Hirschsprung's Disease Associated EnterocolitisNIGNCT03617640
Neuro-Immune Interactions in the Gut
An observational study of Hirschsprung's Disease Associated Enterocolitis, run by University Children's Hospital Basel at 8 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 0 months to 18 yearsHealthy volunteers can take part
- Conditions the study is for
- Hirschsprung's Disease Associated Enterocolitis
- How many people
- 103 participants
- Where
- 8 sitesin 2 countries
- Study dates
- 28 Feb 2015to 28 Feb 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 months to 18 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Study population: patients between 0 and 18 years undergoing bowel resection
Who may be able to join
- Informed consent
Who cannot join
- No signed informed consent No blood from patients with weak general state of health
Trial locations and contacts
8 sites in 2 countries.
8 sites in 2 countries
Switzerland7 sites
Ospedale Regionale di Bellinzona e Valli
Bellinzona, 6500
Inselspital Universität Bern
Bern, 3010
Hôpitaux Universitaires Genève
Geneva, 1205
Bâtiment Hospitalier CHUV
Lausanne, 1011
Luzerner Kantonsspital
Lucerne, 6000
Kinderspital St. Gallen
Sankt Gallen, 9000
Kinderspital Zürich
Zurich, 8032
About this study
Official title: The Enteric Nervous System as Modulator of Mucosal Immune Cells
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.
Read the 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.
- Keywords
- enteric neuropathies, Immune cells, Nervous cells, Microbiom
- Medical subject headings
- Intestinal Pseudo-Obstruction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phenotypic analysis of immune and nervous cell populations
Determining cell frequencies and subtypes using fluorescence-activated cell sorting (FACS) and FlowJo software
Measured: 5 years
Expression profil
RNA expression profile of whole colon tissue and single cell populations
Measured: 5 years
Histological analysis
Microscopic analysis of colonic tissue using immunofluorescence and immunohistochemistry
Measured: 5 years
Secondary outcomes (2)
Microbial metagenomics sequencing
16S/18S/ITS Amplicon
Measured: 5 years
Identifying genetic defect
Targeted Sanger sequencing of known Hirschsprung's disease associated genes
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Aug 2018
- Study start28 Feb 2015
- Primary completion28 Feb 2022
- Study completion28 Feb 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Hirschsprung's Disease Associated EnterocolitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 103 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Children's Hospital Basel
- Sponsor type
- University, hospital or other
- Collaborators
- University Children's Hospital, Zurich, Insel Gruppe AG, University Hospital Bern, Kinderspital St. Gallen, Bâtiment Hospitalier CHUV, University Hospital Heidelberg, Luzerner Kantonsspital, Hôpitaux Universitaires Genève, Ospedale Regionale Bellinzona e Valli
- Responsible party
- Principal investigator, Simone Keck, University Children's Hospital Basel
- Investigators
- Stefan Holland-Cunz, Prof, Principal investigator, University Children's Hospital Basel
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03617640
- Sponsor's protocol ID
- EKNZ 2015-049
- Acronym
- NIG
- Status last verified
- Nov 2022
- First submitted
- 24 Jul 2018
- Last updated
- 4 Nov 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Amiel J, Lyonnet S. Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet. 2001 Nov;38(11):729-39. doi: 10.1136/jmg.38.11.729.
PubMed 11694544Demehri FR, Halaweish IF, Coran AG, Teitelbaum DH. Hirschsprung-associated enterocolitis: pathogenesis, treatment and prevention. Pediatr Surg Int. 2013 Sep;29(9):873-81. doi: 10.1007/s00383-013-3353-1.
PubMed 23913261Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014 Mar;14(3):141-53. doi: 10.1038/nri3608.
PubMed 24566914Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity. 2009 May;30(5):626-35. doi: 10.1016/j.immuni.2009.05.002.
PubMed 19464985Cornet A, Savidge TC, Cabarrocas J, Deng WL, Colombel JF, Lassmann H, Desreumaux P, Liblau RS. Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn's disease? Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13306-11. doi: 10.1073/pnas.231474098. Epub 2001 Oct 30.
PubMed 11687633Flamant M, Aubert P, Rolli-Derkinderen M, Bourreille A, Neunlist MR, Mahe MM, Meurette G, Marteyn B, Savidge T, Galmiche JP, Sansonetti PJ, Neunlist M. Enteric glia protect against Shigella flexneri invasion in intestinal epithelial cells: a role for S-nitrosoglutathione. Gut. 2011 Apr;60(4):473-84. doi: 10.1136/gut.2010.229237. Epub 2010 Dec 7.
PubMed 21139062Rusmini M, Griseri P, Lantieri F, Matera I, Hudspeth KL, Roberto A, Mikulak J, Avanzini S, Rossi V, Mattioli G, Jasonni V, Ravazzolo R, Pavan WJ, Pini-Prato A, Ceccherini I, Mavilio D. Induction of RET dependent and independent pro-inflammatory programs in human peripheral blood mononuclear cells from Hirschsprung patients. PLoS One. 2013;8(3):e59066. doi: 10.1371/journal.pone.0059066. Epub 2013 Mar 18.
PubMed 23527089
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Enteric Nervous System as Modulator of Mucosal Immune Cells
- ClinicalTrials.gov ID
- NCT03617640
- Acronym / sponsor ID
- NIG / EKNZ 2015-049
- Keywords
- enteric neuropathies, Immune cells, Nervous cells, Microbiom
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 103 participants (actual)
- Lead sponsor
- University Children's Hospital BaselUniversity, hospital or other
- Collaborators
- University Children's Hospital, Zurich, Insel Gruppe AG, University Hospital Bern, Kinderspital St. Gallen, Bâtiment Hospitalier CHUV, University Hospital Heidelberg, Luzerner Kantonsspital, Hôpitaux Universitaires Genève, Ospedale Regionale Bellinzona e Valli
- Study start
- 28 Feb 2015 (actual)
- Primary completion
- 28 Feb 2022 (actual)
- Study completion
- 28 Feb 2022 (actual)
- First posted
- 6 Aug 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- 0 months to 18 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
- Study population
- patients between 0 and 18 years undergoing bowel resection
Key inclusion criteria (1 listed)
- Informed consent
Key exclusion criteria (1 listed)
- No signed informed consent No blood from patients with weak general state of health
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
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
Expression profil
Time frame: 5 years
RNA expression profile of whole colon tissue and single cell populations
Histological analysis
Time frame: 5 years
Microscopic analysis of colonic tissue using immunofluorescence and immunohistochemistry
2 secondary outcomes
Microbial metagenomics sequencing
Time frame: 5 years
Identifying genetic defect
Time frame: 5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2022.
- Background: PubMed 11694544Amiel J, Lyonnet S. Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet. 2001 Nov;38(11):729-39. doi: 10.1136/jmg.38.11.729.
- Background: PubMed 23913261Demehri FR, Halaweish IF, Coran AG, Teitelbaum DH. Hirschsprung-associated enterocolitis: pathogenesis, treatment and prevention. Pediatr Surg Int. 2013 Sep;29(9):873-81. doi: 10.1007/s00383-013-3353-1.
- Background: PubMed 24566914Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014 Mar;14(3):141-53. doi: 10.1038/nri3608.
- Background: PubMed 19464985Curotto de Lafaille MA, Lafaille JJ. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity. 2009 May;30(5):626-35. doi: 10.1016/j.immuni.2009.05.002.
- Background: PubMed 11687633Cornet A, Savidge TC, Cabarrocas J, Deng WL, Colombel JF, Lassmann H, Desreumaux P, Liblau RS. Enterocolitis induced by autoimmune targeting of enteric glial cells: a possible mechanism in Crohn's disease? Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13306-11. doi: 10.1073/pnas.231474098. Epub 2001 Oct 30.
- Background: PubMed 21139062Flamant M, Aubert P, Rolli-Derkinderen M, Bourreille A, Neunlist MR, Mahe MM, Meurette G, Marteyn B, Savidge T, Galmiche JP, Sansonetti PJ, Neunlist M. Enteric glia protect against Shigella flexneri invasion in intestinal epithelial cells: a role for S-nitrosoglutathione. Gut. 2011 Apr;60(4):473-84. doi: 10.1136/gut.2010.229237. Epub 2010 Dec 7.
- Background: PubMed 23527089Rusmini M, Griseri P, Lantieri F, Matera I, Hudspeth KL, Roberto A, Mikulak J, Avanzini S, Rossi V, Mattioli G, Jasonni V, Ravazzolo R, Pavan WJ, Pini-Prato A, Ceccherini I, Mavilio D. Induction of RET dependent and independent pro-inflammatory programs in human peripheral blood mononuclear cells from Hirschsprung patients. PLoS One. 2013;8(3):e59066. doi: 10.1371/journal.pone.0059066. Epub 2013 Mar 18.
- Individual participant dataSharing planned: No
Related trials for Hirschsprung's Disease Associated Enterocolitis
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Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)
Hirschprung's Disease, Hirschsprung Disease
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Stefan Holland-Cunz, Prof principal investigator
University Children's Hospital Basel
8 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hirschsprung's Disease Associated Enterocolitis, run by University Children's Hospital Basel at 8 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in Switzerland, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phenotypic analysis of immune and nervous cell populations (time frame: 5 years). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03617640, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2022.