Cow's-Milk Protein as a Specific Immunological Trigger of Necrotising Enterocolitisor Food Proteininduced Enterocolitis Syndrome in Disguise?

Murch, Simon H.

Journal of Pediatric Gastroenterology & Nutrition:
doi: 10.1097/MPG.0b013e31826eea11
Invited Commentaries
Author Information

Department of Paediatrics, Warwick Medical School, Coventry, UK.

Address correspondence and reprint requests to Simon H. Murch, Professor of Paediatrics and Child Health, Warwick Medical School, Coventry CV2 2DX, UK (e-mail:

Received 2 July, 2012

Accepted 7 August, 2012

The author reports no conflicts of interest.

Article Outline

See “Evolution of In Vitro Cow's Milk Protein–specific Inflammatory and Regulatory Cytokine Responses in Preterm Infants With Necrotising Enterocolitis” by Chuang et al on page 5.

Exclusive breast-feeding of preterm infants reduces the risk of developing necrotising enterocolitis (NEC) (1). Even in infants with risk factors such as growth restriction and abnormal Doppler studies, there is evidence that early feeding with colostrum is safe and confers protection (2,3). The issue remains whether the effect of formula feeding upon the incidence of NEC relates to differences in osmolality, lack of breast milk oligosaccharides, and other constituents beneficial to gut maturation and immune defense (4) or an immune response to cow's-milk proteins. The study by Chuang et al (5) in this issue of JPGN suggests the third possibility, building upon their previous work, which has identified milk protein–induced lymphocyte responses in acute disease, including both proinflammatory (TH1 and TH2) and regulatory (interleukin-10 and transforming growth factor-β1 [TGF-β1]) cytokines, although with relatively lower TGF-β1 responses (6). Their study (5) extends these observations to the full recovery phase and identifies a late increase in TGF-β1 responses as other cytokines normalise, consistent with the known role of this cytokine in the development of oral tolerance.

Animal models confirm impaired epithelial permeability, dysmotility, and luminal bacteria as key determinants of progression to NEC. So what are the credentials of cow's-milk protein as a specific trigger? Numerous reports, mostly from earlier decades, have identified infants experiencing episodes of bloody diarrhoea, distension, flank discolouration, and intramural gas, settling after cow's-milk protein was excluded and relapsing on challenge (7–9). Some were diagnosed as milk-induced enterocolitis, others as NEC. The question arises whether food protein–induced enterocolitis syndrome (FPIES) can indeed occur in preterm neonates, and whether this may cause diagnostic confusion with classic NEC. Because infants are usually now fed hydrolysates or amino acid formulae once feeds are recommenced, any link with cow's-milk protein is less likely to be recognised than previously.

Many cases of NEC have atypical features, without a fulminant course, and are managed conservatively. It may be important to compare the presentations and laboratory findings in such infants with those who progress rapidly to perforation. Features that may raise the likelihood of FPIES rather than NEC would include a family history of atopy, evidence of dermatographia, and results such as thrombocytosis and neutrophilia (as opposed to thrombocytopaenia and neutropaenia in classic NEC), or systemic and faecal eosinophilia. Eosinophilia does not always presage a benign course, and progression to perforation may occur in infants with eosinophilia who receive red cell transfusions (10). Such characterisation of infants with suspected NEC may allow distinction of disease subgroups, and confirmation of neonatal FPIES as a distinct clinical entity. It may also clarify whether such infants are at increased risk of transfusion-induced progression to severe NEC.

The studies by Fell's group have been valuable in raising the profile of cow's milk as a trigger of intestinal inflammation in preterm neonates. Similar enhanced lymphocyte response to cow's milk has been identified in infants with FPIES (11). Recognised features of intestinal cow's-milk sensitisation, including induction of epithelial leakiness and dysmotility, could contribute to the pathogenesis of disease, allowing increased penetration of luminal bacterial products. It is possible that what begins as a relatively low-grade pathology can accelerate catastrophically due to unchecked immune regulation, potentially through impaired generation of regulatory T cells or failed adrenocortical responses.

For the moment, the evidence that early feeding with colostrum and maintenance of exclusive breast-feeding protects against NEC continues to mount (2), and the findings of Chuang et al (5) emphasise that feeding preterm infants with formula milk may have significant immunological consequences.

Back to Top | Article Outline


1. Siggers RH, Siggers J, Thymann T, et al. Nutritional modulation of the gut microbiota and immune system in preterm neonates susceptible to necrotizing enterocolitis. J Nutr Biochem 2011; 22:511–521.
2. Meinzen-Derr J, Poindexter B, Wrage L, et al. Role of human milk in extremely low birth weight infants’ risk of necrotizing enterocolitis or death. J Perinatol 2009; 29:57–62.
3. Leaf A, Dorling J, Kempley S, et al. Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial. Pediatrics 2012; 129:e1260–e1268.
4. Bode L. Human milk oligosaccharides: every baby needs a sugar mama. Glycobiology 2012;22:1147–62.
5. Abdelhamid AE, Hayes P, Chuang S, et al. Evolution of in vitro cow's-milk protein–specific inflammatory and regulatory cytokine responses in preterm infants with necrotising enterocolitis. J Pediatr Gastroenterol Nutr 2013;56:5–11.
6. Abdelhamid AE, Chuang SL, Hayes P, et al. In vitro cow's milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotizing enterocolitis and sepsis. Pediatr Res 2011; 69:165–169.
7. Powell GK. Enterocolitis in low-birth-weight infants associated with milk and soy protein intolerance. J Pediatr 1976; 88:840–844.
8. Srinivasan P, Brandler M, D'Souza A, et al. Allergic enterocolitis presenting as recurrent necrotizing enterocolitis in preterm neonates. J Perinatol 2010; 30:431–433.
9. Coviello C, Rodriquez DC, Cecchi S, et al. Different clinical manifestation of cow's milk allergy in two preterm twins newborns. J Matern Fetal Neonatal Med 2012; 25 (Suppl 1):132–133.
10. Christensen RD, Lambert DK, Gordon PV, et al. Neonates presenting with bloody stools and eosinophilia can progress to two different types of necrotizing enterocolitis. J Perinatol 2012;32:874–9.
11. Van Sickle GJ, Powell GK, McDonald PJ, et al. Milk- and soy protein-induced enterocolitis: evidence for lymphocyte sensitization to specific food proteins. Gastroenterology 1985; 88:1915–1921.
Copyright 2013 by ESPGHAN and NASPGHAN