Clinical trial NCT03617640: Neuro-Immune Interactions in the Gut
Official title: The Enteric Nervous System as Modulator of Mucosal Immune Cells
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hirschsprung's Disease Associated Enterocolitis
Keywords: enteric neuropathies
Immune cells
Nervous cells
Microbiom
Lead sponsor: University Children's Hospital Basel
Sponsor class: OTHER
Collaborators: name: University Children's Hospital, Zurich
name: Insel Gruppe AG, University Hospital Bern
name: Kinderspital St. Gallen
name: Bâtiment Hospitalier CHUV
name: Universität Klinikum Heidelberg
name: Luzerner Kantonsspital
name: Hôpitaux Universitaires Genève
name: Ospedale Regionale di Bellinzona e Valli
First posted: 2018-08-06
Enrollment: 103
Sex: ALL
Minimum age (years): 0
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: patients between 0 and 18 years undergoing bowel resection

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.

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.

Eligibility criteria: Inclusion Criteria:

Informed consent

Exclusion Criteria:

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

Primary outcomes:
measure: Phenotypic analysis of immune and nervous cell populations
timeFrame: 5 years
measure: Expression profil
timeFrame: 5 years
measure: Histological analysis
timeFrame: 5 years
Secondary outcomes:
measure: Microbial metagenomics sequencing
timeFrame: 5 years
measure: Identifying genetic defect
timeFrame: 5 years
Other outcomes:
Locations:
city: Heidelberg
country: Germany
facility: Kinderchirurgie Universität Heidelberg
city: Bellinzona
country: Switzerland
facility: Ospedale Regionale di Bellinzona e Valli
city: Bern
country: Switzerland
facility: Inselspital Universität Bern
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires Genève
city: Lausanne
country: Switzerland
facility: Bâtiment Hospitalier CHUV
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital
city: Saint Gallen
country: Switzerland
facility: Kinderspital St. Gallen
city: Zürich
country: Switzerland
facility: Kinderspital Zürich
Study officials:
affiliation: University Children's Hospital Basel
name: Stefan Holland-Cunz, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.
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.
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.
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. doi: 10.1073/pnas.231474098. Epub 2001 Oct 30.
citation: Flamant 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.
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.