Abstract
IntroductionIntestinal dysmotility following human necrotizing enterocolitis suggests that the enteric nervous system is injured during the disease. We examined human intestinal specimens to characterize the enteric nervous system injury that occurs in necrotizing enterocolitis, and then used an animal model of experimental necrotizing enterocolitis to determine whether transplantation of neural stem cells can protect the enteric nervous system from injury.MethodsHuman intestinal specimens resected from patients with necrotizing enterocolitis (n = 18), from control patients with bowel atresia (n = 8), and from necrotizing enterocolitis and control patients undergoing stoma closure several months later (n = 14 and n = 6 respectively) were subjected to histologic examination, immunohistochemistry, and real-time reverse-transcription polymerase chain reaction to examine the myenteric plexus structure and neurotransmitter expression. In addition, experimental necrotizing enterocolitis was induced in newborn rat pups and neurotransplantation was performed by administration of fluorescently labeled neural stem cells, with subsequent visualization of transplanted cells and determination of intestinal integrity and intestinal motility.ResultsThere was significant enteric nervous system damage with increased enteric nervous system apoptosis, and decreased neuronal nitric oxide synthase expression in myenteric ganglia from human intestine resected for necrotizing enterocolitis compared with control intestine. Structural and functional abnormalities persisted months later at the time of stoma closure. Similar abnormalities were identified in rat pups exposed to experimental necrotizing enterocolitis. Pups receiving neural stem cell transplantation had improved enteric nervous system and intestinal integrity, differentiation of transplanted neural stem cells into functional neurons, significantly improved intestinal transit, and significantly decreased mortality compared with control pups.ConclusionsSignificant injury to the enteric nervous system occurs in both human and experimental necrotizing enterocolitis. Neural stem cell transplantation may represent a novel future therapy for patients with necrotizing enterocolitis.
Highlights
Intestinal dysmotility following human necrotizing enterocolitis suggests that the enteric nervous system is injured during the disease
Neuronal nitric oxide synthase-producing neurons and choline acetyl transferase-producing neurons are involved in the regulation of intestinal motility, and nNOS/chAT misbalance has been reported in certain intestinal motility disorders [8]
Enteric nervous system is injured in human necrotizing enterocolitis We compared human intestinal specimens from patients undergoing initial bowel resection for small bowel atresia or for Necrotizing enterocolitis (NEC), as well as stoma closure specimens several months later
Summary
Intestinal dysmotility following human necrotizing enterocolitis suggests that the enteric nervous system is injured during the disease. Current overall mortality rates are ~30%, with higher rates for very low birth weight babies. This high morbidity and mortality represent a significant medical problem and a costly burden to society. The content of neurotrophic factors and cytokines in human breast milk contribute to the postnatal development of the ENS [6]. An immature ENS has been observed in premature infants, represented as decreased organized intestinal motility. It is thought that this intrinsic ENS immaturity may contribute to the development of NEC [7]. The intestinal dysfunction that is present after successful medical or surgical management of NEC suggests that the compromised ENS is not fully recovered from the acute intestinal insult
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