Neuro-Immune Interactions in the Gut

Hirschsprung's Disease Associated Enterocolitis Clinical Trial

— NIG  

Official title:

The Enteric Nervous System as Modulator of Mucosal Immune Cells

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03617640
• Other study ID #: EKNZ 2015-049
• Status: Completed
• Start date: February 28, 2015
• Est. completion date: February 28, 2022

Study information

• Verified date: November 2022
• Source: University Children's Hospital Basel
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 103
• Est. completion date: February 28, 2022
• Est. primary completion date: February 28, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 0 Months to 18 Years

Eligibility

Inclusion Criteria:

Informed consent

Exclusion Criteria:

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

Related Conditions & MeSH terms

• Enterocolitis
• Hirschsprung Disease
• Hirschsprung's Disease Associated Enterocolitis

Locations

Country	Name	City	State
Germany	Kinderchirurgie Universität Heidelberg	Heidelberg
Switzerland	Ospedale Regionale di Bellinzona e Valli	Bellinzona
Switzerland	Inselspital Universität Bern	Bern
Switzerland	Hôpitaux Universitaires Genève	Geneva
Switzerland	Bâtiment Hospitalier CHUV	Lausanne
Switzerland	Luzerner Kantonsspital	Luzern
Switzerland	Kinderspital St. Gallen	Saint Gallen
Switzerland	Kinderspital Zürich	Zürich

Sponsors (9)

Lead Sponsor	Collaborator
University Children's Hospital Basel	Bâtiment Hospitalier CHUV, Hôpitaux Universitaires Genève, Inselspital Universität Bern, Kinderspital St. Gallen, Luzerner Kantonsspital, Ospedale Regionale di Bellinzona e Valli, Universität Klinikum Heidelberg, University Children's Hospital, Zurich

Countries where clinical trial is conducted

Germany,  Switzerland, 

References & Publications (7)

Amiel J, Lyonnet S. Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet. 2001 Nov;38(11):729-39. Review. — View Citation

Cornet 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. Epub 2001 Oct 30. — View Citation

Curotto 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. Review. — View Citation

Demehri 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. Review. — View Citation

Flamant M, Aubert P, Rolli-Derkinderen M, Bourreille A, Neunlist MR, Mahé 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. — View Citation

Peterson 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. Review. — View Citation

Rusmini 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. Erratum in: PLoS One. 2013;8(4). doi:10.1371/annotation/d3a96ff5-2a66-4454-8d8d-932ad4cfe906. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phenotypic analysis of immune and nervous cell populations	Determining cell frequencies and subtypes using fluorescence-activated cell sorting (FACS) and FlowJo software	5 years
Primary	Expression profil	RNA expression profile of whole colon tissue and single cell populations	5 years
Primary	Histological analysis	Microscopic analysis of colonic tissue using immunofluorescence and immunohistochemistry	5 years
Secondary	Microbial metagenomics sequencing	16S/18S/ITS Amplicon	5 years
Secondary	Identifying genetic defect	Targeted Sanger sequencing of known Hirschsprung's disease associated genes	5 years