Neuro-Immune Interactions in the Gut
Condition: Hirschsprung's Disease Associated Enterocolitis
MeSH terms: Enterocolitis; Hirschsprung Disease
Study type: Observational

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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        patients between 0 and 18 years undergoing bowel resection
      
Biospecimen description: 
      -  colonic tissue

        -  blood
    
Keywords: enteric neuropathies; Immune cells; Nervous cells; Microbiom