title: Enteric neural disruption in necrotizing enterocolitis occurs in association with myenteric glial cell CCL20 expression.
abstract: OBJECTIVE
  The aetiology of necrotising enterocolitis (NEC) is unknown, but luminal factors and epithelial leakiness appear critical triggers of an inflammatory cascade. A separate finding has been suggested in mouse models, in which disruption of glial cells in the myenteric plexus induced a severe NEC-like lesion. We have thus looked for evidence of neuroglial abnormality in NEC.
  
  
  METHODS
  We studied full-thickness resected specimens from 20 preterm infants with acute NEC and from 13 control infants undergoing resection for other indications. Immunohistochemical analysis was performed for immunological (CD3, syndecan-1, human leucocyte antigen-DR), neural (glial fibrillary acidic protein [GFAP], nerve growth factor receptor, neurofilament protein, neuron-specific enolase), and functional markers (Ki67), and for potential inflammatory regulators (interleukin-12, transforming growth factor-β, CCL20, CCR6).
  
  
  RESULTS
  Expression of the chemokine CCL20 and its receptor CCR6 was significantly upregulated in myenteric plexus in NEC, with CCL20 strongly expressed by glial cells. In 9 of 20 cases with NEC, myenteric plexus architecture and GFAP+ glial cells were normal, with preserved submucosal and mucosal innervation; however, 11 cases showed disrupted myenteric plexus architecture, reduced GFAP expression, and loss of submucosal and mucosal innervation. Persistent abnormalities were identified in the 2 infants who had ongoing inflammation at ileostomy closure.
  
  
  CONCLUSIONS
  Our findings identified heterogeneity among patients with NEC. Approximately half showed evidence of marked neural abnormality extending from the deeper layers of the intestine, associated with glial activation and myenteric plexus disruption. The factors that may activate enteric glia in this manner, potentially including bacterial products or viruses, remain to be determined.
authors.affiliation: *Department of Paediatric Gastroenterology, Booth Hall Children's Hospital, Manchester †Department of Paediatric Gastroenterology, Addenbrooke's Hospital Cambridge, Cambridge ‡Department of Gastroenterology, Manchester Royal Infirmary, Manchester §Department of Surgery, John Radcliffe Hospital, Oxford ||Department of Histopathology, University Hospital of Coventry and Warwickshire NHS Trust ¶Division of Metabolic and Vascular Health, Warwick Medical School, Coventry, UK.
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Fagbemi
authors.forename: Franco
authors.initials: F
authors.lastname: Torrente
authors.forename: Joanne
authors.initials: J
authors.lastname: Puleston
authors.forename: Kokila
authors.initials: K
authors.lastname: Lakhoo
authors.forename: Sean
authors.initials: S
authors.lastname: James
authors.forename: Simon H
authors.initials: SH
authors.lastname: Murch
mesh_terms: D054418:Chemokine CCL20 / Q000378:metabolism*; D020345:Enterocolitis, Necrotizing / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation / Q000150:complications; D007413:Intestinal Mucosa / Q000294:innervation / Q000378:metabolism; D007422:Intestines / Q000294:innervation / Q000473:pathology; D008297:Male; D009197:Myenteric Plexus / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D054399:Receptors, CCR6 / Q000378:metabolism*
chemical_list: C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D054399:Receptors, CCR6