In a study on mice reported today in the journal Science Translational Medicine, a research team from Johns Hopkins Medicine has provided what may be the most definitive view to date of the biological process leading to necrotizing enterocolitis (ENC), a dangerous inflammatory disease that can destroy the intestinal lining of a premature baby. and cause death in a third of the cases. Researchers have shown that the loss of enteric glia – cells that support specialized nerves in the gut – results in intestinal dysmotility – a condition in which the gastrointestinal tract loses its ability to move food and other material (known under the name of peristalsis) – and that this dysfunction is a key factor in the genesis of NEC.
Symptoms seen in premature infants, such as a distended abdomen and food intolerances – things that result from intestinal dysmotility – have traditionally been viewed as consequences of NEC. Our results suggest, perhaps for the first time, that these conditions may in fact be a cause, rather than a simple results, from NEC. “
David Hackam, MD, Ph.D., senior study author, chief surgeon at Johns Hopkins Children’s Center and professor of surgery at Johns Hopkins University School of Medicine
Hackam and his colleagues say it makes sense that the enteric nervous system and the glial cells that support its function play a crucial role in the genesis of NEC. “This system has been called ‘the body’s second brain’ because of its importance to overall health,” he says.
In their study, the researchers also found that overproduction of a protein called toll-type receptor 4 (TLR4) – shown in previous studies from Johns Hopkins Medicine to be involved in the onset of NEC – triggers enteric loss of glia. In separate experiments, they demonstrated that inhibition of TLR4 and survival of enteric glia allows cells to produce a growth factor called brain-dependent neurotrophic factor (BDNF), which in turn reduces the capricious immune response leading at the NEC.
“This discovery allowed us to test in mice the use of a compound that could ‘start’ the intestine by preserving enteric glia and their ability to produce BDNF, which helped restore bowel movement and, above all, to prevent the NEC. Says lead author of the study, Mark Kovler, MD, resident in general surgery at Johns Hopkins University School of Medicine.
Seen in up to 12% of newborns born before 37 weeks’ gestation, NEC is a rapidly progressive gastrointestinal emergency in which normally harmless gut bacteria invade the underdeveloped colon wall of the premature infant, causing inflammation which can ultimately destroy healthy tissue at the site. . If enough cells necrotize (die) to the point of creating a hole in the intestinal wall, harmful bacteria can enter the bloodstream and cause life-threatening sepsis.
In previous studies on mice, researchers at Johns Hopkins Medicine have shown that NEC occurs when the underdeveloped gut lining in premature infants produces higher than normal amounts of TLR4. TLR4 in full-term babies binds to bacteria in the gut and helps control threatening germs. However, in premature infants TLR4 can act as an immune system switch, with excessive amounts of protein mistakenly directing the body’s defense mechanism against the gut wall.
“Knowing this, we designed our current study to see if TLR4 was involved in enteric glia loss, and if so, how that might pave the way for the development of NEC,” says Kovler.
As a result of their experiments, the researchers were able to provide five sources of evidence that intestinal dysmotility – due to enteric glia loss influenced by TLR4 – is a critical factor in the development of NEC:
- Three different strains of mice raised without enteric glia showed impaired bowel movements and, in turn, more severe NEC than wild-type (genetically normal) mice.
- Mice bred with enteric glial cells that cannot produce TLR4 did not lose glial cells, did not show dysmotility, or did not develop NEC, indicating that TLR4 is required for the loss. glial cells and its link to disease.
- Administration of BDNF to glia-deficient mice reduced the severity of NEC in animals, suggesting that release of BDNF from enteric glia helps cells protect the gut from NEC.
- When too much TLR4 is present in the intestinal wall, the release of BDNF prevents the overabundant protein from signaling the immune system to mistakenly attack healthy tissue.
- Oxolinic acid (designated compound J11 by the Johns Hopkins medical team), a synthetic antibiotic developed in Japan and used in veterinary medicine, has been shown to improve the release of BDNF from enteric glia, restore bowel movement and reduce the severity of NEC in wild type mice. By comparison – and as expected – it didn’t work in mice lacking enteric glia and unable to produce BDNF.
The researchers also studied intestinal tissue damaged by NEC taken from wild-type mice, piglets and human infants (whose tissues had been removed during surgery to treat NEC), finding in all cases that the enteric glia was exhausted.
“Because we have shown that enteric glia protects the intestines of animals from the devastating effects of NEC, it is reasonable to assume that a similar scenario exists in humans,” Hackam explains. “And if we can one day fix the system when it is down and prevent NEC in premature infants – through the use of enteric glia therapies such as J11 – then that will be one less hurdle for us to overcome. these little patients. “
Besides Hackam, the members of the Johns Hopkins medical team are Mark Kovler, Andres Gonzalez Salazar, William Fulton, Peng Lu, Yukihiro Yamaguchi, Qinjie Zhou, Maame Sampah, Asuka Ishiyama, Thomas Prindle Jr., Sanxia Wang, Hongpeng Jia and Chhinder Sodhi. Peter Wipf of the University of Pittsburgh also participated in the study.
The research was funded by National Institutes of Health grants R01DK117186, R01DK121824, R35GM141956, and T32DK00771322.
Hackam, Lu and Sodhi have filed a pending patent cooperation treaty (international patent) application for “compounds and treatments that improve the function of the enteric nervous system”. The other authors declare no competing interests.
Kovler, ML, et al. (2021) The loss of enteric glia mediated by the Toll-like 4 receptor is essential for the development of necrotizing enterocolitis. Scientific translational medicine. doi.org/10.1126/scitranslmed.abg3459.