Dataset Information

Bacterial Microbiome Dynamics in Post Pull-Through Hirschsprung-Associated Enterocolitis (HAEC): An Experimental Study Employing the Endothelin Receptor B-Null Mouse Model.

ABSTRACT: Purpose:Hirschsprung-associated enterocolitis (HAEC) is the most frequent potentially life-threatening complication in children with Hirschsprung disease (HSCR) even after definitive corrective surgery. Mounting evidence suggests that intestinal microbiota likely contribute to the etiology of enterocolitis, so the aim of this study was to use a mouse model of post pull-through HAEC to compare the fecal bacterial communities of animals which developed HAEC to those free of enterocolitis. Methods:Ten Ednrb -/- and 8wild type mice underwent the microsurgical pull-through surgery, and stool was collected at the time of surgery, and then either at 2 and 4 weeks after the operation, or when the mice developed enterocolitis. The mid-colon of all animals was collected, prepared and histologically graded for enterocolitis. Fecal DNA was isolated and bacterial 16S rRNA genes analyzed using Illumina sequencing. Results:Six Ednrb-/- mice developed HAEC with a mean enterocolitis score of 5.7, while the remaining 4 mutant and 8 WT mice remained free of enterocolitis by 4 weeks. The HAEC group had lower alpha diversity by Chao1 analysis compared with WT group, while the Ednrb-/- mice demonstrated distinct bacterial communities from WT mice on beta diversity analysis. The most striking finding was increased proportion of Akkermansia and reduced Bacteroidetes compared with the NO HAEC and WT groups, suggesting Akkermansia may contribute to development of enterocolitis while Bacteroidetes may be protective. Less abundant genera that were reduced in HAEC were Dysgonomas and Clostridium XIVa which may play a protective role. Conclusions:This is the first study to identify Akkermansia as potentially playing a role in HAEC, either as a pathobiont taxa contributing to pathogenesis of enterocolitis, or possibly a protective commensal taxa expanded in response to inflammation. These findings characterized the dynamic shifts in the gut microbial communities through the onset of post pull-through HAEC, and suggests that there may be identifiable bacterial community differences in HSCR patients that are high risk for developing HAEC.

SUBMITTER: Cheng Z

PROVIDER: S-EPMC5897423 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Bacterial Microbiome Dynamics in Post Pull-Through Hirschsprung-Associated Enterocolitis (HAEC): An Experimental Study Employing the Endothelin Receptor B-Null Mouse Model.

Cheng Zhi Z Zhao Lifu L Dhall Deepti D Ruegger Paul M PM Borneman James J Frykman Philip K PK

Frontiers in surgery 20180406

<h4>Purpose</h4>Hirschsprung-associated enterocolitis (HAEC) is the most frequent potentially life-threatening complication in children with Hirschsprung disease (HSCR) even after definitive corrective surgery. Mounting evidence suggests that intestinal microbiota likely contribute to the etiology of enterocolitis, so the aim of this study was to use a mouse model of post pull-through HAEC to compare the fecal bacterial communities of animals which developed HAEC to those free of enterocolitis.< ...[more]

PMID: 29682507

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Project description:Hirschsprung disease (HSCR) is a common cause of intestinal obstruction in the newborn. Hirschsprung-associated enterocolitis (HAEC) is a significant and life-threatening complication of HSCR, affecting up to 60% of patients. Animal models of endothelin receptor B (EdnrB) mutation reliably model human HSCR and HAEC. We previously demonstrated intestinal dysbiosis and a gut-specific deficiency of B-lymphocyte-produced secretory IgA (sIgA), the primary effector molecule of mucosal immunity, in mice with homozygous neural crest cell-conditional deletion of EdnrB (EdnrBNCC-/-). To determine mechanisms for sIgA deficiency, we examined intrinsic and extrinsic aspects of B-lymphocyte development and function. Expression of the endothelin axis components [endothelin-1 (ET-1), endothelin-3 (ET-3), endothelin receptor A (EdnrA), EdnrB] were determined over a developmental time course. B-lymphocyte survival and Ig production were assayed in vitro. Polymeric Ig receptor (pIgR)-mediated IgA transport into the intestinal lumen was interrogated. We found endothelin axis component (EdnrA, EdnrB, ET-1, ET-3) expression in developing extramedullary hematopoietic organs and that some splenic B lymphocytes express EdnrB. Splenic B lymphocytes from EdnrBNCC-/- mice showed no intrinsic defect in survival vs. wild-type (WT) B lymphocytes. In vitro stimulation of splenic B lymphocytes demonstrated decreased IgA, IgG, and IgM production in EdnrBNCC-/- vs. WT mice. Additionally, small intestinal pIgR was decreased ∼50% in EdnrBNCC-/- mice. These results suggest an intrinsic B-lymphocyte defect in antibody production as well as an extrinsic defect in IgA transport in the EdnrBNCC-/- model of HAEC. Our results are consistent with human HAEC observations of decreased luminal sIgA and mouse models of other inflammatory bowel diseases, in which decreased pIgR is seen in concert with a dysregulated microbiota. Finally, our results suggest targeting the dysbiotic microbiome and pIgR-mediated sIgA transport as potential therapeutic approaches in prevention and treatment of HAEC.-Medrano, G., Cailleux, F., Guan, P., Kuruvilla, K., Barlow-Anacker, A. J., Gosain, A. B-lymphocyte-intrinsic and -extrinsic defects in secretory immunoglobulinA production in the neural crest-conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis.

Project description:BackgroundThe Coronavirus Disease 2019 pandemic provided a natural experiment to study the effect of social distancing on the risk of developing Hirschsprung's Associated Enterocolitis (HAEC).MethodsUsing the Pediatric Health Information System (PHIS), a retrospective cohort study of children (<18 years) with Hirschsprung's Disease (HSCR) across 47 United States children's hospitals was performed. The primary outcome was HAEC admissions per 10,000 patient-days. The exposure (COVID-19) was defined as April 2020-December 2021. The unexposed (historical control) period was April 2018-December 2019. Secondary outcomes included sepsis, bowel perforation, intensive care unit (ICU) admission, mortality, and length of stay.ResultsOverall, we included 5707 patients with HSCR during the study period. There were 984 and 834 HAEC admissions during the pre-pandemic and pandemic periods, respectively (2.6 vs. 1.9 HAEC admissions per 10,000 patient-days, incident rate ratio [95% confidence interval]: 0.74 [0.67, 0.81], p < 0.001). Compared to pre-pandemic, those with HAEC during the pandemic were younger (median [IQR]: 566 [162, 1430] days pandemic vs. 746 [259, 1609] days pre-pandemic, p < 0.001) and more likely to live in the lowest quartile of median household income zip codes (24% pandemic vs. 19% pre-pandemic, p = 0.02). There were no significant differences in rates of sepsis (6.1% pandemic vs. 6.1% pre-pandemic, p > 0.9), bowel perforation (1.3% pandemic vs. 1.2% pre-pandemic, p = 0.8), ICU admissions (9.6% pandemic vs. 12% pre-pandemic, p = 0.2), mortality (0.5% pandemic vs. 0.6% pre-pandemic, p = 0.8), or length of stay (median [interquartile range]: 4 [(Pastor et al., 2009; Gosain and Brinkman, 2015) 2,112,11 days pandemic vs. 5 [(Pastor et al., 2009; Tang et al., 2020) 2,102,10 days pre-pandemic, p = 0.4).ConclusionsThe COVID-19 pandemic was associated with significantly decreased incidence of HAEC admissions across US children's hospitals. Possible etiologies such as social distancing should be explored.Level of evidenceII.

Dataset Information

Bacterial Microbiome Dynamics in Post Pull-Through Hirschsprung-Associated Enterocolitis (HAEC): An Experimental Study Employing the Endothelin Receptor B-Null Mouse Model.

Publications

Bacterial Microbiome Dynamics in Post Pull-Through Hirschsprung-Associated Enterocolitis (HAEC): An Experimental Study Employing the Endothelin Receptor B-Null Mouse Model.

Similar Datasets

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