero world including: (i) lung mechanics, surface chemistry and gas exchange, (ii) renal tubular balance of fluid and electrolytes, (iii) barrier functions of the intestine and skin for keeping bacteria out and water in, plus enabling intestinal digestion, as well as (iv) maintaining an intact neuroepithelium lining of the ventricles of the brain and retina. In Part I of this two part review, the authors describe why the gut barrier is a clinically relevant model system for studying the complex interplay between innate and adaptive immunity, dendritic &epithelial cell interactions, intraepithelial lymphocytes, M-cells, as well as the gut associated lymphoid tissues where colonization after birth, clinician feeding practices, use of antibiotics as well as exposure to prebiotics, probiotics and maternal vaginal flora all program the neonate for a life-time of immune competence distinguishing "self" from foreign antigens. These barrier defense capacities become destructive during disease processes like necrotizing enterocolitis (NEC) when an otherwise maturationally normal, yet dysregulated and immature, immune defense system is associated with high levels of certain inflammatory mediators like TNFa. In Part II, the authors will discuss the theoretical advantages of using rhG-CSF in managing NEC or sepsis by augmenting neonatal neutrophil number and killing capacity including an unexpected, paradoxical and potent anti-TNFa function that may serve to limit extension of tissue destruction without impairing bacterial killing capacity. The authors conclude by arguing that NEC may be the ideal disease process for testing whether a clearly defined clinical benefit of cytokine therapy can prove beneficial.