Editors' ChoiceNEONATOLOGY

One More Reason to Love Mother’s Milk

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Science Translational Medicine  29 May 2013:
Vol. 5, Issue 187, pp. 187ec89
DOI: 10.1126/scitranslmed.3006579

Many good things are likened to mother’s milk, but neonatologists know that human breast milk is truly unique in its ability to protect babies from infections and disease. A striking example is the effectiveness of breast milk in preventing necrotizing enterocolitis (NEC)—an inflammatory/ischemic gut disorder that kills premature infants. Toll-like receptor 4 (TLR4) activation and dysregulation of nitric oxide (NO), a known vasodilator, are prominent features of NEC in humans and mouse models. The mechanisms connecting these observations and the protective effects of breast milk have been unclear thus far.

Yazji and colleagues wanted to understand the relationship between endothelial TLR4 activation and NO deficiency in NEC pathogenesis and to determine whether breast milk protects infants, in part, by enhancing intestinal perfusion. To answer these questions, the authors created mice with a selective lack of TLR4 on endothelial cells and evaluated the effect of endothelial TLR4 deficiency on intestinal blood flow and NEC severity in an established model. Endothelial TLR4 deficiency resulted in a marked reduction in ischemia, necrosis, and NEC severity as compared with those of wild-type mice, which appeared to be due to preservation of microvascular perfusion. Follow-up investigations showed that TLR4 activation reduces endothelial nitric oxide synthase (eNOS) expression, leading to decreased microvascular perfusion, ischemia, and more severe NEC disease. The authors validated their findings by showing that eNOS expression is reduced in samples of intestine removed from human infants with NEC and that eNOS deficiency increases NEC severity in mice. Last, having connected endothelial TLR4 activation with decreased endogenous NO production and blood flow in NEC, the authors showed that breast milk provides an exogenous, dietary source of nitrate that is converted to NO by the microbiota and maintains microvascular blood flow. They also verified that infant formula lacks a source of nitrate or nitrite and showed that direct administration of sodium nitrate to formula-fed mice is protective against severe NEC disease.

This study suggests that endothelial TLR4 activation plays a central role in the pathogenesis of severe NEC. It also offers a mechanism by which breast milk protects against ischemia and NEC by providing an exogenous source of nitrate for NO signaling. Additional studies are needed to confirm the role of endothelial TLR4 activation and eNOS suppression in NEC pathogenesis in human infants and to clarify the relative importance of breast milk effects on the microbiota, mucosa, and circulation in NEC prevention. However, dietary supplementation with sodium nitrate may be a new therapeutic option to decrease NEC severity in premature infants.

I. Yazji et al., Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO-nitrite signaling. Proc. Natl. Acad. Sci. U.S.A., 6 May 2013 (doi: 10.1073/pnas.1219997110). [Abstract]

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