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Purpose: Angiopoietin-1 (Ang1) mitigates inflammation as a proangiogenic growth factor. Action of Ang1 on lipopolysaccharide (LPS)-induced endotoxemic inflammation was investigated in endothelin receptor-B null Hirschsprung's disease mice (KO)., Methods: LPS or saline was injected intraperitoneally in KO (KO-LPS; n = 9, KO-sal; n = 5) and wild-type (WT) (WT-LPS; n = 6, WT-sal; n = 6) pups obtained within 24 h of birth. Normoganglionic terminal ileum harvested 6 h after LPS was used for RNA extraction and histology. IL-1β, SELE, VEGFA, Ang1, Angiopoietin-2 (Ang2), and TIE2 expression analyzed by quantitative polymerase chain reaction (qPCR), vascular permeability assessed by the Miles assay, severity of inflammation, and immunofluorescence for phospho-TIE2 and VE-cadherin were used to assess endothelial cell contact integrity and compared with KO pups pretreated with intraperitoneal Ang1 [Ang1(KO-LPS); n = 5] or saline [sal(KO-LPS); n = 6] 2 h before LPS., Results: KO-LPS pups showed significantly increased inflammation (p < 0.05) and expression of IL-1β, SELE, VEGFA, and Ang2 (p = 0.019, 0.003, 0.008 and < 0.0001, respectively); expression of Ang1 and TIE2 remained unchanged when compared with KO-saline. In Ang1(KO-LPS) ileum, changes seen in sal(KO-LPS) were eliminated and phospho-TIE2 and VE-cadherin fluorescence increased., Conclusion: Ang1 successfully attenuated LPS-induced normoganglionic intestinal inflammation, downregulated pro-inflammatory genes, and improved vascular barrier integrity in KO pups., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Daily postoperative anal dilations after endorectal pull-through for Hirschsprung disease (HD) are still considered a common practice. We analyzed the potential risks of this procedure and its effectiveness compared to a new internal protocol., Methods: All infants (< 6 months of age) who underwent transanal endorectal pull-through between January 2021 and January 2023 were prospectively enrolled in a new postoperative protocol group without daily anal dilations (Group A) and compared (1:2 fashion) to those previously treated by postoperative anal dilations (Group B). Patients were matched for age and affected colonic tract. Patients with associated syndromes, extended total intestinal aganglionosis, and presence of enterostomy were excluded. Outcomes considered were: anastomotic complications (stenosis, disruption/leakage), incidence of enterocolitis, and constipation., Results: Eleven patients were included in group A and compared to 22 matched patients (group B). There were no significant differences in the occurrence of anastomotic complications between the two groups. We found a lower incidence of enterocolitis and constipation among group A (p = 0.03 and p = 0.02, respectively)., Conclusion: A non-dilation strategy after endorectal pull-through could be a feasible alternative and does not significantly increase the risk of postoperative anastomotic complications. Moreover, some preliminary advantages such as lower enterocolitis rate and constipation should be further investigated., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Patients with Hirschsprung disease (HD) are at risk of Hirschsprung associated enterocolitis (HAEC) following pull-through. The purpose of this study was to determine if routine Botulinum toxin (BT) injected one-month post pull-through decreases the incidence of HAEC., Methods: We reviewed patients who underwent a primary (not redo) pull-through operation for HD between April 2014 to December 2019. Over the most recent 18 months, BT was administered routinely one-month post-pull-through procedure; these patients were compared to the prior group that did not receive routine BT. A HAEC episode was defined as one that required initiation of treatment for obstructive symptoms in the inpatient or outpatient setting with antibiotics and irrigations. Categorical variables were compared using the nonparametric chi-square test or Fisher's exact test. Continuous variables were compared using the two-tailed Student's t-test. P-value <0.05 was determined to be statistically significant., Results: A total of 70 patients underwent Swenson pull-through during the study period (52% male). There were no statistically significant differences in demographics in the BT vs. non-BT group. Routine post-pull-through BT was given in 28 patients and did not significantly change HAEC incidence compared to the non-BT group (12/28, 43% vs. 16/42, 38%. P = 0.691). Of note, the BT group patients developed HAEC significantly sooner than the patients in the non-BT group (37.5 days vs. 253 days, p = 0.029). More patients in the BT group (n = 18, 64%) required at least one subsequent BT injection compared to the patients in the non-BT group (n = 11, 26%. P = 0.001)., Conclusions: We conclude that routine postoperative botulinum toxin injection given one month postoperatively from Swenson pull-through did not change the incidence of HAEC. A prospective controlled study is necessary to confirm these findings., Competing Interests: Conflicts of interest/Competing interests None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Hirschsprung-associated enterocolitis (HAEC) is a leading cause of serious morbidity and potential mortality in children with Hirschsprung's disease (HD). People with HAEC suffer from intestinal inflammation, and present with diarrhoea, explosive stools, and abdominal distension. Probiotics are live microorganisms with beneficial health effects, which can optimise gastrointestinal function and gut flora. However, the efficacy and safety of probiotic supplementation in the prevention of HAEC remains unclear., Objectives: To assess the effects of probiotic supplements used either alone or in combination with pharmacological interventions on the prevention of Hirschsprung-associated enterocolitis., Search Methods: We searched CENTRAL, PubMed, Embase, the China BioMedical Literature database (CBM), the World Health Organization International Clinical Trials Registry, ClinicalTrials.gov, the Chinese Clinical Trials Registry, Australian New Zealand Clinical Trials Registry, and Clinical Trials Registry-India, from database inception to 27 February 2022. We also searched the reference lists of relevant articles and reviews for any additional trails., Selection Criteria: Randomised controlled trials (RCTs) comparing probiotics and placebo, or any other non-probiotic intervention, for the prevention of HAEC were eligible for inclusion., Data Collection and Analysis: Two review authors independently extracted data and assessed the risk of bias of the included studies; disagreements were resolved by discussion with a third review author. We assessed the certainty of evidence using the GRADE approach. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous outcomes., Main Results: We included two RCTs, with a total of 122 participants. We judged the overall risk of bias as high. We downgraded the evidence due to risk of bias (random sequence generation, allocation concealment, and blinding) and small sample size. The evidence is very uncertain about the effect of probiotics on the occurrence of HAEC (OR 0.58, 95% CI 0.10 to 3.43; I² = 74%; 2 studies, 120 participants; very low-certainty evidence). We found one included study that did not measure serious adverse events and one included study that reported no serious adverse events related to probiotics. Probiotics may result in little to no difference between probiotics and placebo in relation to the severity of children with HAEC at Grade I (OR 0.66, 95% CI 0.14 to 3.16; I² = 25%; 2 studies, 120 participants; low-certainty evidence). The effects of probiotics on the severity of HAEC at Grade II are very uncertain (OR 1.14, 95% CI 0.01 to 136.58; I² = 86%; 2 studies, 120 participants; very low-certainty evidence). Similarly, the evidence suggests that probiotics results in little to no difference in relation to the severity of HAEC at Grade III (OR 0.43, 95% CI 0.05 to 3.45; I² = 0%; 2 studies, 120 participants; low-certainty evidence). No overall mortality or withdrawals due to adverse events were reported. Probiotics may result in little to no difference in the recurrence of episodes of HAEC compared to placebo (OR 0.85, 95% CI 0.24 to 3.00; 1 study, 60 participants; low-certainty evidence)., Authors' Conclusions: There is currently not enough evidence to assess the efficacy or safety of probiotics for the prevention of Hirschsprung-associated enterocolitis when compared with placebo. The presence of low- to very-low certainty evidence suggests that further well-designed and sufficiently powered RCTs are needed to clarify the true efficacy of probiotics., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Patients treated with immune checkpoint inhibitors (ICIs) may develop ICI-associated enterocolitis, for which there is no approved treatment., Aims: We aimed to systematically review the efficacy and safety of medical interventions for the prevention and treatment of ICI-associated enterocolitis., Methods: MEDLINE, EMBASE, and the Cochrane Library were searched to identify randomized controlled trials (RCTs), cohort and case-control studies, and case series/reports, evaluating interventions (including corticosteroids, biologics, aminosalicylates, immunosuppressants, and fecal transplantation) for ICI-associated enterocolitis. Clinical, endoscopic, and histologic efficacy endpoints were evaluated. The Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to assess overall quality of evidence., Results: A total of 160 studies (n = 1514) were included (one RCT, 3 retrospective cohort studies, 156 case reports/case series). Very low quality evidence from one RCT suggests budesonide is not effective for prevention of ICI-associated enterocolitis in ipilimumab-treated patients (relative risk 0.93 [95% confidence interval 0.56, 1.56]). Very low quality evidence suggests that corticosteroids, infliximab, and vedolizumab may be effective for treatment of ICI-associated enterocolitis by inducing clinical response and remission. No validated indices for measuring disease activity were used. Biologic treatment was used in 42% (641/1528) of patients, as reported in 97 studies. ICIs were discontinued in 65% (457/702) of patients, as reported in 63 studies., Conclusions: Current treatment recommendations for ICI-associated enterocolitis are based on very low quality evidence, primarily from case reports and case series. Large-scale prospective cohort studies and RCTs are needed to develop prophylactic and therapeutic treatments to minimize interruption or discontinuation of oncological therapies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Botulinum toxin (BT) injections may play a role in preventing Hirschsprung associated enterocolitis (HAEC) episodes related to internal anal sphincter (IAS dysfunction). Our aim was to determine the association of outpatient BT injections for early obstructive symptoms on the development of HAEC., Methods: A retrospective review of children who underwent definitive surgery for Hirschsprung disease (HSCR) from July 2010 - July 2020 was performed. The timing from pull-through to first HAEC episode and to first BT injection was recorded. Primary analysis focused on the rate of HAEC episodes and timing between episodes in patients who did and did not receive BT injections., Results: Eighty patients were included. Sixty patients (75%) were male, 15 (19%) were diagnosed with trisomy 21, and 58 (72.5%) had short-segment disease. The median time to pull-through was 150 days (IQR 16, 132). Eight patients (10%) had neither an episode of HAEC or BT injections and were not included in further analysis. Forty-six patients (64%) experienced at least one episode of HAEC, while 64 patients (89%) had at least one outpatient BT injection. Compared to patients who never received BT injections (n = 9) and those who developed HAEC prior to BT injections (n = 35), significantly fewer patients who received BT injections first (n = 28) developed enterocolitis (P < 0.001), with no patient developing more than one HAEC episode., Conclusion: Outpatient BT is associated with decreased episodes of HAEC and increased interval between HAEC episodes requiring inpatient treatment. Scheduling outpatient BT injections to manage obstructive symptoms may be beneficial after pull-through for HSCR., (Copyright © 2021. Published by Elsevier Inc.)

In the Mediterranean region, fish is a common cause of food protein-induced enterocolitis syndrome (FPIES) in children. No laboratory tests specific to FPIES are available, and oral food challenge (OFC) is the gold standard for its diagnosis and testing for achievement of tolerance. Children with FPIES to fish are usually advised to avoid all fish, regardless of the species. Fish are typically classified into bony and cartilaginous, which are phylogenetically distant species and therefore contain less cross-reacting allergens. The protein β-parvalbumin, considered a pan-allergenic, is found in bony fish, while the non-allergenic α-parvalbumin is commonly found in cartilaginous fish. Based on this difference, as a first step in the therapeutic process of children with FPIES caused by a certain fish in the bony fish category (i.e., hake, cod, perch, sardine, gilthead sea bream, red mullet, sole, megrim, sea bass, anchovy, tuna, swordfish, trout, etc.), an OFC to an alternative from the category of cartilaginous fish is suggested (i.e., blue shark, tope shark, dogfish, monkfish, skate, and ray) and vice versa. Regarding the increased mercury content in some sharks and other large species, the maximum limit imposed by the European Food Safety Authority (EFSA) for weekly mercury intake must be considered. An algorithm for the management of fish-FPIES, including alternative fish species, is proposed.

A probiotic formulation combining Lactobacillus helveticus Rosell ® -52, Bifidobacterium infantis Rosell ® -33, and Bifidobacterium bifidum Rosell ® -71 with fructooligosaccharides, first commercialized in China, has been sold in over 28 countries since 2002. Clinical studies with this blend of strains were conducted mainly in pediatric populations, and most were published in non-English journals. This comprehensive review summarizes the clinical studies in infants and children to evaluate the efficacy of this probiotic for pediatric indications. Literature searches for pediatric studies on Biostime ® or Probiokid ® (non-commercial name) in 6 international and Chinese databases identified 28 studies, which were classified by indications. Twelve studies show that the probiotic significantly increases the efficacy of standard diarrhea treatment regardless of etiology, reducing the risk of unresolved diarrhea (RR 0.31 [0.23; 0.42]; p < 0.0001) by 69%. In eight studies, the probiotic enhanced immune defenses, assessed by levels of various immune competence and mucosal immunity markers (six studies), and reduced the incidence of common infections (two studies). The probiotic improved iron deficiency anemia treatment efficacy (three studies), reducing the risk of unresolved anemia by 49% (RR 0.51 [0.28; 0.92]; p = 0.0263) and significantly reducing treatment side effects by 47% (RR 0.53 [0.37; 0.77]; p = 0.0009). Other studies support further investigation into this probiotic for oral candidiasis, eczema, feeding intolerance in premature babies, or hyperbilirubinemia in newborns.

Background: Hirschsprung-associated enterocolitis (HAEC) is a serious potential complication after primary pull-through surgery for Hirschsprung's disease (HSCR). Administration of anal botulinum toxin (BT) injection may improve obstructive symptoms at the internal anal sphincter, leading to improved fecal passage. The timing of administration and effects on delay or prevention of HAEC are unknown. We hypothesized that BT administration increased the postoperative time to HAEC and aimed to investigate whether anal BT administration after primary pull-through surgery for HSCR is associated with increased time to inpatient HAEC admission development., Methods: We performed a retrospective cohort study examining children with HSCR at US children's hospitals from 2008 to 2018 using the Pediatric Health Information System database with an associated primary pull-through operation performed before 60 d of age. The intervention assessed was the administration of BT concerning the timing of primary pull-through, and two groups were identified: PRO (received BT at or after primary pull-through, before HAEC) and NOT (never received BT, or received BT after HAEC). The primary outcome was time from pull-through to the first HAEC admission. The Cox proportional hazards model was developed to examine the BT administration effect on the primary outcome after controlling for patient-level covariates., Results: We examined a total of 1439 children (67 in the PRO and 1372 in the NOT groups). A total of 308 (21.4%) developed at least one episode of HAEC, including 76 (5.3%) who had two or more episodes. Between 2008 and 2018, the frequency of BT administration has increased from three to 20 hospitals with a frequency of administration between 2.2% and 16.2%. Prophylactic BT (PRO) was not associated with increased time to HAEC event on adjusted analysis., Conclusions: Among children with HSCR undergoing primary pull-through surgery, prophylactic BT administration did not demonstrate increased time to first HAEC event. A better-powered study with prophylactic BT is required to determine the effect on HAEC occurrence and timing., Level of Evidence: Level II (retrospective cohort study)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In Hirschsprung's disease (HSCR), postoperative course remains unpredictable. Our aim was to define predictive factors of the main postoperative complications: obstructive symptoms (OS) and Hirschsprung-associated enterocolitis (HAEC). In this prospective multicentre cohort study, samples of resected bowel were collected at time of surgery in 18 neonates with short-segment HSCR in tertiary care hospitals. OS and HAEC were noted during postoperative follow-up. We assessed the enteric nervous system and the intestinal epithelial barrier (IEB) in ganglionic segments by combining immunohistochemical, proteomic and transcriptomic approaches, with functional ex vivo analysis of motility and para/transcellular permeability. Ten HSCR patients presented postoperative complications (median follow-up 23.5 months): 6 OS, 4 HAEC (2 with OS), 2 diarrhoea (without OS/HAEC). Immunohistochemical analysis showed a significant 41% and 60% decrease in median number of nNOS-IR myenteric neurons per ganglion in HSCR with OS as compared to HSCR with HAEC/diarrhoea (without OS) and HSCR without complications (p = 0.0095; p = 0.002, respectively). Paracellular and transcellular permeability was significantly increased in HSCR with HAEC as compared to HSCR with OS/diarrhoea without HAEC (p = 0.016; p = 0.009) and HSCR without complications (p = 0.029; p = 0.017). This pilot study supports the hypothesis that modulating neuronal phenotype and enhancing IEB permeability may treat or prevent postoperative complications in HSCR.

Background: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a non IgE-mediated food allergy that generally affects children in the first year of life. Usually symptoms break out when formula milk or solid foods are introduced for the first time but they might also appear in exclusively breastfed infants, since the trigger elements, especially cow's milk proteins, can be conveyed by maternal milk as well. FPIES in exclusively breastfed babies is a very rare clinical condition and only few cases have been reported in the medical literature., Case Presentation: We describe two cases of FPIES in exclusively breastfed babies. The first one is a two-month-old infant with a brief history of vomit and diarrhea that presented to the Emergency Department in septic-like conditions. The main laboratory finding was a significant increase in methemoglobin (13%). Clinically, we noted that, when breastfeeding was suspended, diarrhea drastically improved, and vice versa when maternal milk was reintroduced. An amino acid-based formula allowed a complete normalization of the symptoms. The second one is a three-month-old infant admitted for a 3 days history of persistent vomit and diarrhea. Blood tests showed a raised level of methemoglobin (7%). An esophagogastroduodenoscopy was performed and biopsies showed an eosinophilic infiltration of the duodenal mucosa. A maternal exclusion diet and an amino acid-based formula allowed a rapid regularization of the bowel function., Conclusions: We searched all the cases of FPIES in exclusively breastfed babies reported in the medical literature, identifying eight patients, with an average age of 3 months (range 15 days - 6 months). The majority of the cases were initially diagnosed as gastroenteritis or sepsis, five cases were characterized by an acute on chronic scenario and cow's milk was the most frequently involved food. Methemoglobin was never tested. An oral food challenge test was performed in two patients. FPIES in exclusively breastfed infants is a rare condition that, in the presence of compatible history and symptoms, should be considered also in exclusively breastfed babies. The evaluation of methemoglobin can simplify the diagnostic process.

Immunomodulatory proteins from human milk may enhance the protection and development of the infant's gut. This study compared the immunomodulatory effects of treatment with milk from preterm-(PM) and term-delivering (TM) mothers and pasteurized donor milk (DM) on cytokine gene expression in human macrophage-like cells derived from the monocytic cell line THP-1. The gene expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-12 (p40), IL-10 and GAPDH in macrophages treated with PM, TM and DM at steady and activated (inflammatory) states were measured using real-time reverse transcription-polymerase chain reaction. TNF-α and IL-6 in macrophages (both states) with DM were higher than PM or TM. IL-10 in steady state macrophages with DM was higher than PM whereas DM increased IL-10 in activated macrophages compared with TM. TM increased IL-6 and IL-12 (p40) in steady state macrophages compared with PM. IL-12 (p40) in activated macrophages with TM was higher than PM. IL-10 in steady state macrophages with TM was higher than PM. These results suggest that DM induces higher gene expression of pro-inflammatory and anti-inflammatory cytokines in macrophages compared with PM or TM. PM reduced gene expression of pro-inflammatory cytokines compared with TM, which may decrease the development of necrotizing enterocolitis and systematic inflammation.

The interactions between phenolic compounds and gut microbiota, have gained much attention due to their beneficial effect on humans. The study was also conceived keeping in view the growing popularity of probiotics and emerging interest in designing plant based matrices for probiotic delivery. The synergistic relationship between probiotic, Lactobacillus rhamnosus GG (LR) (ATCC 53103) and phenolic compounds of fruit matrices, sea buckthorn (SBT) and apple juice (APJ) was evaluated on TNBS induced enterocolitis in a zebrafish model (Danio rerio). Addition of LR to SBT matrix conferred higher protection against inflammation than LR in APJ matrix. This could be due to higher content of phenolic compounds in SBT. Isorhamnetin was identified as the predominant phenolic in SBT. The juice matrices were also evaluated for their flow and viscoelastic properties. The consistency index (K) and flow behaviour index (η) were derived from evaluating the shear strength. All the tested juice matrices demonstrated shear-thinning properties. Effect of the matrices on other functionalities of LR during storage period of 14 days was also evaluated. No significant changes were observed on cell surface hydrophobicity depicting protective action of the matrix components on the probiotic strain. Gastrointestinal tolerance increased on Day 7 and 14. Principal Component Analysis of the anti-microbial potential of the probiotic beverage formulations against pathogenic and food spoilage strains showed higher antagonistic ability of LR in SBT during the 14 days storage. The key findings suggest probiotic strain may behave differently in different food matrices. The sustainable functionality of the probiotic strain can be achieved even during the shelf period by optimum design of the delivery matrix., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy with varying degrees of severity. The acute form of the disease is manifested by vomiting, lethargy and pallor, which usually appear within 1-4 hours after food ingestion, and can lead to shock. The most common trigger foods are: cow's milk, soy, rice and oats. Chronic FPIES is typical for infants fed with cow's milk or soy infant formula and is manifested by chronic vomiting, diarrhea and failure to thrive. In the vast majority of patients with FPIES, the analysis of the clinical history is sufficient to diagnose and identify trigger foods. If the history is unclear, use an oral food challenge to help confirm the diagnosis. Long-term management of patients with FPIES involves elimination of the trigger foods, monitoring for FPIES resolution and caregivers' education. The majority of children acquire food tolerance at the age of 3-5.

Background/purpose: The purpose of this study was to review the management of obstructive symptoms and enterocolitis (HAEC) following pull-through for Hirschsprung's disease., Methods: A systematic review and meta-analysis (1992-2017) was performed. Included studies were: randomized controlled trials (RCT), retrospective/prospective case-control (C-C), case-series (C-S). Random-effect model was used to produce risk ratio (RR) [95% CI]. P < 0.05 was considered significant., Results: Twenty-nine studies were identified. Routine postoperative dilatations (5 C-S, 2 C-C; 405 patients): no effect on stricture incidence (RR 0.3 [0.02-5.7]; p = 0.4). Routine postoperative rectal irrigations (2 C-C; 172 patients): reduced HAEC incidence (RR 0.2 [0.1-0.5]; p = 0.001). Posterior myotomy/myectomy (4 C-S; 53 patients): resolved obstructive symptoms in 79% [60.6-93.5] and HAEC in 80% [64.1-92.1]. Botulinum toxin injection (9 C-S; 166 patients): short-term response in 77.3% [68.2-85.2], long-term response in 43.0% [26.9-59.9]. Topical nitric oxide (3 C-S; 13 patients): improvement in 100% of patients. Probiotic prophylaxis (3 RCT; 160 patients): no reduction in HAEC (RR 0.6 [0.2-1.7]; p = 0.3). Anti-inflammatory drugs (1 C-S, sodium cromoglycate; 8 patients): improvement of HAEC in 75% of patients., Conclusions: Several strategies with variable results are available in patients with obstructive symptoms and HAEC. Routine postoperative dilatations and prophylactic probiotics have no role in reducing the incidence of postoperative obstructive symptoms and HAEC., Type of Study: Systematic review and meta-analysis., Level of Evidence: Level II., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Drug-induced enterocolitis is a condition diagnosed with increasing frequency. It includes a variety of morphological and functional alterations of the small and large intestine as a consequence of exposure to pharmacological active compounds. A number of factors play a key role in this condition or participate in the onset of enterocolitis, which is the result of an interplay between the effect of the drug molecule and the tolerance of the bowel to damaging insults. The patient's age, gender, dose of drug, time of exposure, pharmaceutical preparation, drug-drug and drug-food interactions, gut barrier integrity, underlying intestinal conditions, and gut microbiota composition are all involved in the occurrence and extent of the injury. This review approaches the topic from the viewpoint of primary care, and focuses on epidemiology, mechanisms of damage, protective systems and diagnostic tools. Although the first-line therapeutic measure is the discontinuation of the drug, some options for prevention and treatment are discussed., (© 2018 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background/purpose: Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung's disease. HAEC is reported to occur in 6-50% of patients preoperatively and in 2-35% postoperatively. The exact cause of HAEC is not fully understood, but disturbances of intestinal microbiota have recently been reported in patients with HAEC. In recent years, the administration of probiotics has been proposed to reduce the incidence of HAEC. We conducted a systematic review and meta-analysis to determine the effect of probiotics on postoperative HAEC., Methods: A systematic literature search for relevant articles was performed in four databases using the combinations of following terms "probiotics", "microbiota", "enterocolitis", "Lactobacillus", "Bifidobacterium", "Saccharomyces", "Streptococcus", and "Hirschsprung disease/Hirschsprung's disease" for studies published between 2002 and 2017. The relevant cohorts of the effect of probiotics in postoperative patients were systematically searched for clinical outcomes. Odds ratio (OR) or standard mean difference (SMD) with 95% confidence intervals (CI) were calculated using standardized statistical methodology., Results: The search strategy identified 1274 reports. Overall, five studies met defined inclusion criteria, reporting a total of 198 patients. Two studies were prospective multicenter randomized control trials. Lactobacillus, Bifidobacterium, Streptococcus, and Enterococcus were used as probiotics. The incidence of HAEC with/without probiotics was 22.6 and 30.5%, respectively, but this was not statistically different (OR 0.72; 95% CI 0.37-1.39; P = 0.33)., Conclusion: This study shows that the administration of probiotics was not associated with a significant reduction in the risk of HAEC. Additional studies are required to understand more fully the role of microbiota and complex interactions that cause HAEC. With increasing knowledge of the role of microbiota in HAEC, we are likely to understand better the potential benefits of probiotics in this disease.

To summarize the most salient literature regarding the pathogenesis, diagnosis, and prevention of ischemic enterocolitis (IE) in thermal injury. IE is a poorly characterized gastrointestinal complication associated with large burns. This entity occurs irrespective of abdominal trauma. The diagnostic challenges, paucity of treatment options and related complications make IE particularly lethal. Herein we present a case of profound IE in a 40-year-old male who sustained 80% total body surface area (TBSA) burns. We provide an overview of our current understanding of IE, discuss early diagnostic strategies, and review possible treatment options. Although there are several promising biomarkers of early IE and potential treatment strategies, prospective studies are lacking. IE secondary to massive thermal injury is a lethal complication of severely burned patients. Early recognition and evidenced-based treatment strategies are paramount to successful management of patients with IE. Additional research and prospective trials are warranted given this devastating complication of massive burns.

Reactive arthritis (ReA) is an inflammatory condition of the joints that arises following an infection. Salmonella enterocolitis is one of the most common infections leading to ReA. Although the pathogenesis remains unclear, it is known that IL-17 plays a pivotal role in the development of ReA. IL-17-producers cells are mainly Th17, iNKT, and γδT lymphocytes. It is known that iNKT cells regulate the development of Th17 lineage. Whether iNKT cells also regulate γδT lymphocytes differentiation is unknown. We found that iNKT cells play a protective role in ReA. BALB/c Jα18 -/- mice suffered a severe Salmonella enterocolitis, a 3.5-fold increase in IL-17 expression and aggravated inflammation of the synovial membrane. On the other hand, activation of iNKT cells with α-GalCer abrogated IL-17 response to Salmonella enterocolitis and prevented intestinal and joint tissue damage. Moreover, the anti-inflammatory effect of α-GalCer was related to a drop in the proportion of IL-17-producing γδT lymphocytes (IL17-γδTcells) rather than to a decrease in Th17 cells. In summary, we here show that iNKT cells play a protective role against Salmonella -enterocolitis and Salmonella -induced ReA by downregulating IL17-γδTcells.

Whey protein concentrate (WPC) has been reported to have protective effects on the intestinal barrier. However, the molecular mechanisms involved are not fully elucidated. Transforming growth factor-β1 (TGF-β1) is an important component in the WPC, but whether TGF-β1 plays a role in these processes is not clear. The aim of this study was to investigate the protective effects of WPC on the intestinal epithelial barrier as well as whether TGF-β1 is involved in these protection processes in a piglet model after lipopolysaccharide (LPS) challenge. In total, eighteen weanling pigs were randomly allocated to one of the following three treatment groups: (1) non-challenged control and control diet; (2) LPS-challenged control and control diet; (3) LPS+5 %WPC diet. After 19 d of feeding with control or 5 %WPC diets, pigs were injected with LPS or saline. At 4 h after injection, pigs were killed to harvest jejunal samples. The results showed that WPC improved (P<0·05) intestinal morphology, as indicated by greater villus height and villus height:crypt depth ratio, and intestinal barrier function, which was reflected by increased transepithelial electrical resistance and decreased mucosal-to-serosal paracellular flux of dextran (4 kDa), compared with the LPS group. Moreover, WPC prevented the LPS-induced decrease (P<0·05) in claudin-1, occludin and zonula occludens-1 expressions in the jejunal mucosae. WPC also attenuated intestinal inflammation, indicated by decreased (P<0·05) mRNA expressions of TNF-α, IL-6, IL-8 and IL-1β. Supplementation with WPC also increased (P<0·05) TGF-β1 protein, phosphorylated-Smad2 expression and Smad4 and Smad7 mRNA expressions and decreased (P<0·05) the ratios of the phosphorylated to total c-jun N-terminal kinase (JNK) and p38 (phospho-JNK:JNK and p-p38:p38), whereas it increased (P<0·05) the ratio of extracellular signal-regulated kinase (ERK) (phospho-ERK:ERK). Collectively, these results suggest that dietary inclusion of WPC attenuates the LPS-induced intestinal injury by improving mucosal barrier function, alleviating intestinal inflammation and influencing TGF-β1 canonical Smad and mitogen-activated protein kinase signalling pathways.

Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota's contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

Objective: The present study was designed to evaluate the effectiveness of a nursing intervention program for outpatient rehabilitation of children with Hirschsprung-associated enterocolitis (HAEC) after radical colectomy for Hirschsprung disease (HD)., Background: Postoperative outcomes severely affect the quality of life in pediatric HD patients after operation. The improvement in defecation function is regarded as one of the most useful parameters to evaluate the quality of life in HD patients after radical intestinal resection. A close attention should also be paid to the patients' ability of social adaptation., Methods: This prospective, randomized control trial enrolled 85 pediatric patients with HAEC after colectomy. They were randomly divided into the control and intervention groups. All the patients were followed up for 6 to 12 months after initial HAEC treatment., Results: The intervention group had a lower enterocolitis recurrence rate than the control group, with a better ability to control defecation and their parents had better rehabilitation nursing knowledge (p < 0.05). The degree of parents' satisfaction regarding the outcome was significantly better in the intervention group than that in the control group (p < 0.05)., Conclusion: A systemic rehabilitation nursing program could decrease enterocolitis recurrence, improve the recovery of anorectal functions, and enhance the quality of life in the pediatric patients after radical colectomy., (Georg Thieme Verlag KG Stuttgart · New York.)

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, is a potential therapeutic target. MIF is markedly different from other cytokines because it is constitutively expressed, stored in the cytoplasm, and present in the circulation of healthy subjects. Thus, the concept of targeting MIF for therapeutic intervention is challenging because of the need to neutralize a ubiquitous protein. In this article, we report that MIF occurs in two redox-dependent conformational isoforms. We show that one of the two isoforms of MIF, that is, oxidized MIF (oxMIF), is specifically recognized by three mAbs directed against MIF. Surprisingly, oxMIF is selectively expressed in the plasma and on the cell surface of immune cells of patients with different inflammatory diseases. In patients with acute infections or chronic inflammation, oxMIF expression correlated with inflammatory flare-ups. In addition, anti-oxMIF mAbs alleviated disease severity in mouse models of acute and chronic enterocolitis and improved, in synergy with glucocorticoids, renal function in a rat model of crescentic glomerulonephritis. We conclude that oxMIF represents the disease-related isoform of MIF; oxMIF is therefore a new diagnostic marker for inflammation and a relevant target for anti-inflammatory therapy., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Our previous study has shown that mangiferin (MGF), a glucosylxanthone from Mangifera indica, exerts gastrointestinal prokinetic action involving a cholinergic mechanism. Postoperative ileus (POI) is a temporary disturbance in gastrointestinal motility following surgery, and intestinal inflammatory response plays a critical role in the pathogenesis of POI. The present study investigated to know whether MGF having anti-inflammatory and prokinetic actions can ameliorate the intestinal inflammation and impaired gastrointestinal transit seen in the mouse model of POI. Experimental POI was induced in adult male Swiss mice by standardized small intestinal manipulation (IM). Twenty-four hours later, gastrointestinal transit was assessed by charcoal transport. MGF was administered orally 1 h before the measurement of GIT. To evaluate the inflammatory response, plasma levels of proinflammatory cytokines TNF-α, IL-1β, IL-6, and chemokine MCP-1, and the myeloperoxidase activity, nitrate/nitrite level, and histological changes of ileum were determined in mice treated or not with MGF. Experimental POI in mice was characterized by decreased gastrointestinal transit and marked intestinal and systemic inflammatory response. MGF treatment led to recovery of the delayed intestinal transit induced by IM. MGF in ileum significantly inhibited the myeloperoxidase activity, a marker of neutrophil infiltration, and nitrate/nitrite level and reduced the plasma levels of TNF-α, IL-1β, IL-6, and MCP-1 as well. MGF treatment ameliorates the intestinal inflammatory response and the impaired gastrointestinal motility in the mouse model of POI.

Increasing evidence supports the concept that early-life environmental influences, including nutrition and stress, have an impact on long-term health outcomes and disease susceptibility. The objective of the present study was to determine whether dietary spray-dried plasma (SDP), fed during the first 2 weeks post-weaning (PW), influences subsequent immunological and intestinal injury responses to Salmonella typhimurium challenge. A total of thirty-two piglets (age 16-17 d) were weaned onto nursery diets containing 0, 2·5 % SDP (fed for 7 d PW) or 5 % SDP (fed for 14 d PW), and were then fed control diets (without SDP), for the remainder of the experiment. At 34 d PW (age 50 d), pigs were challenged with 3 × 10⁹ colony-forming units of S. typhimurium. A control group (non-challenged) that was fed 0 % SDP in the nursery was included. At 2 d post-challenge, the distal ileum was harvested for the measurement of inflammatory, histological and intestinal physiological parameters. S. typhimurium challenge induced elevated ileal histological scores, myeloperoxidase (MPO), IL-8 and TNF, and increased intestinal permeability (indicated by reduced transepithelial voltage (potential difference) and elevated 4 kDa fluorescein isothiocyanate dextran (FD4) flux rates). Compared with S. typhimurium-challenged controls (0 % SDP), pigs fed the 5 % SDP-14 d diet exhibited reduced ileal histological scores, MPO levels, IL-8 levels and FD4 flux rates. Pigs fed the 5 % SDP-14 d nursery diet exhibited increased levels of plasma and ileal TNF-α in response to the challenge, compared with the other treatments. These results indicate that inclusion of SDP in PW diets can have an influence on subsequent immunological and intestinal injury responses induced by later-life S. typhimurium challenge.

Background: Enterocolitis (EC) is the most common and serious postoperative complication of Hirschsprung's disease (HD). Probiotics potentially play a protective role in maintaining intestinal mucosal integrity. Based on the beneficial effects of probiotics, we hypothesized that oral probiotics could decrease the incidence and severity of Hirschsprung's disease-associated enterocolitis (HAEC)., Methods: We conducted a prospective, multicenter, randomized, and controlled trial to assess whether oral probiotics could decrease the incidence and severity of HAEC. HD patients were randomly assigned into the control group and probiotic-treated group. All children in probiotic-treated group were fed with probiotics per day for 4 weeks. In next 3 months, the incidence and severity of HAEC were analyzed. The peripheral blood T lymphocyte subsets and cytokines, including TNF-α, IFN-γ, IL-6, and IL-10, were analyzed by flow cytometry and enzyme immunoassay (EIA)., Results: Compared with the control group, the incidence of HAEC in the probiotic-treated group was significantly diminished. The severity of EC was also remarkably decreased. Furthermore, probiotics balanced T lymphocyte subsets. Moreover, pro-inflammatory cytokines TNF-α, IFN-γ, and IL-6 were significantly decreased and anti-inflammatory cytokine IL-10 was notably increased in probiotic-treated group., Conclusions: Probiotics not only significantly diminished the incidence but also decreased the severity of HAEC. Moreover, our study revealed that probiotics decreased pro-inflammatory cytokine and increased anti-inflammatory cytokine and furthermore balanced T lymphocytes (registered with ClinicalTrials.gov, NCT number: NCT01934959).

Objectives: A nonrelaxing internal anal sphincter is present in a relatively large proportion of children with surgically treated Hirschsprung disease (HD) and can cause obstructive gastrointestinal symptoms. The short- and long-term outcome and adverse effects of intrasphincteric botulinum toxin (Botox) injections in children with obstruction after surgically treated HD are evaluated., Methods: The outcome of children with surgically treated HD treated with intrasphincteric Botox injections for obstructive symptoms was analyzed with a retrospective chart review between 2002 and 2013 in the University Medical Centers of Maastricht and Nijmegen., Results: A total of 33 patients were included. The median time of follow-up was 7.3 years (range 1-24). A median of 2 (range 1-5) injections were given. Initial improvement was achieved in 76%, with a median duration of 4.1 months (range 1.7-58.8). Proportion of children hospitalized for enterocolitis decreased after treatment from 19 to 7. A good long-term response was found in 49%. Two children experienced complications: transient pelvic muscle paresis with impairment of walking. In both children symptoms resolved within 4 months without treatment., Conclusions: Intrasphincteric Botox injections in surgically treated HD are an effective long-term therapy in approximately half of our patients with obstructive symptoms. The possibility of adverse effects should be noticed.

Introduction: We aim to compare the anastomotic stricture and enterocolitis rates between groups who either had or did not have anal dilatations (AD or NAD) prescribed routinely post pull-through surgery for Hirschsprung disease (HD); by this means, we will evaluate the benefit of routine dilatations., Methods: A retrospective review of the records of all children operated on for HD between 1997 and 2010 was performed. Associated Down syndrome and total colonic aganglionosis were excluded. Two cohorts were identified; those who had anal dilatation prescribed routinely (AD) and those who did not (NAD). In the latter group, if an anastomotic stricture was subsequently diagnosed, anal dilatations were initiated. The anastomotic stricture and enterocolitis rates between groups were compared. Significance was set at p < 0.05., Results: There were 73 children that met the inclusion criteria (30 AD and 43 NAD). The NAD group had the longer mean follow-up period of 91 versus 59 months (p = 0.026); however, follow-up duration was unrelated to the anastomotic stricture rates (p = 0.575) and enterocolitis rates (p = 0.150). The anastomotic stricture rates were 13% (n = 4) versus 14% (n = 6) (p = 1.000) for the AD and NAD groups, respectively (relative risk [95% confidence interval] RR [95% CI], 0.95 [0.29 to 3.09]; p = 0.94). The mean duration between surgery and stricture occurrence was 348 versus 74 days for the AD and NAD groups, respectively. The enterocolitis rates were 23% (n = 7) versus 28% (n = 12) (p = 0.788) for the AD and NAD groups, respectively (RR [95% CI], 0.84 [0.37 to 1.87]; p = 0.66)., Conclusion: We have not shown a reduced risk of developing anastomotic strictures or enterocolitis if anal dilatations are prescribed routinely. However, when routine dilatations were prescribed, predominantly late onset strictures of perhaps a different etiology occurred., (Georg Thieme Verlag KG Stuttgart · New York.)

Hirschsprung's-associated enterocolitis (HAEC) continues to be a significant source of morbidity for patients with Hirschsprung's disease (HD). New clinical and histologic classification systems for HAEC will improve consistency between reports and increase the ability to compare outcomes. A complete understanding of disease pathogenesis is lacking, but evidence suggests that the intestinal microbiota may play a role in the development of HD and HAEC. The benefits of adjunctive therapies, such as anal dilations and botulinum toxin to reduce the incidence of HAEC following corrective endorectal pull-through, remain controversial. Finally, new clinical data have identified an association between HAEC and inflammatory bowel disease and will likely lead to further genetic studies to elucidate the connection between these two disease processes.

Purpose: One of the major toxic side effects of methotrexate (MTX) is enterocolitis. To date, there is no efficient standard treatment for this side effect. Nitrosative stress is reported to play a critical role in MTX-induced mucositis. The purpose of this study is to investigate whether pretreatment with melatonin, an inhibitor of nitro-oxidative stress, prevents MTX-induced mucositis in rats., Methods: Rats were pretreated with melatonin (20 and 40 mg/kg body weight) i.p. daily 1 h before MTX (7 mg/kg body weight) administration for three consecutive days. After the final dose of MTX, the rats were killed and the small intestines were used for analysis., Results: The small intestines of MTX-treated rats showed moderate to severe injury. The villi were distorted, blunted, and atrophied and focally absent in various segments of the small intestines. Crypt abscesses were also found, suggesting an inflammatory response. Pretreatment with melatonin had a dose-dependent protective effect on MTX-induced mucositis. Morphology was saved to a moderate extent with 20 mg melatonin pretreatment, and near-normal morphology was achieved with 40 mg melatonin pretreatment. Damage to the villi and crypt abscess was reduced. The villi/crypt ratio was almost restored. Melatonin pretreatment protected the small intestines from MTX-induced damage by attenuating nitrosative stress, protein tyrosine nitration and PARP expression., Conclusion: Because of its versatility in protecting against nitro-oxidative stress and reducing inflammation, we suggest that melatonin could be beneficial in ameliorating MTX-induced enteritis in humans.

Objective: Hirschsprung-associated enterocolitis (HAEC) is one of the most troublesome problems encountered after a pullthrough. We hypothesized that prophylactic administration of probiotics after a pullthrough procedure would decrease the incidence of HAEC., Study Design: A prospective, double-blind, placebo-controlled, randomized trial was conducted at 2 children's hospitals. Infants undergoing pullthrough were randomized to probiotic or placebo for a period of 3 months post-pullthrough. Primary outcome was incidence of post-operative HAEC. Other outcomes included severity of HAEC by clinical grade, number of HAEC episodes and extent of aganglionosis. Pearson Chi Square analysis, as well as logistic regression, was used for statistical analysis., Results: Sixty-two patients were recruited (Sites: A=40; B=22). One was lost to follow up and one immediate post-op death was not included in final analysis. Probiotics were administered to 32 patients. Distribution of placebo/probiotics was equal between sites (P=0.858). Mean age at pullthrough was 6.5 ± 8.1(± SD) months. The incidence of HAEC was 28.3%. The incidence of HAEC was not statistically different between probiotic and placebo study groups., Conclusions: Incidence of HAEC was not reduced with prophylactic probiotics. Future studies are needed to better determine the etiology and possible ways of preventing this complex condition., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Hirschsprung-associated enterocolitis remains the greatest cause of morbidity and mortality in children with Hirschsprung disease. This chapter details the various approaches used to treat and prevent this disease process. This includes prevention of complications, such as stricture formation, prophylaxis with rectal washouts, and identification of high-risk individuals. The chapter also details approaches to diagnose Hirschsprung-associated enterocolitis as well as to exclude other etiologies., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Immunological diseases such as inflammatory bowel disease (IBD) are infrequent in less developed countries, possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides polygyrus bakeri prevents colitis. It was determined whether H. polygyrus bakeri mediated IBD protection by altering dendritic cell (DC) function. We used a Rag IBD model where animals were reconstituted with IL10⁻/⁻ T cells, making them susceptible to IBD and with OVA Ag-responsive OT2 T cells, allowing study of a gut antigenic response. Intestinal DC from H. polygyrus bakeri-infected Rag mice added to lamina propria mononuclear cells (LPMC) isolated from colitic animals blocked OVA IFN-γ/IL-17 responses in vitro through direct contact with the inflammatory LPMC. DC from uninfected Rag mice displayed no regulatory activity. Transfer of DC from H. polygyrus bakeri-infected mice into Rag mice reconstituted with IL10⁻/⁻ T cells protected animals from IBD, and LPMC from these mice lost OVA responsiveness. After DC transfer, OT2 T cells populated the intestines normally. However, the OT2 T cells were rendered Ag nonresponsive through regulatory action of LPMC non-T cells. The process of regulation appeared to be regulatory T cell independent. Thus, H. polygyrus bakeri modulates intestinal DC function, rendering them tolerogenic. This appears to be an important mechanism through which H. polygyrus bakeri suppresses colitis. IFN-γ and IL-17 are colitogenic. The capacity of these DC to block a gut Ag-specific IFN-γ/IL-17 T cell response also is significant.

Background: Developing countries have a low incidence of inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections and other alterations in intestinal flora and fauna. Helminth infections prevent colitis in various murine models of IBD. IBD may be driven by an aberrant immune response to luminal antigen(s)., Methods: We developed a murine model of IBD in which gut injury was induced by a specific antigen to better simulate the IBD disease process and to determine if helminth infections could abolish gut injury induced by an orally administered antigen. The model features pan-enterocolitis triggered by feeding ovalbumin (OVA)., Results: The intestinal inflammation is antigen-specific and generates interleukin (IL)-17 and interferon-gamma (IFN-γ), but not IL-4. Full expression of the disease required T cells with defective capacity to make IL-10 and treatment with a noninjurious, low dose of a nonsteroidal antiinflammatory drug. Exposure to Heligmosomoides polygyrus abrogated this antigen-induced gut injury. H. polygyrus colonization induced Foxp3(+) T regulatory cells (Tregs) and mucosal production of IL-10 from non-T cells. Lamina propria mononuclear cells from H. polygyrus-infected mice released less IL-17 and IFN-γ constitutively and when stimulated with OVA or anti-CD3/CD28 monoclonal antibodies., Conclusions: We developed a murine IBD model featuring antigen-specific enterocolitis and demonstrate for the first time that gut inflammation induced by an antigen could be abrogated by H. polygyrus infection. Protection was associated with suppressed IL-17 and IFN-γ production, induction of Foxp3(+) Tregs, and elevated secretion of non-T-cell-derived IL-10, all of which could be part of the protective processes., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Patients' care for foodborne infections is sometimes very critical, since these patients exerting high copy numbers of contagious pathogens. Recently, Norovirus infection became the most frequent pathogen for large outbreaks in the community and the hospital around the world. Norovirus is alcohol-resistant and highly contagious. For preventing outbreaks of foodborne infections, standard precaution(and contact precaution for diaper changing patients) is required by the CDC's isolation precaution guideline revised at 2007. We need to provide for infection prevention and control in the epidemic winter period not only in healthcare facilities but also for communities.

Salmonella enterica serovar Typhimurium has long been recognised as a zoonotic pathogen of economic significance in animals and humans. Attempts to protect humans and livestock may be based on immunization with vaccines aimed to induce a protective response. We recently demonstrated that the oral administration of a Salmonella enterica serovar Typhimurium strain unable to synthesize the zinc transporter ZnuABC is able to protect mice against systemic salmonellosis induced by a virulent homologous challenge. This finding suggested that this mutant strain could represent an interesting candidate vaccine for mucosal delivery. In this study, the protective effect of this Salmonella strain was tested in a streptomycin-pretreated mouse model of salmonellosis that is distinguished by the capability of evoking typhlitis and colitis. The here reported results demonstrate that mice immunized with Salmonella enterica serovar Typhimurium (S. Typhimurium) SA186 survive to the intestinal challenge and, compared to control mice, show a reduced number of virulent bacteria in the gut, with milder signs of inflammation. This study demonstrates that the oral administration a of S. Typhimurium strain lacking ZnuABC is able to elicit an effective immune response which protects mice against intestinal S. Typhimurium infection. These results, collectively, suggest that the streptomycin-pretreated mouse model of S. typhimurium infection can represent a valuable tool to screen S. typhimurium attenuated mutant strains and potentially help to assess their protective efficacy as potential live vaccines., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Inflammatory bowel disease (IBD) results from dysfunctional interactions between the intestinal immune system and microbiota, influenced by host genetic susceptibility. Because a key feature of the pathology is intestinal epithelial damage, potential disease factors have been traditionally analyzed within the background of chemical colitis models in mice. The zebrafish has greatly complemented the mouse for modeling aspects of disease processes, with an advantage for high content drug screens. Larval zebrafish exposed to the haptenizing agent trinitrobenzene sulfonic acid (TNBS) displayed impaired intestinal homeostasis and inflammation reminiscent of human IBD. There was a marked induction of pro-inflammatory cytokines, the degradative enzyme mmp9 and leukocytosis. Enterocolitis was dependent on microbiota and Toll-like receptor signaling, that can be ameliorated by antibiotic and anti-inflammatory drug treatments. This system will be useful to rapidly interrogate in vivo the biological significance of the IBD candidate genes so far identified and to carry out pharmacological modifier screens., (© 2010 Wiley-Liss, Inc.)

Purpose: The transanal one-stage pull-through procedure (TERPT) has gained worldwide popularity over open and laparoscopic-assisted one-stage techniques in children with Hirschsprung's disease (HD). It offers the advantages of avoiding laparotomy, laparoscopy, scars, abdominal contamination, and adhesions. However, enterocolitis associated with Hirschsprung's disease (HAEC) still remains to be a potentially life-threatening complication after pull-through operation. The reported incidence of HAEC ranges from 4.6 to 54%. This meta-analysis was designed to evaluate postoperative incidence of HAEC following TERPT procedure., Methods: A meta-analysis of cases of TERPT reported between 1998 and 2009 was performed. Detailed information was recorded regarding intraoperative details and postoperative complications with particular emphasis on incidence of HAEC. Diagnosis of HAEC in a HD patient was based on the clinical presentation of diarrhoea, abdominal distension, and fever., Results: Of the 54 published articles worldwide, 27 articles, including 899 patients were identified as reporting entirely TERPT procedure. Postoperative HAEC occurred in 92 patients (10.2%). Recurrent episodes of HAEC were reported in 18 patients (2%). Conservative treatment of HAEC was successful in 75 patients (81.5%), whereas in 17 patients (18.5%) surgical treatment was needed., Conclusions: This systematic review reveals that TERPT is a safe and less-invasive procedure with a low incidence of postoperative HAEC.

Objective: Neonates with hypoplastic left heart syndrome are prone to gastrointestinal complications, including necrotizing enterocolitis, during initiation or advancement of enteral feeds. A feeding protocol was developed to standardize practice across a multidisciplinary team. The purpose of this study was to examine the impact of a standardized feeding protocol on the incidence of necrotizing enterocolitis and overall postoperative gastrointestinal morbidity., Design: Retrospective case-control study., Setting: Cardiothoracic intensive care unit of a tertiary care children's hospital., Patients: Ninety-eight neonates with hypoplastic left heart syndrome admitted to the cardiothoracic intensive care unit after first-stage palliation., Intervention: A retrospective chart review was performed. Two groups were analyzed: the preprotocol group (n = 52) was examined from January 2000 through December 31, 2001, and the postprotocol group (n = 46) from February 2002 through December 31, 2003., Measurements and Main Results: The incidence of suspected or diagnosed necrotizing enterocolitis as defined by the modified Bell staging criteria was recorded. Data were also collected regarding postoperative day of enteral feed initiation, postoperative day full feeds attained, and postoperative hospital length of stay. Necrotizing enterocolitis was detected in 14 preprotocol (27%) and three postprotocol (6.5%) patients (p < .01). Enteral feeds were initiated later in the postprotocol group (7.5 vs. 5.5 days, p < .001), and number of days to full feeds was also later in the postprotocol group (7 vs. 4 days, p = .02). Hospital length of stay tended to be shorter in the postprotocol group (21.5 vs. 28 days, p = .25)., Conclusion: Measures directed at reducing the incidence of necrotizing enterocolitis may reduce morbidity in neonates with hypoplastic left heart syndrome and reduce cost by decreasing hospital length of stay. A standardized feeding protocol instituted to address these problems likely contributed to reducing the incidence of necrotizing enterocolitis in this high-risk population.

Background: Hirschsprung disease (HD) results from aganglionosis of the colon, is linked to acute and chronic enterocolitis (known as Hirschsprung-associated enterocolitis) despite successful corrective surgery, and can lead to bacteremia and even death. The genetic and molecular mechanisms underlying these disorders are largely unknown., Methods: We developed a microsurgical corrective pull-through procedure in mice, and applied that to Ednrb(-/-) mice, which manifest aganglionic megacolon that is very similar to HD. Wild-type littermates (Ednrb(+/+)) also underwent identical surgery. At prespecified time points postoperatively, mice were sacrificed, and histopathologic analyses of intestinal inflammation were performed. Mice of both genotypes were sacrificed after the postoperative recovery period to determine if corrective surgery itself caused inflammation. Stooling patterns were assessed as well to determine if intestinal function normalized after surgery., Results: There was no difference in histopathological enterocolitis scores after recovery from surgery. Stooling patterns in Ednrb(-/-) and Ednrb(+/+) mice were similar postoperatively, suggesting normalization of intestinal function. However, with time, approximately 40% of Ednrb(-/-) mice developed clinical illness consistent with enterocolitis. No control (Ednrb(+/+)) mice developed clinical enterocolitis. Histopathological enterocolitis scores in the 40% of Ednrb(-/-) mice that developed clinical enterocolitis postoperatively were significantly worse than those of healthy postoperative Ednrb(-/-) mice. In contrast, none of the Ednrb(+/+) control mice exhibited postoperative long-term inflammation., Conclusions: Microsurgical pull-through operation in Ednrb(-/-) mice produces a mouse model that closely resembles key features of Hirschsprung-associated enterocolitis, enabling controlled study of genetic and molecular mechanisms in Ednrb(-/-) mice and other genotypes that produce similar phenotypes., (Copyright 2010 Elsevier Inc. All rights reserved.)

Eighty-eight rabbits weaned at the age of 35 days were divided into four groups. Rabbits of the first two groups were fed a granulated feed, free of antimicrobials. Rabbits of the 3rd and the 4th groups were fed the same diet, supplemented with caprylic acid at 5 g/kg, and with triacylglycerols (TAG) of caprylic and capric acid at 10 g/kg, respectively. Rabbits of the 2nd, 3rd and 4th groups were challenged orally with 10(9) cells of Escherichia coli of the O103 serogroup. Numbers of coliform bacteria in faeces of non-infected rabbits averaged 4.66 log(10)cfu/g. Six days after inoculation, caprylic acid and TAG of caprylic and capric acid decreased faecal output of coliforms from 10.18+/-0.62 to 7.79+/-0.48 log(10)cfu/g and 8.04+/-0.50 log(10)cfu/g, respectively. In the 2nd, 3rd and 4th groups 15, 11 and 9 infected rabbits died, respectively. However, the differences in mortality rate were not statistically significant. Surviving rabbits were slaughtered at 53 days of age. In caecal contents of infected rabbits, numbers of coliform bacteria were significantly reduced from 8.71 log(10)cfu/g to 5.55-5.83 log(10)cfu/g in treated groups. It can be concluded that both antimicrobial lipids are active against coliform bacteria, and may improve the resistance of weaned rabbits to enterocolitis.

Stools sent for culture from patients after three days of hospitalisation have a low yield (<1%) for bacterial enteric pathogens (BEP), excluding Clostridium difficile, and are expensive to process. A 'three-day rule' for rejection of specimens has previously been validated in adults. We evaluated a three-day rule for paediatric stool samples by retrospective review of all stool culture results from 1995 to 2002. Excluding C. difficile, yield for BEP in samples sent within three days following admission was 97/3751 (2.59%) compared with 3/1511 (0.2%) in samples sent more than three days after admission. The criteria for culture would have been met if the rule had been applied for these three samples. We prospectively evaluated potential savings if the rule were applied for both children and adults over a two-month period in 2000. Savings were greater for adults than for children. Of 490 stools from children, 38 (7.8%) samples did not meet the criteria for culture and of 206 stools from adult patients, 64 (31%) did not meet the criteria for culture. We implemented the rule between 1 March 2003 and 31 March 2006. A total of 14 439 stool samples were received from inpatients requesting culture for BEP, excluding C. difficile. Of these, 5744 (39.8%) were rejected because the criteria for culture were not met. This was estimated as an annual saving of 11,848 pounds to the Trust laboratory. If extrapolated to all NHS Trusts, the potential savings could be in the order of 1.18 million pounds annually.

Background: We sought to identify causes of preventable complications related to operations for Hirschsprung disease., Methods: We reviewed the cases of 51 patients with Hirschsprung disease who underwent a primary procedure elsewhere, had a complication, and were referred for reoperation., Results: Thirty-five patients had 1 failed operation, 10 had 2, and 6 had 3. Initial operations were Soave (20), Duhamel (15), Swenson (5), transanal endorectal (4), myectomy (3), unknown (3), and laparoscopic Swenson (1). Thirty-one patients presented with a stoma. Patients without a stoma (20) had fecal impaction (8), recurrent enterocolitis (6), and fecal incontinence (6). None had both enterocolitis and incontinence. Reoperation was performed posterior sagittally (40) or transanally (5). Indications included stricture (21), megarectal Duhamel pouches (12), fistulae (11 [8 rectocutaneous, 2 rectourethral, and 1 rectovaginal]), pouchitis (2), and retained aganglionic bowel (8). After reoperation, 14 were continent, 11 had a stoma (8 permanent), 6 had voluntary bowel movements but soiled occasionally, 6 received rectal irrigations to avoid enterocolitis, 6 were incontinent but clean with bowel management, and 2 were lost to follow-up., Conclusion: Stricture, megarectal pouch, fistula, and retained aganglionic bowel are preventable complications. Enterocolitis is partially preventable but can occur after a technically correct procedure. Fecal incontinence is a preventable complication likely because of anal canal damage.

Enteropathogenic Escherichia coli (EPEC) colibacillosis represents a major cause of lethal diarrhea in young children in developing countries. EPEC strains also infect numerous mammal species and represent a major economical problem in rabbit industry. Protection against this pathogen is a challenging goal both in humans and in other mammal species. Despite a good knowledge of the pathogenicity mechanisms of EPEC, the intrinsic and environmental factors that control the expression of EPEC virulence in mammals remain unknown. For instance, the exacerbated sensitivity of young mammals to EPEC infection is still unexplained. Our goal was to investigate if age or other factors, like milk consumption, could be determinants that trigger the disease. We used rabbits as an animal model to study the role of milk in the sensitivity to an EPEC infection. Weaned and suckling rabbits were orally inoculated with EPEC strain E22 (O103:H2:K-) at 28 days of age, and the evolution of the disease was investigated in the two groups. In addition, in order to better characterize the interactions between milk and EPEC, we determined in vitro bacterial growth and the abilities of EPEC cells to adhere to epithelial cells in the presence of milk. Our results demonstrate a protective role of milk in vivo in association with in vitro antibacterial activity. These effects are independent of the presence of specific anti-EPEC antibodies.

Unlabelled: The object is to determine the utility of rectal irrigation (RI) and bowel decontamination for the prevention of postoperative enterocolitis in Hirschsprung's disease., Material and Methods: Between 1978 and 2005, 37 patients underwent surgical treatment for Hirschsprung's disease. Group 1 (1978-1993): 19 patients, 17 with rectosigmoid or long segment disease, and 2 total colonic aganglionosis (TCA). No postoperative prevention was used. Group II (1994-2005): 18 patients, 11 with rectosigmoid or long segment disease, and 7 TCA. Postoperative rectal irrigation (RI) and bowel decontamination was used. The RI volume was at least 10 ml/kg body weight. It was initiated on postoperative day 10, once a day for two months in the short segments, extending to 1 or more years in patients with iloeocoloplasty. Bowel decontamination, with a duration similar to the RI, was with metronidazol, gentamicin, or nistatin alternatingly. The incidence of enterocolitis, and the morbidity and mortality were evaluated in both groups., Results: In Group I, 9 patients (47%) developed postoperative enterocolitis; 1 patient, with serious preoperative enterocolitis, required digestive rest for 10 days, with parenteral feeding and intravenous antibiotics. The 2 TCA patients, one treated by the L. Martin technique, and the other, with Down's syndrome, by the Kimura technique, suffered recurrent episodes of enterocolitis, with hospitalization, intravenous antibiotic therapy, and RI. In Group I, there were 2 deaths, one related to the postoperative enterocolitis. In Group II, each of 2 patients (11%) with TCA treated by Boley-type ileocoloplasty, with preoperative enterocolitis, had 1 episode of enterocolitis during treatment; one had a further episode after suspension of the treatment. Two patients of this group suffered enterocolitis before beginning the treatment. There was no mortality in this group., Conclusions: Rectal irrigation and bowel decontamination significantly decreased the incidence and severity of enterocolitis in Hirschsprung's disease by preventing faecal stasis and uncontrolled bacterial growth.

Background/purpose: Enterocolitis (EC) is a common and severe complication after pull-through for Hirschsprung's disease; its pathogenesis remains unclear, but the role of coexistent intestinal neuronal dysplasia (IND) in the proximal colon may be relevant. This study evaluated the relationship between postoperative EC and IND and assessed whether a surgical protocol including resection of coexistent IND could prevent postoperative EC., Methods: Between June 1993 and June 2002, 36 patients with aganglionosis were submitted to definitive surgical treatment. There were 2 sequential sets of patients: group I (n = 17), in whom the resection was confined to the aganglionic colon, and group II (n = 19), who were additionally submitted to resection of the coexistent IND segment; excision was restricted to the hepatic flexure in long segmental IND. The prevalence of postoperative EC and anorectal function were evaluated and compared between the 2 groups., Results: There was no mortality. Fifteen patients had isolated aganglionosis, and 21 presented with aganglionosis plus proximal IND. All 6 children who developed postoperative EC had coexistent IND. In group I, 9 patients had coexistent IND and 5 developed postoperative EC (5/17, 29%). In group II, 12 patients had coexistent IND but only 1 patient, with long segmental IND, developed postoperative EC (1/19, 5%). Among the patients with proximal IND, the prevalence of postoperative EC was 29%; but it was significantly lower in group II than in group I (1/12 or 8% vs 5/9 or 56%; P = .02). Anorectal function was excellent or good in more than 80% of the patients in both groups., Conclusions: Postoperative EC was associated with retained proximal IND, suggesting that coexisting IND may be, at least, a predictive marker for this complication. Histochemical characterization of the proximal colon with no radical resection of the IND segment seems to be an effective and safe approach to minimize the prevalence of postoperative EC.

Pretreatment with the probiotic Escherichia colistrain Nissle 1917 (EcN) was assessed in a pig model of intestinal infection to prevent acute secretory diarrhea. In the model 10(10) colony forming units of the porcine enterotoxigenic Escherichia coli Abbotstown (EcA) was given via orogastric tube to weaned piglets at day 21 postpartum (-EcN/+EcA group, n = 7). Forty-eight hours after challenge electrophysiological parameters of isolated intact jejunal epithelia were characterized in Ussing chambers. In agreement with clinical signs of diarrhea, tissues of challenged animals showed an overshoot of secretory response after stimulation of the cAMP-mediated second messenger pathway by forskolin, indicating higher excitability of chloride secretory systems under infected conditions. The data were compared with respective measurements from animals that got a daily dose of 10(10) cfu of the probiotic EcN over 10 days before EcA challenge (+EcN/+EcA group; n = 4), from a group that received only EcN (+EcN/-EcA; n = 4), or from a group that remained totally untreated (-EcN/-EcA; n = 6). EcN pretreatment completely abolished clinical signs of secretory diarrhea in +EcN/+EcA animals. Furthermore, jejunum epithelia of these animals did not exhibit an overshoot of secretory response upon stimulation with forskolin. Our studies demonstrate for the first time the efficacy of prophylactic EcN in pig small intestine for preventing an effect of toxigenic EcA. This infection model with freshly weaned piglets may be predestinated to further characterize EcN effects on the cellular level, i.e., involved second messenger pathways, or it may also be useful to examine the efficacy of other substrates or microbe strains against secretory stimuli.

Neutropenic enterocolitis is a severe complication of high dose chemotherapy in patients with hematologic tumors. Forty two cases of neutropenia due to intensive chemotherapy were analysed. In 6 patients severe enterocolitis with atony and hemorrhage and isolation of vancomycin resistant enterococci from the stool specimens was recorded.