| Autor: |
Kovler ML; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Gonzalez Salazar AJ; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Fulton WB; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Lu P; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Yamaguchi Y; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Zhou Q; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Sampah M; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Ishiyama A; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Prindle T Jr; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Wang S; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Jia H; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Wipf P; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA., Sodhi CP; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA., Hackam DJ; Division of Pediatric Surgery, Johns Hopkins University School of Medicine and the Johns Hopkins Children's Center, Baltimore, MD 21287, USA. |
| Abstrakt: |
Necrotizing enterocolitis (NEC) is a devastating disease of premature infants, whose pathogenesis remains incompletely understood, although activation of the Gram-negative bacterial receptor Toll-like receptor 4 (TLR4) on the intestinal epithelium plays a critical role. Patients with NEC typically display gastrointestinal dysmotility before systemic disease is manifest, suggesting that dysmotility could drive NEC development. Both intestinal motility and inflammation are governed by the enteric nervous system, a network of enteric neurons and glia. We hypothesized here that enteric glia loss in the premature intestine could lead to dysmotility, exaggerated TLR4 signaling, and NEC development. We found that intestinal motility is reduced early in NEC in mice, preceding the onset of intestinal inflammation, whereas pharmacologic restoration of intestinal motility reduced NEC severity. Ileal samples from mouse, piglet, and human NEC revealed enteric glia depletion, and glia-deficient mice ( Plp1 ΔDTR , Sox10 ΔDTR , and Bdnf ΔDTR ) showed increased NEC severity compared with wild-type mice. Mice lacking TLR4 on enteric glia ( Sox10-Tlr4 ko ) did not show NEC-induced enteric glia depletion and were protected from NEC. Mechanistically, brain-derived neurotrophic factor (BDNF) from enteric glia restrained TLR4 signaling on the intestine to prevent NEC. BDNF was reduced in mouse and human NEC, and BDNF administration reduced both TLR4 signaling and NEC severity in enteric glia–deficient mice. Last, we identified an agent (J11) that enhanced enteric glial BDNF release, inhibited intestinal TLR4, restored motility, and prevented NEC in mice. Thus, enteric glia loss might contribute to NEC through intestinal dysmotility and increased TLR4 activation, suggesting enteric glia therapies for this disorder. |
