Researchers Discover Biological Process Leading to NEC
Necrotizing enterocolitis, or NEC, is an unfortunate and tragic disease that affects premature infants. NEC is an intestinal disease caused by bacteria invading the tissues of the intestines. Inflammation causes tissue damage and death, and can lead to bowel perforation, sepsis, and infant death.
As many as 12% of premature babies experience NEC. The saddest part is that the mortality rate for the disease is around 50%.
Researchers have been exploring the causes of NEC for many years. Only recently have researchers discovered groundbreaking information about the biological process that leads to NEC. In other words, we now have more information than ever before about what happens inside the body when NEC is developing.
Important Terms to Know
- Glia: Non-neuronal cells located in both the central nervous system (CNS) and peripheral nervous system (PNS). Glial cells provide nourishment to neurons.
- Enteric glia: These are glial cells that live in the walls of the intestinal tract. Enteric glial cells regulate intestinal motility, or movement.
- Motility: Motility also means movement. In this case, movement of the contents of the intestines.
- TLR4: Toll-like receptor 4 (TLR4) is a protein. It serves as an intracellular signaling pathway, and is part of what activates the innate immune system.
- BDNF: Brain-derived neurotrophic factor (BDNF) is a growth factor found in the gut, CNS, and various bodily tissues. BDNF is a crucial component of healthy growth and development.
Biological Process Leading to NEC
Researchers with Johns Hopkins Medicine have discovered what a premature baby’s body goes through as NEC develops. This is important because identifying potential causes and triggers can help healthcare providers develop and offer better preventative measures and treatment options.
Research published in the journal Science Translational Medicine describes the process as,
“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.”
Some researchers are not surprised by the link between the enteric nervous system and glial cells. Prior research in mice, piglets, and humans have found that those with NEC lacked enteric glia. This additional information confirms much of what researchers already knew, and offers deeper insight into how it all takes place in the body. 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.”
Five Lines of Evidence
In the recent study, researchers noted five lines of evidence to support their assertions. These are:
- Mice that were bred without enteric glia had less intestinal movement than their genetically-normal counterparts.
- Mice bred with enteric glia that could not produce TLR4 did not have glial cell loss, did not have impaired movement, and did not develop NEC.
- Administering brain-dependent neurotrophic factor (BDNF) to mice with no enteric glia reduced the severity of NEC. This means that BDNF protects cells in the intestinal tract.
- If there is too much TLR4 in the intestinal wall, releasing BDNF prevents too much production, and prevents the immune system from attacking healthy tissue.
- Using oxolinic acid (known as compound J11 – traditionally used in veterinary medicine) enhances BDNF release, restores intestinal motility, and reduces the severity of NEC.
How New Research Could Prevent Severe NEC and Related Deaths
Researchers now know that TLR4 proteins trigger enteric glial cell loss. In experiments, scientists have tested inhibiting TLR4 overproduction to see if glial cells survived. They did. With glial cells surviving, BDNF was produced enough to block wayward immune responses that lead to the body attacking the intestinal tissue. As a result, there is healthy growth and NEC is less likely.
In full-term babies, enteric glia and BDNF production is more stable, which is why NEC is less common. In premature babies, TLR4 turns on the immune system response, which causes excess proteins to trigger the body’s defense. Instead of targeting bacteria, however, the body targets the intestinal wall.
Using the research we discuss above, researchers believe a key to preventing NEC, and certainly reducing the severity, is preserving enteric glia and helping them produce BDNF. 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.”