Review
Hell J Surg. 2024 Oct-Dec;94(3):142–150
doi: 10.59869/24038
Anastasia Dimopoulou1, Konstantina Dimopoulou2, Dimitra Dimopoulou3, Emmanouil Iakomidis4, Efrosini Tsekoura5, Nikolaos Zavras6
1Department of Paediatric Surgery, Children’s General Hospital “Aghia Sophia”, Athens, Greece
2Department of Gastroenterology, Korgialenio-Benakio Red Cross Hospital, Athens, Greece
3Second Department of Pediatrics, Children’s General Hospital “Aghia Sophia”, Athens, Greece
4Third Department of Paediatric Surgery, Mitera Children’s Hospital, Athens, Greece
5Department of Paediatrics, Asklepieion Voula’s General Hospital, Athens, Greece
6Department of Paediatric Surgery, “Attikon” General University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
Correspondence: Anastasia Dimopoulou, Department of Paediatric Surgery, “Aghia Sophia” Children’s Hospital, Thivon and Papadiamantopoulou Str, 11527 Athens, Greece, Tel.: +30 210 7467218, e-mail: natasa_dimo@hotmail.com
Abstract
Necrotising enterocolitis remains (NEC) a major source of morbidity and mortality among preterm infants. The use of breast milk is a major protective factor against NEC, with its anti-infective nutritional and immunological properties. Breast milk, expressed either from the mother’s own milk, or in the form of pasteurised donor milk, is the preferred nutritional source of enteral feeding for very low and extremely birth weight infants. Although there is a lack of definite data, breast milk is superior to preterm commercial formulas. However, breast milk seems not only to protect the immature bowel of preterm neonates but also treat the immature host defense system of the gut. The present review presents the currently available data in the literature on the diverse aspects of the role of breast milk not only as a useful feeding strategy to prevent NEC, but also as a means to treat the immature gut of preterm infants.
Key Words: Breast milk, intestinal microbiota, necrotising enterocolitis, premature neonates, preterm formula
Submission: 18.12.2024, Acceptance: 20.12.2024
INTRODUCTION
Necrotising enterocolitis (NEC) is the most common acquired neonatal disease of the gastrointestinal tract (GIT). The pathogenesis of NEC is not clearly elucidated and consequently questions arise on how to treat or prevent the disease [1]. NEC incidence may vary significantly between different neonatal intensive care units. The overall prevalence of NEC is estimated to be 1 to 3 per 1000 live births [2]. Ninety per cent of NEC affected neonates are premature, and 14% of them are weighing less than 1000g. Notably, 50% of the extremely low birth weight neonates may need a surgical intervention. Despite advancements in the treatment of NEC, the mortality rates in premature neonates remains high, ranging from 10% to 50% [1,2].
Advances in medical knowledge have demonstrated that breast milk (BM) is the most favourable source of nutrition of neonates and its health, nutritional, immunological, developmental, and physiological benefits are universally established [3]. In addition, numerous studies have shown that BM minimises the occurrence and severity of NEC in premature neonates by reducing the influence of risk factors in the development of NEC [4,5]. On the basis of these data, the present review aims to investigate the effectiveness of BM in the management of NEC. We sought to test the hypothesis that after reviewing the current literature, we could propose BM not only as a means to prevent NEC, but as a modulator of the immature gut of premature neonates.
METHODS
The review of the literature was performed through PubMed and Google Scholar databases. Inclusion criteria concerned original and review articles, systematic reviews and meta-analyses published from January 1, 1980 to December 31, 2023, without language restrictions. The search strategy was performed using the Boolean operators AND/OR. The search terms used were: human milk OR breast milk OR breast feeding OR enteral nutrition OR donor milk OR human-milk- based fortifiers AND premature neonates OR low birth weight neonates OR very low birth weight neonates OR extremely low birth weight neonates AND intestinal microbiota OR bioactive factors AND necrotizing enterocolitis OR experimental necrotizing enterocolitis OR intestinal inflammation. Furthermore, the references of the articles were investigated by hand for related articles. All articles were selected systematically for inclusion and critically evaluated.
Necrotizing enterocolitis
- Factors associated with pathogenesis of NEC in premature neonates
Although it is generally accepted that NEC is a multifactorial disease, preterm birth, the gastrointestinal microbiota and the intestinal immaturity are the major risk factors for the pathogenesis of NEC in premature neonates. Intrauterine infection is the leading cause of preterm birth and recent research focuses on the association of uterine microbiome and preterm birth [6]. The role of gastrointestinal microbiota is very important in protecting mucosal integrity and alterations in its synthesis may lead to sepsis, NEC and systemic inflammatory bowel disease. Intestinal immaturity related factors such as impaired gut motility, digestion, absorption, barrier function, immune defense and circulatory regulation, may be responsible for the pathogenesis of NEC in premature neonates [7]. Furthermore, additional factors such as genetics, the type of diet, e.g. human milk versus formula, the exposure to antibiotics and the mode of delivery, all may contribute to NEC development [8-10].
- Gastrointestinal microbiota: from fetal life to early postnatal days
2a. Fetal gastrointestinal microbiota
Although GIT is thought to be sterile in normal fetuses, with microbial colonisation of the gut beginning at birth from vaginal bacteria in vaginal delivery or from maternal skin surface and the surrounding milieu in caesarian section, cultured-dependent studies have discovered microorganisms in amniotic fluid, fetal membranes, umbilical cord, and placenta [11]. Moreover, several studies based on non-cultured dependent studies by using high throughput 16S ribosomal RNA gene analysis, revealed the presence of substantially diverse assemblages of bacteria, such as Enterococci and Staphylococci, isolated from human meconium, obviously suggesting that this material was composed during fetal life [12,13].
2b. Early postnatal life
The early postnatal life comprises a period of roughly 7-9 days, during the course of which the development of intestinal microbiota is settled [14]. In full-term neonates, the first bacteria that colonize the intestine include Streptococcus, Staphylococcus, Escherichia coli, Lactobacillus, and Enterobacter species. These bacteria by consuming oxygen produce a low oxygen environment, giving the opportunity to grow and, finally, prevail anaerobic bacteria species such as Clostridia, Bifidobacterium species and members of Firmicutes phyla [14]. However, other factors, including the mode of delivery and diet play a significant role in the initial colonization. More specifically, neonates born vaginally are seeded with maternal vaginal flora, such as Lactobacillus and Prevotella species, while those born by caesarian section are colonised by skin flora, such as Staphylococcus and Corynebacterium [15]. Moreover, neonates born by caesarian delivery show a decreased amount of Bifidobacteria and a delay in colonization [15]. BM is another potential provider of bacteria to the neonatal gut such as Staphylococcus, Streptococcus, Lactobacillus and Weissella species. Nevertheless, full term neonates fed with formula show a different microbial pattern, promoting the presence of Enterobacteriaceae, Bacteroides species, and Clostridium difficile [16]. Yet, there is a controversy concerning the amount of Bifidobacteria provided by formula fed neonates, which may reflect the different composition of formulas [15].
Preterm neonates are characterised by some unique characteristics, usually derived from an unexpected delivery due to an inflammation of the maternal/fetal membrane. For instance, preterm neonates are fed earlier and usually by formula milk, they are exposed to antibiotics and they are usually grown up in a hospital environment that is host to many atypical bacteria [16]. Consequently, the preterm intestinal microbiota is characterised by a decreased overall diversity and a different microbial load than those of full-term neonates, consisted by bacteria, such as Escherichia coli, Staphylococcus and Klebsiella species, facultative anaerobes, such as Enterobacteriaceae, Enterococcaceae, and Weissella and decreased proportion of beneficial bacteria such as Bifiiobacteria and Lactobacillus [17].
2c. The impact of the preterm intestinal microbiota in the pathogenesis of NEC
Intestinal dysbiosis with lower microbiota diversity has been found to be related with the development of NEC in preterm neonates. Mai et al. [17], by comparing the intestinal microbiota of premature neonates with NEC with this of unaffected control neonates, found an increase of 34% of Proteobacteria and a decrease of 32% of Firmicutes, in samples collected one week but less than 72 hours prior to NEC, but not in matched samples. Similarly, Torrazza et al. [11], by analysing fecal samples of premature neonates, using 16S rRNA methods, at two, one and zero weeks prior to NEC development, found a higher proportion of phylum Proteobacteria (61%) and Actinobacteria (3%) two weeks and one week respectively compared to controls, and lower numbers of Bifidobacteria and Bacteroides. Additionally, certain bacteria of the Klebsiella genus were found before the NEC presentation. A prospective control study evaluated the intestinal microbiota between premature neonates, who developed NEC, and unaffected controls. They revealed that in the early onset of NEC, the abundances of Clostridium sensu stricto were much higher than those of case controls, while in the late onset of NEC, Gammaproteobacteria (Escherichia coli, Shigella, and Cronobacter) predominated and were significantly higher than controls [18]. They suggested that the precise infectious agent of NEC may change by the age of premature neonates, while antibiotics administration may have an impact on the microbial diversity [18]. Moreover, in a control study, Heidi et al. [19] reported the existence and plethora of Clostridium perfringens and Bacteroides dorei in meconium samples of preterm neonates (aged 24-29 weeks) who developed NEC, compared to those who did not. They suggested that the pre-existence of a NEC-linked gut microbiota with Clostridium perfringens and Bacteroides dorei in the meconium, predisposes to a NEC-associated microbiota development. Conflicting are the findings of Wang et al. [20] and McMurtry et al. [21]. The former noticed low microbiota diversity in neonates with NEC, an increase in Gammaproteobacteria and decrease in other bacteria species, suggesting the impact of a single dominant microorganism responsible for NEC. The latter reported that bacterial diversity tended to decrease with the severity of NEC and lack of Clostridia in lethal cases of NEC, suggesting the perception of bacterial dysbiosis. In summary, it seems that the intestinal microbiota of preterm neonates, who develop NEC later, is different than those who do not. Most studies suggest that there is not a distinct pattern of intestinal colonisation associated with NEC development, while the age of onset may be an additional contributing factor to the microbial colonisation of the intestine.
- The GIT host defense system
3a. Physical barriers
Epithelial cells represent the physical barrier of the intestinal lumen from the other parts of the human body. The integrity of this barrier is sustained by the presence of tight junction among epithelial cells comprised by enterocytes, goblet cells and Paneth cells. Enterocytes not only provide a physical barrier, but also produce a substantial number of immunomodulatory factors [22]. The recognition of bacteria is first made by Toll like receptors (TLRs) molecules expressed by enterocytes. Among different TLRs molecules, TLR4 is implicated in the pathogenesis of NEC [23]. Goblet cells, first recognised at 9 to 10 weeks of gestation, are involved in the secretion of mucin glycoproteins, which generate the mucus layer of the intestine. Mucus layer supports the underlying epithelium from digestive enzymes and bacterial toxins, and any loss in its production or composition may allow bacteria invasion and induction of NEC [24]. Paneth cells are specialised epithelial cells located in the crypts of Lieberkühn secreting defensins and other anti-microbial peptides that kill invasive pathogens, frame the intestinal microbiota, protect the intestinal stem cells from pathogens, trigger the stem cells differentiation, and participate to the regeneration of blood vessels after injuries to the gut.24 According to the hypothesis of McElroy et al. [25], Paneth cells have a pivotal role in the onset of NEC in premature neonates. Destruction of Paneth cells by microbial toxins leads to bacterial invasion, severe inflammation, pneumatosis intestinalis and vascular closure in the submucosa, triggering the ultimate pathway to NEC. Tight junctions between epithelial cells restrict the translocation of bacteria, while helping the absorption of macromolecules produced during the process of digestion [25]. Immaturity in the composition and function of tight junctions lead to increased permeability of the epithelial barrier to the products of bacteria such as lipopolysaccharide, which in turn stimulate the secretion of several pro-inflammatory cytokines by the epithelial cells, involving tumor necrosis factor (TNF), IL-6, IL-8, all of them contributing to the distinctive inflammatory process of NEC [25].
3b. The gut immune system-the role of enterocytes in NEC
Directly below the epithelial barrier, specific immune cells reside that are capable of initiating immune feedback. These include macrophages, dendritic cells, T cells and B cells. Furthermore, specialised epithelial cells, called microfold cells (M cells), are believed to act as an antigen sampling system. Any damage to M cells may lead to an increased uptake of microorganisms, as it may be seen during gut inflammation [26].
Activation of the immune system is achieved by the recognition of a pathogen-associated molecular pattern by the host immune pattern recognition receptors (PRRs). TLR4 is an important PRR that recognises lipopolysaccharide (LPS), a crucial endotoxin in the pathogenesis of NEC and its activation in the premature gut is required for the development of NEC [27]. Accordingly, strategies that inhibit TLR4 signaling, including amniotic fluid, breast milk, and genetic deletion of TLR4 from the intestinal epithelium in animal models, constrict the NEC severity [28,29].
The expression of CD14 (cluster of differentiation 14, the co-receptor of LPS) on enterocytes is thought to be an important factor in the induction of NEC [30]. Enterocytes are capable of producing large amount of interleukin-8 (IL-8) in response to LPS, bacteria or inflammatory cytokines, and compared to control neonates, premature infants have higher levels of IL-8 in NEC affected tissue and serum [31]. In conclusion, enterocytes are not exclusively a physical barrier but also participate in gut homeostasis by secreting and activating various immunomodulatory factors in response to various strains of NEC-associated bacteria.
BM
A substantial number of short- and long-term studies have documented BM as the normative standard for infant feeding and nutrition [31]. The beneficial properties of ΒM are based not only on nutrients, but also on various bio-active compounds with growth, anti-pathogenic and anti-inflammatory properties, that play a pivotal role in neonate health and survival [31] (Figure 1). BM is a potential native immune system that protects mother’s offspring through three ways: a) inhibition of pathogen binding, b) prebiotic activity, and c) immune control, and adjustments of infection [32]. The impact of immunomodulating components of BM on NEC are shown in Table 1.
Figure 1. Summary of immunomodulating components of BM and protection against NEC.
Immunomodulating components of BM and protection against NEC
Lactoferrin
Lactoferrin is an iron-binding glycoprotein that acts as a part of inherent immune system and is found in human BM [33]. It acts by many mechanisms which target in the protection of intestine from systemic infection and NEC in premature neonates: a) in stomach, under the influence of pepsin is transformed to lactoferricin which acts against gram-negative bacteria by disrupting their cell-membrane, b) synergistically with lysozyme may kill gram-negative bacteria in the stomach, c) it may bind to TLR4 and CD14 receptors blocking the adherence of bacteria to the intestinal epithelium, d) it promotes the apoptosis of infected intestinal epithelial cells, e) it stimulates the growth of commensal bacteria, and f) reduces the production of inflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-8 via blockage of nuclear factor κB [33,34]. Published studies demonstrated that prophylactic enteral lactoferrin supplementation prevented late-onset sepsis and NEC in preterm neonates [32,33]. In contrast, the findings of a recent study revealed that lactoferrin enteral supplementation did not decrease incidence of NEC and infection [34].
Lysozyme
BM lysozyme is an antibacterial immune-active enzyme, which in synergy with lactoferrin, binds to lipopolysaccharide in the outer wall of bacteria, resulting in degradation of internal proteoglycan matrices of bacterial membranes [35]. It has been also found that lysozyme is secreted by Paneth cells in the GIT in response to enteric pathogens [35]. Concerning NEC, it has been suggested that neonates with NEC have reduced concentration of Paneth cells [25]. As a result, the role of lysozyme in protecting breast fed neonates from intestinal inflammation and NEC is significant [36].
Oligosaccharides
The human milk oligosaccharides (HMOs) consistof three to 32 sugars in size, that they are not digestible by the human intestinal tract, and represent roughly 20% of the whole carbohydrate concentration of BM [37]. HMOs lie on the position of microbial receptors and inhibit pathogens from adhering with epithelial cell walls of the intestine. Also, it has been found that they preserve the growth of lactobacilli and Bifidobacteria in the gastrointestinal tract, and reduce the presence of pathogens [38]. Studies have shown that only Bifidobacteria and Bacteroides are able to consume HMOs by encoding the complex array of glycosidases necessary to transport and digest HMOs [39]. In a randomised control study of 75 preterm neonates (birth weight less than 1500 g and gestational age equal or less than 34 weeks), Armanian et al. [40] investigated the effect of enteral supplementation with a probiotic mixture of short- and long- chain oligosaccharides versus no intervention on incidence of NEC in preterm neonates fed exclusively BM. They noticed a reduced incidence of NEC in the group with probiotic supplementation. Moreover, it has been demonstrated that the concentration of HMOs can predict NEC, as lower concentration is associated with higher incidence of NEC [41].
Cytokines
Cytokines represent protein hormones that interfere in both natural and specific immunity of the newborn infant. BM is the main source of cytokines, specifically anti-inflammatory cytokines, for neonates that are in general deficient of these proteins [42]. Cytokines have antimicrobial, anti-inflammatory and immunomodulatory activities, providing passive protection and modulating the immunological system of the host. Furthermore, cytokines include chemokines, which stimulate movements of other cells, interleukins and interferons [43]. The spectrum of cytokines of BM encompasses pro-inflammatory cytokines (Tumor Necrosis Factor-a, IL-6, IL-8, -1L-12, IL-2 and Tumor Necrosis Factor-γ) and anti-inflammatory cytokines (Transforming Growth Factor-β, IL-7, IL-10, Granulocyte -Colony Stimulating Factor) [42]. Maheshwari et al. [44] studied the level of cytokines in blood in extremely low birth weight neonates who develop NEC in early neonatal period, and found that the diagnosis of NEC was associated with elevated blood levels of IL-1β, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1/CC, C-reactive protein, and lower blood levels of TGF-β, and IL-2. Emami et al. [45], in an experimental NEC study, investigated the anti-inflammatory properties of IL-10, and found an increase in its concentration, suggesting a protective role in the pathogenesis of NEC by weakening the degree of intestinal inflammation. Moreover, Wang et al. [46] investigated the levels of pro-inflammatory cytokines IL-1, and TNF-α and anti-inflammatory IL-10 in premature neonates with NEC and compared them with premature and full-term neonates without NEC. The results showed a statistically significant increase of the above-mentioned cytokines in patients who developed NEC, suggesting a role in the pathogenesis of NEC.
L-glutamine
L-glutamine is present in BM and can stimulate intestinal cell proliferation and small bowel growth, by supplying metabolic nourishment to intestinal epithelial cells. Studies in cells and experimental models indicated that L-glutamine exerts multiple biological activities such as antioxidants, anti-apoptosis and anti-inflammations, which are involved in the pathogenesis of NEC [47]. A lack of glutamine has been proposed to be a risk factor for NEC [48]. In addition, Pawlik et al. [49] reported a lower incidence of NEC after enteral administration of glutamine in a clinical study that included 106 very low birth weight premature neonates versus the control group. However, other studies showed no effect on the incidence of NEC in premature neonates after enteral supplementation with glutamine [50]. More studies are needed to investigate the beneficial intestinal effects of glutamine.
Breast milk secretory IgA
Secretory IgA (sIgA) are derived from the enteromammary and bronchomammary immune system and contribute to the defensive character of BM. BM sIgA has an immunomudulatory role in the GI as a result of entrapping dietary antigens and microbes in the mucus, or down-regulating the expression of pro-inflammatory bacterial antigenic determinants on commensal bacteria [51]. A recent study revealed the important role of BM IgA concentration, as IgA deficiency and reduced IgA-bound bacteria in the intestine was associated with increased risk of NEC development [52].
Breast milk lipids and fatty acids
The effect of BM lipids and fatty acids on gut development is not well-studied, but a lot of mechanisms have been suggested by which fatty acids may modulate the risk of intestinal injury and inflammation. Among different categories of fatty acids, long-chain polyunsaturated fatty acids (LCPUFA) have been reported to contribute to NEC prevention, because of their effect on intestinal barrier function and their critical role in regulating inflammation [53]. Several animal studies have shown that LCPUFA supplementation reduces NEC incidence, but despite these promising results, most current preterm human infant studies did not find any benefit of LCPUFA supplementation regarding the risk of NEC development [53,54].
Growth factors
BM growth factors, such as lactadherin, epidermal growth factor, heparin-binding epidermal growth factor and transforming growth factor-β2, have been reported to contribute to NEC prevention, by maintaining homeostasis of intestinal epithelium, facilitating intestinal mucosal barrier maturation or playing a role in GTI epithelium development pre- and postnatally [55,56]. More specifically, animal and human studies’ findings about growth factors administration in NEC experimental models are promising and suggest a potential protective role, as decline incidence and severity of NEC [56,57].
Human-milk based fortifiers
Several studies indicate that BM alone provides insufficient nutrients for preterm infants and cannot meet the increased demands for growth particularly in extremely premature newborns [58]. So, human milk fortification is currently recommended and widely accepted, in order to improve the nutritional profile of this population [58]. The recent availability of human-milk-based fortifiers overcame the concerns existing about the association between the administration of cow’s milk-based fortifiers and NEC [59]. A recent meta-analysis of randomised control trials revealed that there was a reduction in the incidence of NEC with human milk-based fortifiers compared with cow’s milk-based fortifiers [60]. However, further trials are required before this therapeutic strategy can be routinely implemented for preterm infants.
Human donor milk and prevention of NEC
Despite the fact that some immunomodulatory constituents of human milk are reduced after pasteurisation of donor milk, its beneficial effects are not completely lost. Although premature neonates receiving their own mother’s milk have better feeding tolerance and lower incidence of NEC, there is no evidence that pasteurised donor milk does not administer some health benefits as does mother’s own milk [61]. In a randomised trial, Schanler et al. [62] found an increased incidence of NEC in premature neonates fed with formula or donor BM compared with those premature neonates fed with their own mothers’ milk. In addition, Christofalo et al [5] in a randomised controlled trial noticed that extremely preterm neonates who received bovine-based preterm formula showed significantly greater duration of parenteral nutrition and higher percentage of surgical NEC compared to those premature neonates fed with either donor human milk or human milk-based human milk fortifier. So, regarding the prevention of NEC, donor milk seems to maintain some of the immunological advantages of fresh human milk [63].
CONCLUSION
Prematurity and low birth weight due to prematurity remains a leading cause of neonatal mortality and morbidity. NEC is known to participate largely among gastrointestinal complications in this age group due to immature immunologic and host defense gastrointestinal systems. BM is considered as a tissue similar to plasma as it contains a variety of immunomodulatory components such as immunoglobulins, cytokines, lactoferrin, lysozyme and other factors that potentially deliberate protection against a diverse range of diseases. Despite ongoing research on the pathogenesis of NEC, the understanding of this devastating disease has increased slowly in recent years. Intestinal epithelial barrier, intestinal microbiota and the immature immunologic environment of the gastrointestinal tract have a crucial influence in the development of NEC, particularly in premature neonates. However, there is ongoing evidence that BM contains multiple components that aid to prevent, and modulate the immature immune system of premature neonates. From this point of view, BM is considered not only a choice of diet but rather a modulator of the immature immune system of the preterm neonate.
Conflict of interest: None
REFERENCES
- Garg PM, Garg PP, Lai CV. Necrotizing enterocolitis (NEC): A devastating disease of prematurity. J Neonatal Biol [Internet]. 2015 [cited 2015 Nov 10];4:1000202. Available from: https://pubmed.ncbi.nlm.nih.gov/37525717/
- Rees CM, Eaton S, Pierro A. National prospective surveillance study of necrotizing enterocolitis. In neonatal intensive care units. J Pediatr Surg. 2010 Jul;45(7):1391-7.
- American academy of pediatrics section on breastfeeding: Breastfeeding and the use of human milk. Pediatrics [Internet]. 2012 [cited 2012 Mar 01];129:e827-41. Available from: https://publications.aap.org/pediatrics/article/129/3/e827/31785/Breastfeeding-and-the-Use-of-Human-Milk
- Kimak KS, de Kastro Antunes MM, Braga TD, Brandt KG, de Carvalho Lima M. Influence of enteral nutrition on occurrence of necrotizing enterocolitis in very-low-birth-weight infants. J Pediatr Gastroenterol Nutr. 2015 Oct;61(4):445-50.
- Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, Kiechl-Kohlendorfer U, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr. 2013 Dec;163(6):1592-5.
- Vinturache AE, Gyamfi-Bannerman C, Hwang J, Mysorekar IU, Jacobsson B. The preterm Birth International Collaborative (PREBIC). Maternal microbiome-a pathway to preterm birth. Sem Fetal Neon Med. 2016 Apr;21(2):94-9.
- Neu J. Necrotizing enterocolitis. World Rev Nutr Diet. 2014;110:253-63.
- Neu J. Preterm infant nutrition, gut bacteria, and necrotizing enterocolitis. Curr Opin Clin Nutr Metab Care. 2015 May;18(3):285-8.
- Greenwood C, Morrow AL, Lagomarcino AJ, Altaye M, Taft DH, Yu Z, et al. Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of Enterobacter. J Pediatr. 2014 Jul;165(1):23-9.
- Hällström M, Eerola E, Vuento R, Janas M, Tammela O. Effects of mode of delivery and necrotising enterocolitis on the intestinal microflora in preterm infants. Eur J Clin Microbiol Infect Dis. 2004 Jun;23(6):463-70.
- Torraza RM, Ukhanova M, Wang X, Sharma R, Hudak ML, Neu J, et al. Intestinal microbial ecology and environmental factors affecting necrotizing enterocolitis. PLoS One [Internet]. 2013 Dec [cited 2013 Dec 30];8(12):e83304. Available from: https://pubmed.ncbi.nlm.nih.gov/24386174/
- Moles L, Gómez M, Heiling H, Bustos G, Fuentes S, de Vos W, et al. Bacterial diversity in meconium of preterm neonates and evolution of their fecal microbiota during the first month of life. PLoS One [Internet]. 2013 Jun [cited 2013 Jun 28];8(6):e66986. Available from: https://pubmed.ncbi.nlm.nih.gov/23840569/
- Solt I. The human microbiome and great obstetrical syndrome: A new frontier in maternal-fetal medicine. Best Pract Res Clin Obstet Gynaecol. 2015 Feb;29(2):165-75.
- Elgin TG, Kern SL, McElroy SJ. Development of the neonatal intestinal microbiota and its association with necrotizing enterocolitis. Clin Ther. 2016 Apr;38(4):706-15.
- Dominguez-Bello, Costelli EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010 Jun;107(26):11971-5.
- Arboleya S, Binetti A, Salaazar N, Fernádez E, Solis G, Hernádez-Barranco A, et al. Establishment and development of intestinal microbiota in preterm neonates. FEMS Microbiol Ecol. 2012 Mar;79(3):763-72.
- Mai V, Young CM, Ukhanova M, Wang X, Sun Y, Casella G, et al. Fecal microbiota in preterm infants prior to necrotizing enterocolitis. PLoS One [Internet]. 2011 [cited 2011 Jun 6];6 (6):e20647. Available from: https://pubmed.ncbi.nlm.nih.gov/21674011/
- Zhou Y, Shan G, Sodergren E, Weinstock G, Walker WA, Gregory KE. Longitudinal analysis of the premature infant intestinal microbiome prior to necrotizing enterocolitis: a case-control study. PLoS One [Internet]. 2015 Mar [cited 2015 Mar 5];10(3):e0118632. Available from: https://pubmed.ncbi.nlm.nih.gov/21674011/
- Heidi FH, van Zoonen AGJF, Hulscher JBF, Te Kiefte MJ, Wessels R, Kooi EM, et al. A necrotizing enterocolitis-associated gut microbiota is already present in the meconium: results of a prospective study. Clin Infect Dis. 2016 Apr;62(7):863-70.
- Wang Y, Hoening JD, Malin KJ, Qamar S, Petrol EO. 16S rRNA gene-based analysis if fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J. 2009 Aug;3(8):944-54.
- McMurtry VE, Gupta RW, Tran L, Blanchard EU, Penn D, Tayloe CM, et al. Bacterial diversity and Clostridia abundance decrease with increasing severity of necrotizing enterocolitis. Microbiome. 2015 Mar:3:11.
- Tanner SM, Berryhill TF, Ellenburg JL, Jilling T, Cleveland DS, Lorenz RG, et al. Pathogenesis of necrotizing enterocolitis. Am J Pathol. 2015 Jan;185(1):4-16.
- Jilling T, Simon D, Lu J, Meng FJ, Li D, Schy R, et al. The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. J Immunol. 2006 Sep;177(5):3273-82.
- Kim YS, Ho SB. Intestinal goblet cells and mucins in health and disease: Recent insights and progress. Curr Gastroenterol Rep. 2010 Oct;12(5):319-30.
- McElroy SJ, Underwood MA, Sherman MP. Paneth cells and necrotizing enterocolitis: A novel hypothesis for disease pathogenesis. Neonatology. 2013;103(1):10-20.
- Kucharzik T, Lügering N, Rautenberg K, Lügering A, Schmodt DA, Stoll R, et al. Role of M cells in intestinal barrier function. Ann N Y Acad Sci. 2000;915:171-83.
- Egan CE, Sodhi CP, Good M, Lin J, Yamaguchi Y, Lu P, et al. Toll-like receptor 4-mediated lymphocyte induces neonatal necrotizing enterocolitis. J Clin Invest. 2016 Feb;126(2):495-508.
- Good M, Siggers SH, Sodhi CP, Afrazi A, Alkhudari F, Egan CE, et al. Amniotic fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc Natl Acad Sci U S A. 2012 Jul;109(28):11330-5.
- Afrazi A, Branca MF, Sodhi CP, Good M, Yamaguchi Y, Egan CE, et al. Toll-like receptor 4-mediated endoplasmic reticulum stress in intestinal crypts induces necrotizing enterocolitis. J Biol Chem. 2014 Apr;289(14):9584-99.
- Mollen KP, Gribar SC, Anand RJ, Kaczorowski DJ, Kohler JW, Branca MF, et al. Increased expression and internalization of the endotoxin co-receptor CD14 in enterocytes occur as an early event in the development of experimental necrotizing enterocolitis. J Pediatr Surg. 2008 Jun;43(6):1175-81.
- Maheshwari A, Corbin L, Schelonka R. Neonatal necrotizing enterocolitis. Research and Reports in Neonatology [Internet]. 2011 [cited 2011 Aug 24];1;39-53. Available from: https://www.dovepress.com/article/download/8142
- He Y, Cao L, Yu, J. Prophylactic lactoferrin for preventing late-onset sepsis and necrotizing enterocolitis inpreterm infants. Medicine (Baltimore) 2018;97 (35):e11976.
- Pammi M, Suresh G. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017 Jun;6(6):CD007137.
- Griffiths J, Jenkins P, Vargova M, Bowler U, Juszczak E, King A, et al. Enteral lactoferrin to prevent infection for very preterm infants: The ELFIN RCT. Health Technol Assess. 2018 Dec;22(74):1-60.
- Mara MA, Good M, Weitkamp JH. Innate and adaptive immunity in necrotizing enterocolitis. Semin Fetal Neonatal Med. 2018 Aug;23(6):394-9.
- Lueschow SR, Stumphy J, Gong H, Kern SL, Elgin TG, Undrewood MA, et al. Loss of murine Paneth cell function alters the immature intestinal microbiome and mimics changes seen in neonatal necrotizing enterocolitis. PLoS One [Internet]. 2018 Oct [cited 2018 Oct 1];13(10):e0204967. Available from: https://pubmed.ncbi.nlm.nih.gov/30273395/
- Okburan G, Kızıler S. Human milk oligosaccharides as prebiotics. Pediatr Neonatol. 2023 May;64(3):231-8
- Vongbhavit K, Underwood MA. Prevention of necrotizing enterocolitis through manipulation of intestinal microbiota of the premature infant. Clin Ther. 2016 Apr;38(4):716-32.
- Kim JH, An HJ, Carrido D. Proteomic analysis of Bifidobacteria longum subs. infantis reveals the metabolic insight on consumption of prebiotics and host glycans. PloS One 2013;8(2):e57535.
- Armanian AM, Sadeghnia M, Mirlohi M, Feizi A, Salehimehr N, Saee N, et al. The effect of neutral oligosaccharides on reducing the incidence of necrotizing enterocolitis in preterm infants: A randomized clinical trial. Int J Prev Med. 2014 Nov;5(11):1387-95.
- Masi AC, Embleton ND, Lamp CA, Young G, Granger CL, Najera J, et al. Human milk oligosaccharide DSLNT and gut microbiome in preterm infants predicts necrotizing enterocolitis. Gut. 2021 Dec;70(12):2273-82.
- Kiełbasa A, Gadzała-Kopciuch R, Buszewski B. Cytokines-Biogenesis and Their Role in Human Breast Milk and Determination. Int J Mol Sci. 2021 Jun;22(12):6238.
- Garofalo R. Cytokines in human milk. J Pediatr. 2010 Feb;156(2 Suppl):S36-40
- Maheshwari A, Schelonka RL, Dimmitt RA, Carlo WA, Munoz-Hernandez B, Das A. Cytokines associated with necrotizing enterocolitis in extremely- low-birth-weight infants. Pediatr Res. 2014 Jul;76(1):100-8.
- Emami CN, Chokshi N, Wang J, Hunter C, Guner Y, Goth K, et al. Role of interleukin-10 in the pathogenesis of necrotizing enterocolitis. Am J Surg. 2012 Apr;203(4):428-35.
- Wang W, Xue L, Ma T, Li Y, Li Z. Non-intervention observation: Dynamic evolution laws of inflammatory response in necrotizing enterocolitis. Exp Ther Med. 2016 Sep;12(3):1770-4.
- Zhou P, Li Y, Ma LY, Lin HC. The role of immunonutrients in the prevention of necrotizing enterocolitis in preterm very low birth weight infants. Nutrients. 2015 Aug;7(9):7256-70.
- Good M, Sodhi CP, Hackam DJ. Evidence based feeding strategies before and after the development of necrotizing enterocolitis. Expert Rev Clin Immunol. 2014 Jul;10(7):875-84.
- Pawlik D, Lauterbach R, Hurkala J, Radziszewska R. The effects of enteral administration of glutamine enriched solution on very lowe birth weight infants on reducing the symptoms of feeding intolerance. Med Wieku Rozwoj. 2012 Jul-Sep;16(3):205-11.
- Moe-Byrne T, Brown JVE, McGuire W. Glutamine supplementation to prevent morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 2016 Apr;4(4):CD001457.
- Rogier EW, Frantz AL, Bruno ME, Wedlund L, Cohen DA, Stromberg AJ, et al. Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. Proc Natl Acad Sci U S A. 2014 Feb;111(8):3074-9.
- Gopalakrishna KP, Macadangdang BR, Rogers MB, Tometich JT, Firek BA, Baker R, et al. Maternal IgA protects against the development of necrotizing enterocolitis in preterm infants. Nat Med. 2019 Jul;25(7):1110-5.
- Caplan MS, Jilling T. The role of polyunsaturated fatty acid supplementation in intestinal inflammation and neonatal necrotizing enterocolitis. Lipids. 2001 Sep;36(9):1053-7.
- Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized controlled trials. Am J Clin Nutr. 2008 Apr;87(4):912-20.
- Nair RR, Warner BB, Warner BW. Role of epidermal growth factor and other growth factors in the prevention of necrotizing enterocolitis. Semin Perinatol. 2008 Apr;32(2):107-13.
- Sitarik AR, Bobbitt KR, Havstad SL, Fujimura KE, Levin AM, Zoratti EM, et al. Breast Milk Transforming Growth Factor β Is Associated With Neonatal Gut Microbial Composition. J Pediatr Gastroenterol Nutr. 2017 Sep;65(3):e60-7.
- Shen H, Lei Y, He X, Liu D, He Z. Role of lactadherin in intestinal barrier integrity in experimental neonatal necrotizing enterocolitis. J Cell Biochem. 2019 Dec;120(12):19509-17.
- Carlson S, Wojcik B, Barker A, Klien J. Guidelines for the use of human milk fortifier in the neonatal intensive care unit. University of Iowa Neonatology Handbook 2011 [Internet] [accessed 2019 May 15]. Available from: https://uichildrens.org/health-library/guidelines-use-human-milk-fortifier-neonatal-intensive-care-unit
- Vaks Y, Birnie KL, Carmichael SL, Hernandez-Boussard T, Benitz WE. Temporal relationship of onset of necrotizing enterocolitis and introduction of enteric feedings and powdered milk fortifier. Am J Perinatol 2018 Jun; 35(7):616-23.
- Grace E, Hilditch C, Gomersall J, Collins CT, Rumbold A, Keir AK. Safety and efficacy of human milk-based fortifier in enterally fed preterm and/or low birthweight infants: A systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2021 Mar;106(2):137-42.
- Schanler RJ. Mother’s own milk, donor milk, and preterm formula in the feeding of extremely preterm infants. J Pediatr Gastroenterol Nutr. 2007 Dec:45 Suppl 3:S175-7.
- Schanler RJ, Lau C, Hurst N, O’Brian Smith E. Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feeding of extremely premature infants. Pediatrics. 2005 Aug;116(2):400-6
- Bertino E, Giuliani F, Occhi L, Coscia A, Tonetto P, Marchino F, et al. Benefits of donor human milk for preterm infants: current evidence. Early Hum Dev. 2009 Oct;85(10 Suppl):S9-S10.