The story begins with a baby who is born too early, meaning before 36 weeks gestation, said senior author David Hackam, M.D.,Ph.D., Watson Family Professor of Surgery, Pitt School of Medicine, and co-director of the Fetal Diagnosis and Treatment Center at Children's Hospital.
Once stable, typically the baby is fed with formula because often breast milk is not readily available to premature infants.
"Within about 10 days of birth, the baby starts to vomit and a few hours later, the belly becomes distended and discolored," Dr. Hackam said.
"It becomes clear that the child has developed a major problem in his or her tummy, and an X-Ray will usually confirm the diagnosis of necrotizing enterocolitis, or NEC, in which the intestinal tissue is dying. We have no choice but to remove the dead parts of the intestine, but despite surgery, half of these preemie babies still die from the condition," he said.
Dr. Hackam and his team noted NEC occurs when the intestines start getting colonized with bacteria, a process that occurs normally after birth.
They focused on toll-like receptor 4 (TLR4), an immune protein that is involved in recognizing microbes and which they recently discovered plays a role in gut development.
In the current work, Hackam and colleagues found that TLR4 is present in higher amounts in the blood vessel lining in preemies than in full-term babies.
The study shows that unlike normal mice, those bred to lack TLR4 in their blood vessels did not develop NEC in a model designed to induce the condition.
The findings indicate that bacteria in the blood activate TLR4 leading to a reduction in nitric oxide, which in turn narrows blood vessels and decreases blood flow, Dr. Hackam said.
"This pathway can be dangerous when the preemie's immature gut becomes inflamed from exposure to the bacteria normally present in the intestine," he said.
"Abundant TLR4 triggers a shutdown of the blood supply to the intestine, leading to tissue death or necrosis," he added.
Premature babies who are nursed rather than formula-fed are more likely to survive NEC, so co-author and nitric oxide expert Mark Gladwin, M.D., chief, Division of Pulmonary Allergy and Critical Care Medicine, Pitt School of Medicine, and director of Pitt's Vascular Medicine Institute, and the team took a closer look at the components of breast milk.
They found that breast milk contains high levels of sodium nitrate, which is converted to nitrite by gut bacteria.
Nitrite can be directly converted to the vasodilator nitric oxide, which can both protect the intestinal lining and improve blood flow.
The study has been published online in the Proceedings of the National Academy of Sciences.