Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants

Autran, Chloe; Kellman, Benjamin P.; Kim, Jae; Asztalos, Elizabeth; Blood, Arlin B.; Spence, Erin C Hamilton; Patel, Aloka L.; Hou, Jiayi; Lewis, Nathan E.; Bode, Lars

doi:10.1136/gutjnl-2016-312819

Cited by 206 publications

(204 citation statements)

References 28 publications

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“…One such component is human milk oligosaccharides (HMOs), a highly abundant group of indigestible oligosaccharides (5–15 g L –1 ) that: i) stimulate growth of gut commensals, ii) prevent adhesion of enteropathogens, and iii) modulate host immunity . In humans, reduced HMO exposure during the first month of life is linked to the development of NEC . Conversely, when incorporated into infant formula, HMOs promote survival and decrease the formation of NEC lesions in preclinical models .…”

Section: Introductionmentioning

confidence: 99%

“…In the absence of fiber, the mucus barrier narrows resulting in greater susceptibility to intestinal injury. In NEC, mucus depletion and deficiency in specific oligosaccharides are associated with disease development. On the other hand, the administration of mucin‐secretagogues and HMOs can both decrease NEC severity, but whether these observed effects are related has not yet been tested.…”

Section: Introductionmentioning

confidence: 99%

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Human Milk Oligosaccharides Increase Mucin Expression in Experimental Necrotizing Enterocolitis

Koike

et al. 2018

Molecular Nutrition Food Res

114

117

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Scope Necrotizing enterocolitis (NEC) is a leading cause of morbidity and death in preterm infants, occurring more often in formula‐fed than breastfed infants. Studies in both rats and humans show that human milk oligosaccharides (HMOs) lower the incidence of NEC, but the mechanism underlying such protection is currently unclear. Methods and Results By extracting HMOs from pooled human breastmilk, the impact of HMOs on the intestinal mucin levels in a murine model of NEC are investigated. To confirm the results, the findings are validated by exposing human intestinal epithelial cells and intestinal organoids to HMOs and evaluated for mucin expression. HMO‐gavage to pups increases Muc2 levels and decreases intestinal permeability to macromolecular dextran. HMO‐treated cells have increased Muc2 expression, decreased bacterial attachment and dextran permeability during challenge by enteric pathogens. To identify the mediators involved in HMO induction of mucins, it is demonstrated that HMOs directly induce the expression of chaperone proteins including protein disulfide isomerase (PDI). Suppression of PDI activity removes the protective effects of HMOs on barrier function in vitro as well as NEC protection in vivo. Conclusions Taken together, the results provide insights to the possible mechanisms by which HMOs protect the neonatal intestine through upregulation of mucins.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human Milk Oligosaccharides Increase Mucin Expression in Experimental Necrotizing Enterocolitis

Koike

et al. 2018

Molecular Nutrition Food Res

114

117

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“…Prebiotics in breast milk are resistant to gastric acid digestion, and feeding very preterm infants with formula supplemented with prebiotics, typically a mixture of galacto- and fructo-oligosaccharides, stimulates the growth of an intestinal microflora that is similar to that found in infants fed with maternal breast milk [35]. Randomised controlled trials have indicated that prebiotic supplements are safe and well tolerated by preterm infants.…”

Section: Prebiotics and Probioticsmentioning

confidence: 99%

Immunonutrition for Preterm Infants

Walsh

McGuire²

2019

Neonatology

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Care and outcomes for very preterm infants continue to improve, but important causes of mortality and acute and long-term morbidity associated with prolonged hospitalisation remain. Necrotising enterocolitis (NEC) and late-onset infection have emerged as the major causes of death beyond the early neonatal period and of neurodisability in very preterm infants. Although the pathogenesis of these conditions is incompletely understood, it appears to be related to the content and mode of delivery of the enteral diet, particularly the impact of immunonutrients from human breast milk on the microbial and metabolic balance within the immature intestine. Evidence exists to support investment in measures to help mothers to express breast milk as the primary source of nutrition for their very preterm infants. In the absence of maternal milk, pasteurised donor breast milk provides protection against NEC, but its nutritive adequacy is not clear and its cost-effectiveness is uncertain. Supplementation with individual immunonutrients, including immunoglobulins and lactoferrin, has not been shown to be effective in preventing NEC or infection in randomised controlled trials. The evidence base for prebiotics and probiotics is stronger, but concerns exist about the choice, safety and availability of formulations. Other strategies – including avoidance of drugs such as gastric acid suppressants that compromise innate immunity, as well as evidence-based progressive feeding strategies that reduce exposure to invasive interventions – are emerging as key components of care packages to reduce the burden of NEC, infection and associated growth and developmental faltering for very preterm infants.

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“…Human milk has many nutrients and bioactive factors that are beneficial to both term and preterm infants. Carbohydrates, particularly human milk oligosaccharides (HMO), are important for protection against infection, particularly NEC [29]. Furthermore, a multitude of proteins are present in human milk that form its essential nutrition and also play contributory roles in infant immune protection as well as the development of the immune system and the gut [30,31].…”

Section: Discussionmentioning

confidence: 99%

A randomized controlled trial protocol comparing the feeds of fresh versus frozen mother’s own milk for preterm infants in the NICU

Sun

Cao

Han

et al. 2020

Trials

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Background: Necrotizing enterocolitis (NEC) is the leading cause of death among preterm infants born at < 30 weeks' gestation. The incidence of NEC is reduced when infants are fed human milk. However, in many neonatal intensive care units (NICUs), it is standard practice to freeze and/or pasteurize human milk, which deactivates bioactive components that may offer additional protective benefits. Indeed, our pilot study showed that one feed of fresh mother's own milk per day was safe, feasible, and can reduce morbidity in preterm infants. To further evaluate the benefits of fresh human milk in the NICU, a randomized controlled trial is needed.Methods: Our prospective multicenter, double-blinded, randomized, controlled trial will include infants born at < 30 weeks' gestation and admitted to one of 29 tertiary NICUs in China. Infants in the intervention (fresh human milk) group (n = 1549) will receive at least two feeds of fresh human milk (i.e., within 4 h of expression) per day from the time of enrollment until 32 weeks' corrected age or discharge to home. Infants in the control group (n = 1549) will receive previously frozen human milk following the current standard protocols. Following informed consent, enrolled infants will be randomly allocated to the control or fresh human milk groups. The primary outcome is the composite outcome mortality or NEC ≥ stage 2 at 32 weeks' corrected age, and the secondary outcomes are mortality, NEC ≥ stage 2, NEC needing surgery, late-onset sepsis, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), weight gain, change in weight, increase in length, increase in head circumference, time to full enteral feeds, and finally, the number and type of critical incident reports, including feeding errors.Discussion: Our double-blinded, randomized, controlled trial aims to examine whether fresh human milk can improve infant outcomes. The results of this study will impact both Chinese and international medical practice and feeding policy for preterm infants. In addition, data from our study will inform changes in health policy in NICUs across China, such that mothers are encouraged to enter the NICU and express fresh milk for their infants.

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Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants

Abstract: DSLNT content in breast milk is a potential non-invasive marker to identify infants at risk of developing NEC, and screen high-risk donor milk. In addition, DSLNT could serve as a natural template to develop novel therapeutics against this devastating disorder.

Cited by 206 publications

References 28 publications

Human Milk Oligosaccharides Increase Mucin Expression in Experimental Necrotizing Enterocolitis

Human Milk Oligosaccharides Increase Mucin Expression in Experimental Necrotizing Enterocolitis

Immunonutrition for Preterm Infants

A randomized controlled trial protocol comparing the feeds of fresh versus frozen mother’s own milk for preterm infants in the NICU

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