Lack of Mucosal Cholinergic Innervation Is Associated With Increased Risk of Enterocolitis in Hirschsprung's Disease
| Autor: | Simone Keck, Virginie Galati-Fournier, Urs Kym, Michèle Moesch, Jakob Usemann, Isabelle Müller, Ulrike Subotic, Sasha J. Tharakan, Thomas Krebs, Eleuthere Stathopoulos, Peter Schmittenbecher, Dietmar Cholewa, Philipp Romero, Bertram Reingruber, Elisabeth Bruder, NIG Study Group, Stefan Holland-Cunz |
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| Přispěvatelé: | University of Zurich, Keck, Simone |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Pathology FISH fluorescence in situ hybridization Lipopolysaccharide Receptors RC799-869 SEMA semaphorin Enteric Nervous System 0302 clinical medicine AChE acetylcholinesterase FACS fluorescence-activated cell sorting Interleukin 23 Intestinal Mucosa Child NOS nitric oxide synthase 610 Medicine & health Hirschsprung's disease Original Research Foxp3+ forkhead box P3 positive Enterocolitis VN vagus nerve Gastroenterology ILC innate lymphoid cell Diseases of the digestive system. Gastroenterology Cholinergic Neurons Editorial Child Preschool Acetylcholinesterase Cytokines CCR2 C-C chemokine receptor type 2 030211 gastroenterology & hepatology EPHB2 ephrin type B-receptor 2 NK natural killer 360 Social problems & social services PBMC peripheral blood mononuclear cell medicine.medical_specialty MΦ macrophages Cholinergic Nerve Fibers 03 medical and health sciences OTU operational taxonomic unit Humans Hirschsprung Disease RNA Messenger UNC5B UNC-5 homology B ENS enteric nervous system MMΦ muscle macrophages Macrophages HSCR Hirschsprung’s disease Infant GDF growth/differentiation factor Epithelial Cells medicine.disease IL interleukin NRP1 neuropilin-1 030104 developmental biology APC antigen-presenting cell Th17 Cells 2721 Hepatology Microbiome NCR NK cell receptors 0301 basic medicine Neuroimmunology VIP vasoactive intestinal peptide Cohort Studies Risk Factors LP lamina propria CAIP cholinergic anti-inflammatory pathway TNF tumor necrosis factor qRT-PCR quantitative real-time polymerase chain reaction DC descending colon Intestines CX3CR1 CX3X chemokine receptor 1 Phenotype medicine.anatomical_structure Female VAChT vesicular acetylcholine transporter medicine.symptom TH tyrosine hydroxylase PBS phosphate-buffered saline Inflammation Nerve fiber Immune system medicine 2715 Gastroenterology 10220 Clinic for Surgery Th17 T-helper 17 PCA principal component analysis Hepatology ACh acetylcholine business.industry Infant Newborn BMP bone morphogenetic protein α7nAChR α7-nicotinic ACh receptor Ig immunoglobulin Treg regulatory T cells 10036 Medical Clinic POI postoperative ileus Dysbiosis Cholinergic business |
| Zdroj: | Keck, Simone; Galati-Fournier, Virginie; Kym, Urs; Moesch, Michèle; Usemann, Jakob; Müller, Isabelle; Subotic, Ulrike; Tharakan, Sasha J.; Krebs, Thomas; Stathopoulos, Eleuthere; Schmittenbecher, Peter; Cholewa, Dietmar; Romero, Philipp; Reingruber, Bertram; Bruder, Elisabeth; NIG, Study Group; Holland-Cunz, Stefan (2021). Lack of Mucosal Cholinergic Innervation Is Associated With Increased Risk of Enterocolitis in Hirschsprung’s Disease. Cellular and molecular gastroenterology and hepatology, 12(2), pp. 507-545. Elsevier 10.1016/j.jcmgh.2021.03.004 Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 2, Pp 507-545 (2021) Cellular and Molecular Gastroenterology and Hepatology |
| DOI: | 10.5167/uzh-216782 |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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