Lack of Mucosal Cholinergic Innervation Is Associated With Increased Risk of Enterocolitis in Hirschsprung's Disease.
Acetylcholinesterase
/ metabolism
Child
Child, Preschool
Cholinergic Neurons
/ pathology
Cohort Studies
Cytokines
/ metabolism
Dysbiosis
/ immunology
Enterocolitis
/ etiology
Epithelial Cells
/ metabolism
Female
Hirschsprung Disease
/ complications
Humans
Infant
Infant, Newborn
Inflammation
/ immunology
Intestinal Mucosa
/ innervation
Lipopolysaccharide Receptors
/ metabolism
Macrophages
/ metabolism
Male
Phenotype
RNA, Messenger
/ genetics
Risk Factors
Cholinergic Nerve Fibers
Enterocolitis
Macrophages
Microbiome
Neuroimmunology
Th17 Cells
Journal
Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302
Informations de publication
Date de publication:
2021
2021
Historique:
received:
14
07
2020
revised:
09
03
2021
accepted:
09
03
2021
pubmed:
21
3
2021
medline:
28
1
2022
entrez:
20
3
2021
Statut:
ppublish
Résumé
Hirschsprung's disease (HSCR) is a congenital intestinal motility disorder defined by the absence of enteric neuronal cells (ganglia) in the distal gut. The development of HSCR-associated enterocolitis remains a life-threatening complication. Absence of enteric ganglia implicates innervation of acetylcholine-secreting (cholinergic) nerve fibers. Cholinergic signals have been reported to control excessive inflammation, but the impact on HSCR-associated enterocolitis is unknown. We enrolled 44 HSCR patients in a prospective multicenter study and grouped them according to their degree of colonic mucosal acetylcholinesterase-positive innervation into low-fiber and high-fiber patient groups. The fiber phenotype was correlated with the tissue cytokine profile as well as immune cell frequencies using Luminex analysis and fluorescence-activated cell sorting analysis of colonic tissue and immune cells. Using confocal immunofluorescence microscopy, macrophages were identified in close proximity to nerve fibers and characterized by RNA-seq analysis. Microbial dysbiosis was analyzed in colonic tissue using 16S-rDNA gene sequencing. Finally, the fiber phenotype was correlated with postoperative enterocolitis manifestation. The presence of mucosal nerve fiber innervation correlated with reduced T-helper 17 cytokines and cell frequencies. In high-fiber tissue, macrophages co-localized with nerve fibers and expressed significantly less interleukin 23 than macrophages from low-fiber tissue. HSCR patients lacking mucosal nerve fibers showed microbial dysbiosis and had a higher incidence of postoperative enterocolitis. The mucosal fiber phenotype might serve as a prognostic marker for enterocolitis development in HSCR patients and may offer an approach to personalized patient care and new therapeutic options.
Sections du résumé
BACKGROUND & AIMS
Hirschsprung's disease (HSCR) is a congenital intestinal motility disorder defined by the absence of enteric neuronal cells (ganglia) in the distal gut. The development of HSCR-associated enterocolitis remains a life-threatening complication. Absence of enteric ganglia implicates innervation of acetylcholine-secreting (cholinergic) nerve fibers. Cholinergic signals have been reported to control excessive inflammation, but the impact on HSCR-associated enterocolitis is unknown.
METHODS
We enrolled 44 HSCR patients in a prospective multicenter study and grouped them according to their degree of colonic mucosal acetylcholinesterase-positive innervation into low-fiber and high-fiber patient groups. The fiber phenotype was correlated with the tissue cytokine profile as well as immune cell frequencies using Luminex analysis and fluorescence-activated cell sorting analysis of colonic tissue and immune cells. Using confocal immunofluorescence microscopy, macrophages were identified in close proximity to nerve fibers and characterized by RNA-seq analysis. Microbial dysbiosis was analyzed in colonic tissue using 16S-rDNA gene sequencing. Finally, the fiber phenotype was correlated with postoperative enterocolitis manifestation.
RESULTS
The presence of mucosal nerve fiber innervation correlated with reduced T-helper 17 cytokines and cell frequencies. In high-fiber tissue, macrophages co-localized with nerve fibers and expressed significantly less interleukin 23 than macrophages from low-fiber tissue. HSCR patients lacking mucosal nerve fibers showed microbial dysbiosis and had a higher incidence of postoperative enterocolitis.
CONCLUSIONS
The mucosal fiber phenotype might serve as a prognostic marker for enterocolitis development in HSCR patients and may offer an approach to personalized patient care and new therapeutic options.
Identifiants
pubmed: 33741501
pii: S2352-345X(21)00056-4
doi: 10.1016/j.jcmgh.2021.03.004
pmc: PMC8258990
pii:
doi:
Substances chimiques
Cytokines
0
Lipopolysaccharide Receptors
0
RNA, Messenger
0
Acetylcholinesterase
EC 3.1.1.7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
507-545Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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