Dataset Information

Hirschsprung's associated enterocolitis.

ABSTRACT: Hirschsprung's disease (HSCR) is characterized by an absence of ganglion cells in the distal hindgut, extending from the rectum to a variable distance proximally, and results from a failure of cranial-caudal neural crest cell migration. Hirschsprung's-associated enterocolitis (HAEC) is a condition with classic manifestations that include abdominal distention, fever and foul-smelling stools, and is a significant and life-threatening complication of HSCR. The purpose of this review was to critically evaluate recent findings regarding the pathophysiology of HAEC.Several recent studies have investigated the cause of HAEC in humans and mouse models. These studies suggest that alterations in the intestinal barrier, including goblet cell number and function, and Paneth cell function, impaired gastrointestinal mucosal immunity, including B-lymphocyte trafficking or function and secretory immunoglobulin A production, and dysbiosis of the intestinal microbiota may contribute to the development of HAEC.Recent studies add to the body of literature, suggesting that the intestinal defects observed in HSCR are not restricted to the aganglionic segment but extend to the mucosal immune system within and beyond the gastrointestinal tract. Future studies further dissecting the mechanisms of HAEC and validating these findings in humans will allow for the development of directed therapeutic interventions.

SUBMITTER: Gosain A

PROVIDER: S-EPMC4451822 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Hirschsprung's associated enterocolitis.

Gosain Ankush A Brinkman Adam S AS

Current opinion in pediatrics 20150601 3

<h4>Purpose of review</h4>Hirschsprung's disease (HSCR) is characterized by an absence of ganglion cells in the distal hindgut, extending from the rectum to a variable distance proximally, and results from a failure of cranial-caudal neural crest cell migration. Hirschsprung's-associated enterocolitis (HAEC) is a condition with classic manifestations that include abdominal distention, fever and foul-smelling stools, and is a significant and life-threatening complication of HSCR. The purpose of t ...[more]

PMID: 25944307

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Project description:We aimed at identifying potential bacterial factors linking clostridia with necrotizing enterocolitis (NEC). We compared the phenotypic traits, stress responses, cellular cytotoxicity, and inflammatory capabilities of the largest collection of Clostridium butyricum and Clostridium neonatale strains isolated from fecal samples of NEC preterm neonates (PN) and control PNs. When strain characteristics were used as explanatory variables, a statistical discriminant analysis allowed the separation of NEC and control strains into separate groups. Strains isolated from NEC PN were characterized by a higher viability at 30°C (P = 0.03) and higher aerotolerance (P = 0.01), suggesting that NEC strains may have a competitive and/or survival advantage in the environmental gastrointestinal tract conditions of NEC PN. Heat-treated NEC bacteria induced higher production of interleukin-8 in Caco-2 cells (P = 0.03), suggesting proinflammatory activity. In vitro, bacteria, bacterial components, and fecal filtrates showed variable cytotoxic effects affecting the cellular network and/or cell viability, without specific association with NEC or control samples. Altogether, our data support the existence of a specific clostridial strain signature associated with NEC.IMPORTANCE Clostridia are part of the commensal microbiota in preterm neonates (PN). However, microbiota analyses by culture and metagenomics have linked necrotizing enterocolitis (NEC) and intestinal colonization with clostridial species. Nevertheless, little is known about the specific characteristics that may be shared by clostridia associated with NEC compared to commensal clostridia. Therefore, our goal was to identify specific bacterial factors linking clostridial strains with NEC. We report the existence of a specific bacterial signature associated with NEC and propose that activation of the innate immune response may be a unifying causative mechanism for the development of NEC independent of a specific pathogenic organism. The present study provides new insights into NEC pathophysiology that are needed for better diagnostics and strategies for implementing prevention of the disease.

Project description:BACKGROUND: Hirschsprung disease (HSCR) is a complex disorder with traditional germline mutations in RET in up to 30% of familial cases and in 3% of sporadic cases in a population-based series. We have previously demonstrated that an ancestral haplotype at the 5' end of RET (haplotype 0) was strongly associated with a large subset of isolated HSCR cases and that a putative low penetrance susceptibility locus was encompassed within this ancestral haplotype, anchored by exon 2 SNP A45A. OBJECTIVE: To determine the 5' extent of the HSCR-associated ancestral haplotype by defining the linkage disequilibrium breakpoint in search for the low penetrance susceptibility locus. METHODS: Systematic screening of the region upstream of the anchoring A45A SNP, comprising RET intron 1, exon 1, and promoter in 117 population-based HSCR cases and 100 controls. Dual luciferase assay to determine differential activities between SNP combinations near a transcription start site. RESULTS: New SNP's were found which formed upstream haplotypes, anchored by A45A, in linkage disequilibrium with HSCR (2 = 76.96, p<0.00000001). Linkage disequilibrium appeared to break at the -1249C/T SNP. Further, the HSCR-associated genotype (00) was found in >60% of HSCR but only 2% of controls. Because only 2 variants, -200A>G and -196C>A, lie within the promoter region and are in proximity to the transcriptional start site (at -195), we modelled these combinations into constructs for luciferase reporter assay. The HSCR-associated SNP combination showed the lowest activity and the control-associated combination, the highest. CONCLUSIONS: Our observations seem to discard the existence of a HSCR-causing mutation as it is conceived in the traditional sense, but strengthen the idea of a specific combination of variants conferring susceptibility to the disease in a low penetrance fashion. The data derived from our functional "in vitro" studies would suggest that the HSCR-associated haplotype 0 may result in a lower level of expression of the RET gene [corrected]

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Hirschsprung's associated enterocolitis.

Publications

Hirschsprung's associated enterocolitis.

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