Scientists Identify Process Leading to NEC in Preemies

Until recently, scientists and doctors had little information about what happens biologically in premature babies (preemies) that leads them to develop necrotizing enterocolitis (NEC). A new study published in Science Translational Medicine offers new insight.

A team of researchers from Johns Hopkins Medicine believe they have identified the biological process that leads up to NEC. NEC is a dangerous intestinal disease that destroys the lining of the infant’s intestines and is fatal in one-third of all cases.

Before diving into the research, let’s review some of the terms you will read in this article:

  • Glia: Non-neuronal cells in the central nervous system (CNS) and peripheral nervous system (PNS). These cells nourish neurons.
  • Enteric glia: glial cells that live in the walls of the intestinal tract. These cells regulate intestinal motility.
  • Motility: Movement, such as movement of the contents of the intestines.
  • TLR4: Toll-like receptor 4 (TLR4) is a protein that serves as an intracellular signaling pathway. Activates the innate immune system.
  • BDNF: Brain-derived neurotrophic factor (BDNF) is a growth factor common in the gut, CNS, and other tissues. Crucial to healthy growth and development.

Research Provides New Insight for NEC Process

According to a study using mice, the process of NEC development includes,

“The loss of enteric glia — cells that support specialized nerves in the intestine — leads to intestinal dysmotility — a condition in which the gastrointestinal tract loses its ability to move food and other materials along (known as peristalsis) — and that this malfunction is a key factor in the genesis of NEC.”

The enteric nervous system and glial cells are both factors deemed logical in the process of NEC. Furthermore, scientists believe that symptoms – distended abdomen and food intolerance – are not consequences of NEC as previously thought. Instead, scientists believe that they are part of what causes NEC.

During their experiments, researchers noted five lines of evidence that support this process as being a primary factor in NEC development.

5 Lines of Evidence

  1. Mice bred without enteric glia had impaired intestinal movement as compared to their genetically-normal counterparts.
  2. Mice bred with enteric glia unable to produce TLR4 did not lose glial cells, did not have dysmotility, and did not develop NEC.
  3. Providing brain-dependent neurotrophic factor (BDNF) to mice without enteric glia reduced the severity of NEC that did develop. This suggests that BDNF helps protect cells in the intestines.
  4. If there is too much TLR4 in the intestinal wall, releasing BDNF prevents overabundant production, and prevents the immune system from being signaled to attack healthy tissue.
  5. Using oxolinic acid (compound J11 traditionally used in veterinary medicine) enhances the release of BDNF, restores intestinal movement, and reduces the severity of NEC in cases that do develop. This treatment did not work in mice that lacked enteric glia or that were unable to produce BDNF.

Researchers have found that tissue samples taken from mice, piglets, and human infants during NEC surgery all were depleted of enteric glia. Study senior author, David Hackman, M.D. Ph.D. says,

“Because we have shown that enteric glia protect animal intestines from the devastating effects of NEC, it is reasonable to assume a similar scenario exists in humans. And if we can one day repair the system when it’s broken and prevent NEC in premature infants — through the use of enteric glia therapies such as J11 — then that will be one less obstacle for these tiny patients to overcome.”

What the Research Means for Prevention and Treatment of NEC

Having a better understanding of what causes NEC can help scientists and doctors better understand how to prevent and treat the disease. During the study, researchers found that overproduction of TLR4 protein triggers enteric glia loss. This was previously reported in other Johns Hopkins studies.

In experiments, scientists inhibited the TLR4 overproduction, which ensured that glial cells survived, causing cells to produce the growth factor BDNF. BDNF stops the wayward immune response that leads to NEC and promotes healthy growth.

Study lead author, Mark Kovler, M.D., says,

“This finding enabled us to test in mice the use of a compound that could ‘kick-start’ the intestine by preserving enteric glia and their ability to produce BDNF, resulting in restored intestinal movement — and most importantly, the prevention of NEC.”

In full-term babies, TLR4 binds to bacteria and keeps the gut microbiome in check. That’s why NEC is less common in full-term babies. In premature babies, however, TLR4 switches on the immune system and excess amounts of protein cause the body’s defense response to target the intestinal wall.

Conclusion

Now that scientists have a better understanding of the biological processes that lead to NEC, there is hope that they can find ways to identify at-risk infants and prevent NEC from occurring. While we know that feeding preemies human milk instead of cow’s milk-based formulas reduces the risk of NEC, that is not always possible.

For mothers who cannot breastfeed, or in cases where breastmilk is not available, finding ways to protect preemies and prevent NEC is imperative. Now more than ever, there is hope that preventing NEC, reducing the severity of illnesses that do occur, and reducing the risk of infant death are all possibilities.

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