Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor.

Breast milk is the most effective strategy to protect infants against necrotizing enterocolitis (NEC), a devastating disease that is characterized by severe intestinal necrosis. Previous studies have demonstrated that the lipopolysaccharide receptor Toll-like receptor 4 (TLR4) plays a critical role in NEC development via deleterious effects on mucosal injury and repair. We now hypothesize that breast milk protects against NEC by inhibiting TLR4 within the intestinal epithelium, and sought to determine the mechanisms involved. Breast milk protected against NEC and reduced TLR4 signaling in wild-type neonatal mice, but not in mice lacking the epidermal growth factor receptor (EGFR), whereas selective removal of EGF from breast milk reduced its protective properties, indicating that breast milk inhibits NEC and attenuates TLR4 signaling via EGF/EGFR activation. Overexpression of TLR4 in the intestinal epithelium reversed the protective effects of breast milk. The protective effects of breast milk occurred via inhibition of enterocyte apoptosis and restoration of enterocyte proliferation. Importantly, in IEC-6 enterocytes, breast milk inhibited TLR4 signaling via inhibition of glycogen synthase kinase-3ß (GSK3ß). Taken together, these findings offer mechanistic insights into the protective role for breast milk in NEC, and support a link between growth factor and innate immune receptors in NEC pathogenesis.

Prevalence and lack of clinical significance of blood group incompatibility in mothers with blood type A or B.

PURPOSE: To examine the prevalence and clinical significance of blood group incompatibility in infants whose mothers have blood type A or B. METHODS: We prospectively analyzed cord blood samples from 4996 consecutive love-born infants for blood type, hematocrit, and results of direct antiglobulin (Coombs) test (DAT) and indirect Coombs test (ICT). OUTCOME MEASURES: Erythrocyte sensitization was determined by positive DAT or ICT results. Significant hyperbilirubinemia (> or = 224 mumol/L (12.8 mg/dl) and mean cord hematocrits were compared between mother-infant pairs with ABO incompatibility and positive DAT or ICT results and those with negative Coombs test results. RESULTS: Of all births, 6.9% (343/4996) were of infants who had ABO incompatibility and had been born to mothers with blood type B or A; 44 (13%) of 343 infants had a positive antiglobulin test result, of whom 43 had a positive ICT result only. Type A or B mothers were 5.5 times less likely to have sensitization than type O mothers; A-B, B-A, A-AB, and B-AB mother-infant pairs with a positive antiglobulin test result had mean cord hematocrits and rates of significant hyperbilirubinemia similar to those of corresponding pairs whose antiglobulin tests both showed negative results. Infants with a positive DAT result had lower mean cord hematocrits than infants with negative results on both antiglobulin tests or on a positive ICT result only. Significant hyperbilirubinemia was more frequent in infants with a positive DAT result than in infants with negative results on both antiglobulin tests or a positive ICT result only. CONCLUSION: Sensitization is much rare when the mother has blood type A or B than when she has blood type O, as demonstrated by the antiglobulin test. The incidence of significant hyperbilirubinemia and lower cord hematocrit is not increased by sensitization when the mother has type A or B.