Patient case: 11-year-old male with Peutz-Jeghers syndrome; genetic feature: STK11

Clinical trial: Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung's Disease

Summary: Hirschsprung's disease (HD) is a rare disease defined as a congenital absence of enteric ganglia, resulting usually in neonatal bowel obstruction. The current treatment is the operative removal of the aganglionic bowel and anastomosis to the ganglionic zone considered as 'healthy'. However, postoperative course remains unpredictable.
  Functional intestinal disorders are present in up to 45% of patients and can occur in the immediate postoperative period or few weeks/years later.
  Until now, there are neither predictive factors of postoperative digestive complications nor established treatment for postoperative dysmotility in HD. Abnormalities in enteric nervous system (ENS) phenotype and functions in the 'healthy' ganglionic segment are increasingly suspected to be directly responsible for postoperative intestinal dysfunctions in HD. Therefore, approaches aimed at restoring the nitrergic phenotype could be of major therapeutical interest. Among targets regulating the nitrergic phenotype of ENS are the microbiota and/or derived metabolites. Indeed preclinical animal models deficient in bacterial sensing molecules have a loss of nitrergic neurons and reduced colonic transit. Conversely, microbiota transfer to newborn germ-free mice restored colonic transit time. Alternatively the investigators has shown that bacterial metabolites such as short-chain fatty acids, in particular butyrate, can increase nitrergic phenotype and enhance colonic motility in a gut immaturity animal model. Therefore the investigators hypothesize preoperative butyrate enema will reduce postoperative intestinal complications at short-term and medium/long-term.

Detailed description: Hirschsprung's disease (HD) is a rare disease (1/5000) defined as a congenital absence of enteric ganglia, secondary to developmental defects in colonization of the gut by the enteric nervous system (ENS) and in its maturation, resulting usually in neonatal bowel obstruction. The current treatment is the operative removal of the aganglionic bowel and anastomosis to the ganglionic zone considered as 'healthy'. However, postoperative course remains unpredictable. Functional intestinal disorders, mainly functional obstructive symptoms, are present in up to 45% of patients and can occur in the immediate postoperative period or few weeks/years later. Postoperative enterocolitis also occurs in up to 25% of patients following a similar time course. Until now, there are neither predictive factors of postoperative digestive complications nor established treatment for postoperative dysmotility in HD, in part due to a lack of understanding of the physiopathological mechanisms involved. Abnormalities in ENS phenotype and functions in the 'healthy' ganglionic segment are increasingly suspected to be directly responsible for postoperative intestinal dysfunctions in HD. In an ongoing multicentre study (Ente-Hirsch project), he investigators have identified a reduced density of nitrergic enteric neurons associated with a reduced neuromuscular transmission that could account for digestive dysfunctions in HD. Therefore, approaches aimed at restoring the nitrergic phenotype could be of major therapeutical interest. Among targets regulating the nitrergic phenotype of ENS are the microbiota and/or derived metabolites. Indeed preclinical animal models deficient in bacterial sensing molecules have a loss of nitrergic neurons and reduced colonic transit. Conversely, microbiota transfer to newborn germ-free mice restored colonic transit time. Alternatively he investigators has shown that bacterial metabolites such as short-chain fatty acids, in particular butyrate, can increase nitrergic phenotype and enhance colonic motility in a gut immaturity animal model. Therefore the investigators hypothesize preoperative butyrate enema will reduce postoperative intestinal complications at short-term and medium/long-term.

Eligibility: Inclusion Criteria:
  -  Newborn with a diagnosis of Hirschsprung's disease the 2 first months of life,
  -  Born at or after 35 weeks of gestation (37 weeks of amenorrhea),
  -  With a short-segment Hirschsprung's disease limited to the rectum and/or sigmoid colon diagnosed on rectal biopsy with established pathological criteria (absence of ganglionic cells +/- hypertrophic extrinsic nerve fibres) (Kapur, Sem Ped Surg 2009),
  -  Managed successfully with colonic decompressions/irrigations before curative surgery (usually performed 2-3 times a day),
  -  Uncomplicated form (without enterocolitis and/or diverting colostomy),
  -  Curative surgery and follow-up in one of the included centres,
  -  With consent of the 2 parents or legal(s) representative(s),
  -  Absence of severe or lethal associated malformations,
  -  Affiliation with the French social security system.
  Exclusion Criteria:
  -  - Long segment Hirschsprung's disease prior to the junction between the left colon and the sigmoid colon,
  -  Hirschsprung's disease not managed successfully with colonic decompressions/irrigations and requiring a diverting colostomy before the curative surgery,
  -  Hirschsprung-associated enterocolitis occurring before the randomization,
  -  Severe or lethal associated malformation, including Down syndrome,
  -  Intestinal associated malformations (intestinal atresia, gastroschisis, omphalocele, intestinal malrotation and volvulus),
  -  Any pathological condition that can modify intestinal motility or intestinal transit time (cystic fibrosis, hypothyroidism),
  -  Refusal of parent(s) or legal representative(s).
  -  Patients under curatorship or tutorship

Relevance to patient case: not relevant