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Neuro-Immune Interactions in the Gut (NIG)

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ClinicalTrials.gov Identifier: NCT03617640
Recruitment Status : Recruiting
First Posted : August 6, 2018
Last Update Posted : August 6, 2018
Sponsor:
Collaborators:
University Children's Hospital, Zurich
Inselspital Universität Bern
Kinderspital St. Gallen
Bâtiment Hospitalier CHUV
Universität Klinikum Heidelberg
Luzerner Kantonsspital
Hôpitaux Universitaires Genève
Ospedale Regionale di Bellinzona e Valli
Information provided by (Responsible Party):
Simone Keck, University Children's Hospital Basel

Brief Summary:
Hirschsprung`s disease (HD) is diagnosed shortly after birth and is characterized by the presence of megacolon. HD is caused when ganglion cells of the enteric nervous system (ENS) in the wall of the large intestine do not develop before birth. This results in a lack of gastrointestinal motility and leads to stool obstruction. It is known that ablation of enteric nerves is associated with intestinal infection and inflammation. Indeed the most severe complication in HD is Hirschsprung`s associated enterocolitis (HAEC), characterized by explosive diarrhea, abdominal distension, fever and impending septic shock. Bacteria overgrowth and changes in colonic mucosal immune cell populations during HAEC suggest a possible defect in mucosal immune homeostasis. Under steady state conditions, the mucosal immune system must be tightly controlled to avoid harmful reactions against commensal flora and food antigens, while allowing protective immune responses against invading pathogens. This balance between tolerance and defense is influenced by the mucosal microenvironment, which in turn determines the phenotype and stability of mucosal immune cell populations. The goal of this project is to understand if the enteric nervous system plays a role in regulating mucosal immunity and how this might contribute to the development of HAEC.

Condition or disease
Hirschsprung's Disease Associated Enterocolitis

Detailed Description:
Hirschsprung`s disease (HD) is diagnosed shortly after birth and is characterized by the absence of enteric nerves in parts of colon [Amiel et al.]. Following surgical correction many patients develop HD-associated enterocolitis (HAEC), a condition distinguished by intestinal inflammation resulting in abdominal distension, severe diarrhea, fever and sepsis [Demehri et al.]. The underlying factors leading to HAEC remain poorly understood and likely involve a defect in epithelial barrier, including decreased mucin production and insufficient immunoglobulin translocation. The establishment of the epithelial barrier is dependent on epithelial recognition of microbial products by innate immune receptors, like toll-like receptors (TLRs) [Peterson et al.]. TLR-dependent epithelial recognition of microflora also coordinates the immune response away from harmless commensal bacteria and towards pathogenic invaders. Both innate and adaptive effector cell functions are influenced by epithelial-derived signals. Under homeostatic conditions commensal bacteria induce anti-inflammatory cytokines in epithelial cells which trigger a tolerogenic phenotype in mucosal antigen presenting cells (APC) resulting in generation of commensal-specific regulatory T cells (Tregs) [Curotto de Lafaille et al.]. During infection, recognition of pathogenic organisms by epithelial cells leads to secretion of inflammatory cytokines thereby inducing an inflammatory APC phenotype which promotes T effector cell (Th1, Th17) generation. The enteric nervous system is directly located underneath the epithelium and controls epithelial cell function. Ablation of enteric glia cells, one of the two cell types of the ENS, in mice is associated with inflammation and enterocolitis [Cornet et al.]. In a study from 2011 Flamant and co-workers demonstrate that enteric glia cells protect from a shigella flexneri invasion by preventing lesions in the epithelial barrier mediated by the glia cell derived neurothrophic factor S-nitrosoglutathione (GSNO) [Flamant et al.]. We hypothesize that the lack of an enteric nervous system in HD patients modulates the microbial recognition of epithelial cells and thereby the phenotype of underlying mucosal APCs and effector T cells; this might be associated with the manifestation of HAEC.

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Study Type : Observational
Estimated Enrollment : 180 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Enteric Nervous System as Modulator of Mucosal Immune Cells
Actual Study Start Date : February 28, 2015
Estimated Primary Completion Date : February 28, 2020
Estimated Study Completion Date : February 28, 2020


Group/Cohort
Hirschsprung's disease patients
Children diagnosed with Hirschsprung's disease or Hirschsprung's disease associated enterocolitis
control patients
Children diagnosed and treated for miscellaneous bowel diseases



Primary Outcome Measures :
  1. Phenotypic analysis of immune and nervous cell populations [ Time Frame: 5 years ]
    Determining cell frequencies and subtypes using fluorescence-activated cell sorting (FACS) and FlowJo software

  2. Expression profil [ Time Frame: 5 years ]
    RNA expression profile of whole colon tissue and single cell populations

  3. Histological analysis [ Time Frame: 5 years ]
    Microscopic analysis of colonic tissue using immunofluorescence and immunohistochemistry


Secondary Outcome Measures :
  1. Microbial metagenomics sequencing [ Time Frame: 5 years ]
    16S/18S/ITS Amplicon

  2. Identifying genetic defect [ Time Frame: 5 years ]
    Targeted Sanger sequencing of known Hirschsprung's disease associated genes


Biospecimen Retention:   Samples With DNA
  • colonic tissue
  • blood


Information from the National Library of Medicine

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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
patients between 0 and 18 years undergoing bowel resection
Criteria

Inclusion Criteria:

Informed consent

Exclusion Criteria:

No signed informed consent No blood from patients with weak general state of health


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03617640


Contacts
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Contact: Simone Keck, PhD 0041617042813 simone.keck@unibas.ch
Contact: Stefan Holland-Cunz, Prof 0041617042840 Stefan.Holland-Cunz@ukbb.ch

Locations
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Germany
Kinderchirurgie Universität Heidelberg Recruiting
Heidelberg, Germany, 69120
Contact: Philipp Romero, Dr. med    00496221566281    philipp.romero@med.uni-heidelberg.de   
Principal Investigator: Philipp Romero, Dr. med         
Switzerland
Ospedale Regionale di Bellinzona e Valli Recruiting
Bellinzona, Switzerland, 6500
Contact: Mario Mendoza Sagaon, Dr. med    0041918119165    mario.mendozasagaon@eoc.ch   
Principal Investigator: Mario Mendoza Sagaon, Dr. med         
Inselspital Universität Bern Recruiting
Bern, Switzerland, 3010
Contact: Dietmar Cholewa, Dr. med.    0041316329256    Dietmar.Cholewa@insel.ch   
Principal Investigator: Dietmar Cholewa, Dr. med         
Hôpitaux Universitaires Genève Recruiting
Geneva, Switzerland, 1205
Contact: Barbara Wildhaber, Prof    0041223724663    Barbara.wildhaber@hcuge.ch   
Principal Investigator: Barbara Wildhaber, Prof         
Bâtiment Hospitalier CHUV Recruiting
Lausanne, Switzerland, 1011
Contact: Eleuthere Stathopoulos, Dr. med    004179 556 82 57    Eleuthere.Stathopoulos@chuv.ch   
Principal Investigator: Blaise-Julien Meyrat, Dr. med         
Luzerner Kantonsspital Recruiting
Luzern, Switzerland, 6000
Contact: Philipp Szavay, Dr. med    0041412053155    philipp.szavay@luks.ch   
Principal Investigator: Philipp Szavay, Dr. med         
Kinderspital St. Gallen Recruiting
Saint Gallen, Switzerland, 9000
Contact: Thomas Krebs, Dr. med    0041712437502    thomas.krebs@kispisg.ch   
Principal Investigator: Thomas Krebs, Dr. med         
Kinderspital Zürich Recruiting
Zürich, Switzerland, 8032
Contact: Sasha Tharakan, Dr. med    0041 44 266 7111    Sasha.Tharakan@kispi.uzh.ch   
Principal Investigator: Sasha Tharakan, Dr. med         
Sponsors and Collaborators
University Children's Hospital Basel
University Children's Hospital, Zurich
Inselspital Universität Bern
Kinderspital St. Gallen
Bâtiment Hospitalier CHUV
Universität Klinikum Heidelberg
Luzerner Kantonsspital
Hôpitaux Universitaires Genève
Ospedale Regionale di Bellinzona e Valli
Investigators
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Principal Investigator: Stefan Holland-Cunz, Prof University Children's Hospital Basel

Publications:

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Responsible Party: Simone Keck, Dr. Simone Keck, University Children's Hospital Basel
ClinicalTrials.gov Identifier: NCT03617640    
Other Study ID Numbers: EKNZ 2015-049
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: August 6, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Simone Keck, University Children's Hospital Basel:
enteric neuropathies
Immune cells
Nervous cells
Microbiom
Additional relevant MeSH terms:
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Enterocolitis
Hirschsprung Disease
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Digestive System Abnormalities
Megacolon
Colonic Diseases
Congenital Abnormalities