Search

Many widely held beliefs and assumptions concerning childhood constipation continue to interfere with rational management of childhood constipation. Although many still believe that constipation is not a common disease, about 9.5% of the world’s children suffer from chronic constipation. Most of these children live in non-Western countries. There are major misconceptions about the etiology of constipation as a significant proportion of clinicians still believe that constipation is caused by some form an organic pathology, whereas in reality, the majority have functional constipation. Contrary to a commonly held belief that children outgrow constipation without long-term problems, there is evidence that constipation leads to significant bowel and psychological consequences and has a major impact on the quality of life which detrimentally affects future health and education. Finally, ineffective management strategies such as increasing fiber and water in the diet, and short duration of treatment owing to the fear that long-term laxative treatment leads to colonic dysfunction, interfere with effective therapeutic strategies. Conclusions: It is apparent that myths and misconception often lead to wrong assumptions regarding the distribution of the disease, its etiology, pathophysiology, and management leading to ordering incorrect investigations and ineffective therapeutic strategies while spending large sums of public funds unnecessarily. Poorly treated constipation leads to deleterious psychological consequences predisposing children to develop significant psychological damage and bowel dysfunctions. This review aims to challenge these myths about various elements of constipation by exploring the existing literature and encouraging clinicians to have a fresh look at old concepts that could interfere with the well-being of children with constipation.What is Known:• Childhood constipation is a growing problem in the world leading to significant suffering and high healthcare expenditure• Myths and misconceptions lead to poor management strategies causing psychological and bowel damageWhat is New:• Organic, systemic, and bowel disorders leading to constipation are uncommon, and in the majority, it arises due to deliberate fecal withholding and most investigations ordered by clinicians are not very helpful in the management• Most non-pharmacological interventions are not effective in the day-to-day management of childhood constipation.

To explore the perceptions and practices of Australasian paediatric gastroenterologists in diagnosing coeliac disease (CD) before and during the COVID-19 pandemic.Paediatric gastroenterologists in Australasia were invited via email to complete an anonymous online questionnaire over a 2-week period in 2021.The questionnaire was completed by 39 respondents: 33 from Australia and six from New Zealand (NZ) equating to a 66% response rate. Thirty-four (87%) of the 39 respondents reported they currently practised non-biopsy diagnosis of CD in eligible children, while the rest diagnosed CD using biopsy confirmation only. All NZ respondents practised non-biopsy CD diagnosis. A majority of responders (76%) who practised non-biopsy CD diagnosis followed the 2020 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines. Twenty-two (56%) respondents reported that they started using a non-biopsy CD diagnosis protocol before the pandemic and did not change their practice during the pandemic, 10 (26%) started diagnosing non-biopsy CD during the pandemic, 5 (13%) stated their practices of CD were not impacted by the pandemic and 2 (5%) did not respond on whether the pandemic changed their practice.The majority of Australasian gastroenterologist respondents reported they routinely utilised the 2020 ESPGHAN diagnostic criteria in eligible children; half of them started prior to the pandemic and another quarter started this approach due to the pandemic. A minority of practitioners routinely rely only on biopsy confirmation to diagnose CD.

Studies in adults have suggested that high-resolution technology increases the diagnostic yield of antroduodenal manometry (ADM). However, there is no study comparing high-resolution with low-resolution ADM recordings as well as comparing the 2 types of high-resolution display [conventional line plot (CLP) and pressure topographic plots (PTP)]. We hypothesized that high-resolution ADM is a superior diagnostic modality with higher inter-observer and intra-observer agreement compared with low-resolution recordings.Twenty-four anonymized ADM studies were blindly analyzed by 3 experienced pediatric neurogastroenterologists. All studies had been performed using a low-compliance water-perfused system with a 20-channels catheter. Data were displayed as CLP, as both high-resolution and low-resolution, and PTP in different sessions with at least 6-week interval. Accuracy was evaluated using previous established diagnosis and specific pre-prandial and post-prandial manometric patterns. Inter-observer and intra-observer agreements were calculated.Analysis with high-resolution CLP revealed a substantial inter-observer agreement among the 3 observers regarding the diagnosis (Krippendorff's alpha: 0.832; average pairwise percentage agreement: 88.9%). Conversely, PTP and low-resolution CLP showed poor agreement for diagnoses (Krippendorff's alpha: 0.600; average pairwise percentage agreement: 75.3%; Krippendorff's alpha: 0.390; average pairwise percentage agreement: 60.2%, respectively). For the intra-observer agreement, Krippendorff's alpha ranges were 0.891-1 for CLP and 0.19393-0.34621 for PTP.Our study demonstrated higher diagnostic accuracy for high-resolution ADM compared to the low-resolution recordings. However, although it is well established for other motility investigations, PTP is not yet reliable in assessing foregut motor patterns. Advanced and more sophisticated software are clearly required for analyzing PTP display.

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Background: Coeliac disease is one of the most prevalent immune-mediated gastrointestinal disorders in children. Aim: To review the incidence and prevalence of paediatric coeliac disease, and their trends, regionally across Europe, overall and according to age at diagnosis. Methods: Systematic review and meta-analysis from January 1, 1950 to December 31, 2019, based on PubMed, CINAHL and the Cochrane Library, searches of grey literature and websites and hand searching of reference lists. A total of 127 eligible studies were included. Results: The prevalence of previously undiagnosed coeliac disease from screening surveys (histology based) ranged from 0.10% to 3.03% (median = 0.70%), with a significantly increasing annual trend (P = 0.029). Prevalence since 2000 was significantly higher in northern Europe (1.60%) than in eastern (0.98%), southern (0.69%) and western (0.60%) Europe. Large increases in the incidence of diagnosed coeliac disease across Europe have reached 50 per 100 000 person-years in Scandinavia, Finland and Spain. The median age at diagnosis increased from 1.9 years before 1990 to 7.6 since 2000. Larger increases in incidence were found in older age groups than in infants and ages

INTRODUCTION: 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and

Proton pump inhibitors (PPIs) are amongst the most commonly prescribed drugs in infants and children with the last decades witnessing a dramatic rise in their utilization. Although PPIs are clearly effective when used appropriately and have been regarded as safe drugs, there is growing evidence regarding their potential adverse effects. Although, largely based on adult data it is clear that many of these are also relevant to pediatrics. PPI use potentially affects gastrointestinal microbiota composition and function, decreases defence against pathogens resulting in increased risk for infections, interferes with absorption of minerals and vitamins leading to specific deficiencies and increased risk for bone fractures as well as interferes with protein digestion resulting in increased risk of sensitization to allergens and development of allergic diseases and eosinophilic esophagitis. An association with gastric, liver and pancreatic cancer has also been inferred from adult data but is tenuous and causation is not proven. Overall, evidence for these adverse events is patchy and not always compelling. Overall, the use of PPIs, for selected indications with a good evidence base, has significant potential benefit but carries more caution in infants and children. Pediatricians should be aware of the concerns regarding the potential adverse events associated with their use.

Functional fecal incontinence (FI) is a worldwide problem in children and comprises constipation-associated FI and nonretentive FI. Irrespective of pathophysiology, both disorders impact negatively on the psychological well-being and quality of life of affected children. A thorough clinical history and physical examination using the Rome IV criteria are usually sufficient to diagnose these conditions in most children. Evolving investigations such as high-resolution anorectal and colonic manometry have shed new light on the pathophysiology of functional FI. Although conventional interventions such as toilet training and laxatives successfully treat most children with constipation-associated FI, children with nonretentive FI need more psychologically based therapeutic options. Intrasphincteric injection of botulinum toxin, transanal irrigation and, in select cases, surgical interventions have been used in more resistant children with constipation-associated FI.

In the original article, there was an error. Figures 2, 3, 4 and 5 were referenced incorrectly. All references to Figure 5 should have been Figure 2, all references to Figure 4 should have been Figure 3, all references to Figure 3 should have been Figure 4, all references to figure 2 should have been Figure 5. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.[This corrects the article DOI: 10.3389/fnmol.2021.757646.].

The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal (GI) tract, is a vast, mesh-like network of neurons and glia embedded within the bowel wall. Through its complex circuitry and neuronal diversity, the ENS is capable of functioning autonomously but is modulated by inputs from the central nervous system (CNS). The communication between the ENS and CNS is bidirectional and, together with crosstalk of these systems with microbiota housed within the GI tract, underpins the so-called microbiota-gut-brain axis. The ENS functions as a master regulator and coordinates many of the essential functions of the body, including GI motility, sensation and secretion. It is also capable of interacting with other cells, including intestinal epithelial, neuroendocrine and immune cells, to regulate their development as well as structural and functional integrity. Disruption of these ENS interactions, especially during early life, is likely to contribute to the aetiopathogenesis of disorders of the GI tract as well as elsewhere in the body, including neurodegenerative diseases. In this article, we highlight recent advances in our understanding of the roles of the ENS, especially in its complex and reciprocal interactions that influence GI motility, sensation, intestinal epithelial integrity, immunity and neuroendocrine function, particularly focusing on the influence of the ENS in early life and early life programming.

Gastric emptying (GE) requires precise antropyloroduodenal coordination for effective transpyloric flow, the mechanisms of which are still unclear. We aimed to correlate gastric antral function assessed by antroduodenal manometry (ADM) with GE scintigraphy (GES) for liquid feeds in children with suspected gastrointestinal dysmotility.Children who underwent both ADM and GES over a five-year period were reviewed. ADM tracings were re-analyzed to assess antral frequency, amplitude, and motility index (MI) pre-prandially and postprandially. Transpyloric propagation (TPP) was defined as antegrade propagated antral activity preceding duodenal phase III of the migrating motor complex (MMC). TPP was defined as "poor" if occurring in50% of all presented duodenal phases III. For GES, regions of interest over the whole stomach, fundus, and antrum were drawn to calculate GE half-time (GE-TForty-seven children (median age: 7.0 years) were included. Twenty-two had PIPO, 14 functional GI disorders, and 11 gastroparesis. Children with poor TPP had longer GE-TTPP during phase III of the MMC correlated with gastric emptying of liquid and its assessment on ADM might predict abnormalities in postprandial gastric function.

The enteric nervous system (ENS) plays a central role in gut physiology and mediating the crosstalk between the gastrointestinal (GI) tract and other organs. The human ENS has remained elusive, highlighting the need for an in vitro modeling and mapping blueprint. Here we map out the developmental and functional features of the human ENS, by establishing robust and scalable 2D ENS cultures and 3D enteric ganglioids from human pluripotent stem cells (hPSCs). These models recapitulate the remarkable neuronal and glial diversity found in primary tissue and enable comprehensive molecular analyses that uncover functional and developmental relationships within these lineages. As a salient example of the power of this system, we performed in-depth characterization of enteric nitrergic neurons (NO neurons) which are implicated in a wide range of GI motility disorders. We conducted an unbiased screen and identified drug candidates that modulate the activity of NO neurons and demonstrated their potential in promoting motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define the developmental programs involved in NO neuron specification and discovered that PDGFR inhibition boosts the induction of NO neurons in enteric ganglioids. Transplantation of these ganglioids in the colon of NO neuron-deficient mice results in extensive tissue engraftment, providing a xenograft model for the study of human ENS in vivo and the development of cell-based therapies for neurodegenerative GI disorders. These studies provide a framework for deciphering fundamental features of the human ENS and designing effective strategies to treat enteric neuropathies.

The majority of the enteric nervous system is formed by vagal neural crest cells which enter the foregut and migrate rostrocaudally to colonise the entire length of the gastrointestinal tract. Absence of enteric ganglia from the distal colon are the hallmark of Hirschsprung disease, a congenital disorder characterised by severe intestinal dysmotility. Mutations in the receptor tyrosine kinase RET have been identified in approximately 50% of familial cases of Hirschsprung disease but the cellular processes misregulated in this condition remain unclear. By lineage tracing neural crest cells in mice homozygous for a knock-in allele of Ret (Ret51/51), we demonstrate that normal activity of this receptor is required in vivo for the migration of enteric nervous system progenitors throughout the gut. In mutant mice, progenitors of enteric neurons fail to colonise the distal colon, indicating that failure of colonisation of the distal intestine is a major contributing factor for the pathogenesis of Hirschsprung disease. Enteric nervous system progenitors in the ganglionic proximal guts of mutant mice are also characterised by reduced proliferation and differentiation. These findings suggest that the functional abnormalities in Hirschsprung disease result from a combination of colonic aganglionosis and deficits in neuronal circuitry of more proximal gut segments. The reduced neurogenesis in the gut of Ret51/51 mutants was reproduced in the multilineage enteric nervous system progenitors isolated from these animals. Correction of the molecular defects of such progenitors fully restored their neurogenic potential in culture. These observations enhance our understanding of the pathogenesis of Hirschsprung disease and highlight potential approaches for its treatment.

The enteric nervous system (ENS), the inherent nervous system of the gastrointestinal (GI) tract is a vast nervous system that controls key GI functions, including motility. It functions at a critical interface between the gut luminal contents, including the diverse population of microorganisms deemed the microbiota, as well as the autonomic and central nervous systems. Critical development of this axis of interaction, a key determinant of human health and disease, appears to occur most significantly during early life and childhood, from the pre-natal through to the post-natal period. These factors that enable the ENS to function as a master regulator also make it vulnerable to damage and, in turn, a number of GI motility disorders. Increasing attention is now being paid to the potential of disruption of the microbiota and pathogenic microorganisms in the potential aetiopathogeneis of GI motility disorders in children. This article explores the evidence regarding the relationship between the development and integrity of the ENS and the potential for such factors, notably dysbiosis and pathogenic bacteria, viruses and parasites, to impact upon them in early life.

This study explored the link between duodenal eosinophils and mast cells in patients with functional dyspepsia (FD).MEDLINE (PubMed) and Embase electronic databases were searched until June 2021 for case-control studies reporting duodenal eosinophils and mast cells in FD. Pooled standardized mean difference (SMD), odds ratio, and 95% CIs of duodenal eosinophils and mast cells in FD patients and controls were calculated, using a random-effects model.Twenty-two case-control studies with 1108 FD patients and 893 controls were identified. Duodenal eosinophils (SMD, 1.29; 95% CI, 0.85-1.73; P = .0001) and mast cells (SMD, 2.11; 95% CI, 1.14-3.07; P = .0001) were increased in FD patients compared with controls. Substantial heterogeneity was found (Isup2/sup = 93.61, P = .0001; and Isup2/sup = 96.69, P = .0001, respectively) and visual inspection of funnel plots confirmed publication bias. Degranulation of duodenal eosinophils was significantly higher in FD patients compared with controls (odds ratio, 3.78; 95% CI, 6.76-4.48; P = .0001), without statistically significant heterogeneity. We conducted a sensitivity analysis for duodenal eosinophils, by including only high-quality studies, and the results remained unchanged (SMD, 1.73; 95% CI, 1.06-2.40; P = .0001), with substantial heterogeneity. Postinfectious FD patients had increased duodenal eosinophils compared with controls (SMD, 3.91; 95% CI, 1.32-6.51; P = .001) and FD patients without any history of infection (SMD, 1.42; 95% CI, 0.88-1.96; P = .001). Helicobacter pylori-negative FD patients had significantly higher duodenal eosinophils compared with controls (SMD, 3.98; 95% CI, 2.13-5.84; P = .0001), with substantial heterogeneity. No significant difference in duodenal eosinophils was seen according to FD subtypes.This meta-analysis suggests a link between duodenal microinflammation and FD. However, the quality of evidence is very low, largely owing to the unexplained heterogeneity and serious risk of publication bias in all comparative analyses. Thus, causality remains uncertain and further studies are required.

BACKGROUND Antroduodenal manometry (ADM) and histopathology are currently employed to aid the diagnosis of pediatric intestinal pseudo-obstruction (PIPO). Limited data are available on the reliability of ADM analysis and its correlation with histopathology. We aimed to develop a protocol for enhanced analysis of ADM contractile patterns, including a scoring system, and explore whether this provided better correlation with histopathology. METHODS Children referred with suspected PIPO between April 2012-December 2019 who underwent both ADM and full-thickness biopsies were included. ADM tracings were analyzed using both standard (conventional ADM) and novel (enhanced ADM) motility parameters. A novel ADM score (GLASS score) was generated based on the enhanced ADM analysis. Conventional and enhanced ADM analyses were then correlated with histopathology. RESULTS Forty patients were included. Using conventional clinical criteria, 29 of these were diagnosed with PIPO and the other 11 with non-PIPO diagnoses. Twenty-three of the PIPO patients had abnormal histopathology: 6 myopathy, 4 neuropathy, 3 neuro-myopathy, and 10 non-specific changes. No agreement in diagnosis was found between conventional ADM analysis and histopathology (ϰ = 0.068; p = 0.197), whereas the latter significantly correlated with enhanced ADM analysis (ϰ = 0.191; p = 0.003). The enhanced ADM score was significantly higher in PIPO versus non-PIPO (16.0 vs. 8.0; p

Hirschsprung disease (HSCR) and Paediatric Intestinal Pseudo-obstruction (PIPO) comprise two of the most recognized and severe disorders of gastrointestinal (GI) motility. HSCR is a developmental disorder of the enteric nervous system invariably affecting the large intestine, whereas the majority of PIPO conditions represent congenital disorders of one or more components of the neuromusculature and more diffusely affect the GI tract. Histopathology is deemed the gold standard for the diagnosis of HSCR and, arguably, of PIPO, but, other diagnostic modalities such as manometric and genetic studies have seen recent advances that may increase their utility. Especially for PIPO, management is multidisciplinary and best performed in specialist referral centres. Surgery remains the only viable treatment for HSCR and appears essential to optimize and sustain feeding and viability of intestinal function in PIPO patients. Novel therapies such as neural stem cell transplants show promise for the future.

International audience; Acute diarrhoea is a leading cause of morbidity and mortality in the paediatric population. Racecadotril is an antisecretory drug recommended as an adjuvant anti-diarrhoeal treatment.In the small bowel, the enzyme neutral endopeptidase (NEP) inhibits the action of enkephalins, which prevent water and electrolyte hypersecretion. By inhibiting NEP, racecadotril allows enkephalins to exhibit their antisecretory effects. Consequently, racecadotril reduces the secretion of water and electrolytes in the small intestine, without having an effect on intestinal motility. No serious adverse events related to racecadotril have been reported.Racecadotril has proven its efficacy as an adjuvant anti-diarrhoeal drug with a good safety profile. Its addition to oral rehydration solution (ORS) appears clinically beneficial and potentially leads to health care savings.

To evaluate clinical, endoscopic, and pH-impedance measures in a cohort of children with esophageal atresia and concomitant eosinophilic esophagitis (EoE) and compared it with disease-matched controls, to identify predictive factors for the development of EoE and esophageal stricture.We reviewed 63 patients with esophageal atresia assessed for refractory upper gastrointestinal symptoms between January 2015 and September 2017 at 2 tertiary referral centers. All patients underwent upper gastrointestinal endoscopy and pH-impedance monitoring. Based on esophageal histology, patients were classified as (1) esophageal atresia without evidence of esophagitis; (2) esophageal atresia with evidence of esophagitis (including esophageal eosinophilia not meeting the criteria for EoE); (3) esophageal atresia with concomitant EoE. Age and sex matched patients with gastroesophageal reflux disease were used as disease controls.The presence of atopy and peripheral eosinophilia at baseline were significantly associated with EoE (P .05). Although there was a tendency toward an increased number of strictures in patients with esophageal atresia-EoE, this did not reach statistical significance (P = .06). Higher esophageal acid exposure time and lower baseline impedance values were significantly associated with eosinophilic infiltration (P .05 and P .01, respectively). Using logistic regression analysis, the presence of mucosal eosinophilia was the most predictive factor for stricture formation (P .05).A history of atopy and the presence of peripheral eosinophilia in patients with esophageal atresia are predictive factors for the development of EoE, which in turn is a predictive factor for stricture occurrence. Higher esophageal acid exposure time and lower baseline impedance are associated with esophageal eosinophilic infiltration, suggesting their value in selecting which patients with esophageal atresia should undergo endoscopic examination.

Objectives To critically appraise ileocolonoscopy (IC) practice in a large tertiary center, where IC is exclusively performed by experienced pediatric colonoscopists, particularly focusing on indications for the procedure; bowel preparation efficacy; IC completion rates and timings; diagnostic yield; and complications. Patients and methods We prospectively evaluated all patients referred to our clinic between July 2015 and June 2016. Data on age, height and weight, sex, surgical history, indications for colonoscopy, bowel preparation given, and bowel cleansing efficacy were collected. The following were calculated: percentage of terminal ileal (TI) intubation; time to terminal ileum; total duration of each procedure. In addition, we evaluated the number and the type of complications encountered and the number of patients readmitted within 30 days from the elective procedure. Endoscopic diagnostic yield, stratified for indication, was calculated. Results A total of 1392 patients were referred; 181 required an endoscopic evaluation of the lower gastrointestinal (GI) tract (Outpatient Department conversion rate: 13%). Main indications for IC were: recurrent abdominal pain 38.1%; unexplained chronic diarrhea 16%; suspected inflammatory bowel disease (IBD) 24.9%; isolated rectal bleeding 13.2%; occult GI bleeding 1.6%; unexplained faltering growth 1.6%; IBD restaging 2.6%; and miscellaneous 1.6%. Terminal ileum was reached in all the patients (TI intubation rate = 100%). Median time to TI was 9.8 minutes (1-50 minutes). Time to TI was lower in younger patients compared to older ones (P = 0.005). Bowel cleansing was judged as grade 1 in 49.2%; grade 2 in 33.7%; grade 3 in 13.3%; and grade 4 in 3.9%. A significant statistical correlation was recorded between bowel cleansing and time to TI. The positive diagnostic yield was: 11.6% in patients with abdominal pain; 37.9% in patients with chronic diarrhea; 51.1% in patients with suspected IBD; 29.2% in patients with isolated rectal bleeding; 33.3% in patients with occult GI bleeding; 0% in patients with faltering growth; and 33% in the miscellaneous group. Conclusions In conclusion, appropriately targeted IC in the management of children with GI symptoms is a safe, fast, and useful investigation. TI intubation rates of 100% are achievable and desirable and can be conducted quickly. Poor bowel preparation impacts negatively on this and IC duration may be faster in younger children. High diagnostic yields have been recorded in patients with a clinical suspicion of IBD. Diagnostic yield in isolated recurrent abdominal pain is low. Training to excellence in pediatric IC should be a persistent goal.

Pediatric functional gastrointestinal disorders including irritable bowel syndrome with constipation and functional constipation are common conditions in childhood, but no drugs are U.S. Food and Drug Administration (FDA) approved for chronic use in pediatric patients with these disorders. Despite efforts to better standardize the diagnosis of these conditions in children (including recent modifications to the Rome criteria), conducting pediatric clinical trials to support drug approval remains a challenge. In March 2018, FDA, in collaboration with the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, American Gastroenterological Association, and American College of Gastroenterology, convened a public workshop to discuss the challenges and opportunities in conducting pediatric clinical trials in functional gastrointestinal conditions. The workshop assembled gastroenterologists, psychologists, patients, patient advocates, regulators, and industry representatives to discuss trial design and conduct including alternative designs, eligibility criteria, instruments for patient- and observer-reported outcomes, and optimal primary endpoints to support regulatory approval. This report summarizes the workshop, key challenges and knowledge gaps identified, and outlines areas where further research efforts are needed to overcome barriers to developing drugs to treat these conditions.

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analysed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non cell-autonomous manner. Analysis of human gut fetal tissues with aKIAA0586mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning

Introduction 13C‐breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. Methods This consensus‐based clinical practice guideline defines the clinical indications, performance, and interpretation of 13C‐breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and

Paediatric functional abdominal pain disorders, currently referred to as disorders of gut-brain interaction, comprise irritable bowel syndrome, functional dyspepsia, abdominal migraine and functional abdominal pain not otherwise specified, as defined by the Rome IV diagnostic criteria. Functional abdominal pain disorders are common disorders with a prevalence of 3-16% depending on country, age and sex. A greater understanding of aetiopathogenesis and pathophysiology is emerging and includes intestinal components (inflammation, motility and the microbiota), central factors (psychological aspects, sensitization and/or differences in connectivity or activity of certain brain regions) as well as extrinsic factors (infections). In particular, the timing of disruption of the microbiota-gut-brain axis seems to be important. Diagnosis is challenging but is primarily based on clinical symptoms and exclusion of other organic causes, with an emphasis on avoiding unnecessary invasive diagnostic procedures. The available pharmacological interventions are limited in children and, therefore, management has focused on combined approaches, including mind-targeted interventions (hypnotherapy and cognitive behavioural therapy), diet (probiotics) and percutaneous electrical nerve field stimulation. The evidence for their clinical efficacy, although limited, is favourable, with positive impacts on symptoms and overall quality of life. The coming decades hold promise for improved understanding and management of these enigmatic disorders.

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global public health emergency. COVID-19 typically manifests as a respiratory illness but an increasing number of clinical reports describe gastrointestinal (GI) symptoms. This is particularly true in children in whom GI symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. By contrast, fetuses seem to be rarely affected by COVID-19, although the virus has been detected in placentas of affected women. These observations raise the question of whether the virus can infect and replicate within the stomach once ingested. Moreover, it is not yet clear whether active replication of SARS-CoV-2 is possible in the stomach of children or in fetuses at different developmental stages. Here we show the novel derivation of fetal gastric organoids from 8-21 post-conception week (PCW) fetuses, and from pediatric biopsies, to be used as an in vitro model for SARS-CoV-2 gastric infection. Gastric organoids recapitulate human stomach with linear increase of gastric mucin 5AC along developmental stages, and expression of gastric markers pepsinogen, somatostatin, gastrin and chromogranin A. In order to investigate SARS-CoV-2 infection with minimal perturbation and under steady-state conditions, we induced a reversed polarity in the gastric organoids (RP-GOs) in suspension. In this condition of exposed apical polarity, the virus can easily access viral receptor angiotensin-converting enzyme 2 (ACE2). The pediatric RP-GOs are fully susceptible to infection with SARS-CoV-2, where viral nucleoprotein is expressed in cells undergoing programmed cell death, while the efficiency of infection is significantly lower in fetal organoids. The RP-GOs derived from pediatric patients show sustained robust viral replication of SARS-CoV-2, compared with organoids derived from fetal stomachs. Transcriptomic analysis shows a moderate innate antiviral response and the lack of differentially expressed genes belonging to the interferon family. Collectively, we established the first expandable human gastric organoid culture across fetal developmental stages, and we support the hypothesis that fetal tissue seems to be less susceptible to SARS-CoV-2 infection, especially in early stages of development. However, the virus can efficiently infect gastric epithelium in pediatric patients, suggesting that the stomach might have an active role in fecal-oral transmission of SARS-CoV-2.

Background: Colonic manometry with intraluminal bisacodyl infusion can be used to assess colonic neuromuscular function in children with treatment-refractory constipation. If bisacodyl does not induce high-amplitude propagating contractions (HAPCs), this can be an indication for surgical intervention. A detailed characterization of the colonic response to intraluminal bisacodyl in children with constipation may help to inform clinical interpretation of colonic manometry studies. Methods: Studies were performed in five pediatric hospitals. Analysis included identification of HAPCs, reporting HAPCs characteristics, and an area under the curve (AUC) analysis. Comparisons were performed between hospitals, catheter type, placement techniques, and site of bisacodyl infusion. Results: One hundred and sixty-five children were included (median age 10, range 1-17 years; n = 96 girls). One thousand eight hundred and ninety-three HAPCs were identified in 154 children (12.3 ± 8.8 HAPCs per child, 0.32 ± 0.21 HAPCs per min; amplitude 113.6 ± 31.5 mm Hg; velocity 8.6 ± 3.8 mm/s, propagation length 368 ± 175 mm). The mean time to first HAPC following bisacodyl was 553 ± 669 s. Prior to the first HAPC, there was no change in AUC when comparing pre- vs post-bisacodyl (Z = −0.53, P =.60). The majority of HAPCs terminated in a synchronous pressurization in the rectosigmoid. Defecation was associated with HAPCs (χ 2(1)=7.04, P

Motility of the gastrointestinal tract plays a critical role in the maintenance of its many physiological functions. These motility patterns, which vary along the gastrointestinal tract, are achieved by highly coordinated interactions between the neuromusculature of the gut (smooth muscle layers, enteric nervous system, interstitial cells of Cajal), central nervous system, autonomic nervous system, hormones, peptides and the microbiome. Other external factors such as diet, and age related changes in the gastrointestinal tract also, ultimately, affect gastrointestinal motility. A subtle change in any of the above factors could significantly impact on gastrointestinal function leading to pediatric gastrointestinal motility disorders. Here, we review common motility disorders in children and provide an indepth understanding of the pathophysiology and management of these problem.

The gut-brain axis has recently emerged as a key modulator of human health and the intestinal microbiome has a well-recognised pivotal role in this strong connection. The aim of this narrative review is to update and summarise the effect and clinical applicability of probiotics in paediatric neurogastroenterology. The Cochrane Database and PubMed were searched using keywords relating to different subtypes of functional gastrointestinal disorders (FGIDs) and their symptoms, those relating to the CNS and related neurological or behavioural dysfunction as well as 'probiotic' OR 'probiotics'. Included papers were limited to those including children (aged 0-18 years) and using English language. Although significant effects of specific strains have been reported in infants with FGIDs, heterogeneity amongst the studies (different products and concentrations used and FGID subtypes), has limited the ability to draw an overall conclusion on the clinical value of probiotics. According to different meta-analyses of randomised controlled trials, the use of Lactobacillus reuteri (DSM 17938) was associated with a significant decrease in average crying time in infantile colic. There is moderate evidence for this strain and LGG and limited evidence (based on one study each) for the beneficial effect of VSL#3 and a three-strain bifidobacteria mix in abdominal pain FGIDs, particularly in the irritable bowel disease subgroup of children, but not in functional dyspepsia. There is currently no clear evidence of positive effects of oral probiotics in autistic spectrum disorder. Efficacy and safety of other strains or beneficial effects in other conditions still need to be proven, as probiotic properties are strain-specific, and data cannot be extrapolated to other brain-gut or mood diseases or to other probiotics of the same or different species. To transform the use of probiotics from a tempting suggestion to a promising treatment modality in neurogastroenterological disorders more accurate differentiation of the efficacy-proven strains, clarification of dose, duration, and outcome and a careful selection of the target patients are still necessary. KEYWORDS: autism; behaviour; brain; functional gastrointestinal disorders; mood

The bewildering complexity of the enteric nervous system makes it susceptible to develop a wide array of motility disorders, collectively called enteric neuropathies. These gastrointestinal conditions are among the most challenging to manage, mainly given poor characterization of their etiopathophysiology and outcomes. Not surprisingly, therefore, targeted or curative therapies for enteric neuropathies are lacking and management is largely symptomatic. Nonetheless, recent advances in neurogastroenterology have witnessed improvements in established strategies, such as intestinal transplantation and the emergence of new treatments including novel drugs, electrical pacing, and manipulation of fecal microbiota, as well as stem cell and gene therapy.

Resumen: Los trastornos funcionales de dolor abdominal tienen una alta prevalencia en los niños. Estos trastornos pueden estar presentes por sí solos o en combinación con enfermedades orgánicas, tales como la enfermedad celíaca y las enfermedades inflamatorias intestinales. La inflamación intestinal (infecciosa y no infecciosa) predispone a los niños al desarrollo de hipersensibilidad visceral que puede manifestarse como trastornos funcionales de dolor abdominal, entre ellos el síndrome de intestino irritable. La aparición de síntomas de síndrome de intestino irritable en un paciente con una enfermedad orgánica subyacente, como la enfermedad inflamatoria intestinal, es un reto clínico, dado que la misma sintomatología puede representar un periodo de exacerbación de la enfermedad inflamatoria intestinal o un trastorno de dolor abdominal funcional sobrepuesto. Así mismo, puede ser que los síntomas del síndrome de intestino irritable en un niño con diagnóstico de enfermedad celíaca ocurran por un inadecuado control de la enfermedad celíaca o por la sobreposición con un trastorno de dolor abdominal funcional. Existe poca investigación acerca de la sobreposición de los trastornos funcionales abdominales y las enfermedades orgánicas en niños. Los estudios sugieren que la sobreposición entre los trastornos funcionales de dolor abdominal y la enfermedad inflamatoria intestinal es más común en adultos que en niños. Las causas de estas diferencias de prevalencia son aún desconocidas. Solo se han publicado unos cuantos estudios que tratan el tema de la sobreposición entre la enfermedad celíaca y los trastornos funcionales abdominales en niños. El presente artículo proporciona una revisión de la literatura acerca de la sobreposición entre la enfermedad celíaca, la enfermedad inflamatoria intestinal, y los trastornos funcionales de dolor abdominal en niños, además de establecer comparaciones con estudios realizados en adultos. Abstract: Functional abdominal pain disorders are highly prevalent in children. These disorders can be present in isolation or combined with organic diseases, such as celiac disease and inflammatory bowel diseases. Intestinal inflammation (infectious and non-infectious) predisposes children to the development of visceral hypersensitivity that can manifest as functional abdominal pain disorders, including irritable bowel syndrome. The new onset of irritable bowel syndrome symptoms in a patient with an underlying organic disease, such as inflammatory bowel disease, is clinically challenging, given that the same symptomatology may represent a flare-up of the inflammatory bowel disease or an overlapping functional abdominal pain disorder. Similarly, irritable bowel syndrome symptoms in a child previously diagnosed with celiac disease may occur due to poorly controlled celiac disease or the overlap with a functional abdominal pain disorder. There is little research on the overlap of functional abdominal disorders with organic diseases in children. Studies suggest that the overlap between functional abdominal pain disorders and inflammatory bowel disease is more common in adults than in children. The causes for these differences in prevalence are unknown. Only a handful of studies have been published on the overlap between celiac disease and functional abdominal pain disorders in children. The present article provides a review of the literature on the overlap between celiac disease, inflammatory bowel disease, and functional abdominal pain disorders in children and establish comparisons with studies conducted on adults. Palabras clave: Dolor abdominal, Enfermedad celíaca, Enfermedad inflamatoria intestinal, Niños, Inflamación gastrointestinal, Keywords: Abdominal pain, Celiac disease, Inflammatory bowel disease, Children, Gastrointestinal inflammation

Background The N-Myc Downstream-Regulated Gene (NDRG) family comprises four members that function in cellular processes like proliferation and differentiation. While NDRG1 and NDRG2 are extensively studied, knowledge regarding NDRG3 and NDRG4, despite its recognition as a well-established early-detection marker for colorectal cancer (Cologuard®), is sparse. Scope of review To summarize expression, biomarker potential and functional mechanisms of the NDRGs in the developing, mature and cancerous gut, we combine current literature and in silico analyses from the TCGA-database, GTEX Project, E14.5 mouse intestine and enteric neural crest cells, and an RNA-sequencing time-series of human embryonic colonic samples. Major conclusions This study reveals that all members display a differential expression pattern in the gut and that NDRG1, NDRG2 and NDRG4 (1) can serve as biomarker for colorectal cancer and (2) have tumor suppressive properties mainly affecting cell proliferation and epithelial-mesenchymal transition. General significance Similar effects of the NDRGs on the key-hallmarks of cancer, could implicate analogous functions in other tissue/cancer types.

Spinal cord injury (SCI) causes paralysis, multisystem impairment and reduced life expectancy, as yet with no cure. Stem cell therapy can potentially replace lost neurons, promote axonal regeneration and limit scar formation, but an optimal stem cell source has yet to be found. Enteric neural stem cells (ENSC) isolated from the enteric nervous system (ENS) of the gastrointestinal (GI) tract are an attractive source. Here, we used the chick embryo to assess the potential of ENSC to integrate within the developing spinal cord. In vitro, isolated ENSC formed extensive cell connections when co‐cultured with spinal cord (SC)‐derived cells. Further, qRT‐PCR analysis revealed the presence of TuJ1(+) neurons, S100(+) glia and Sox10(+) stem cells within ENSC neurospheres, as well as expression of key neuronal subtype genes, at levels comparable to SC tissue. Following ENSC transplantation to an ablated region of chick embryo SC, donor neurons were found up to 12 days later. These neurons formed bridging connections within the SC injury zone, aligned along the anterior/posterior axis, and were immunopositive for TuJ1. These data provide early proof of principle support for the use of ENSCs for SCI, and encourage further research into their potential for repair.

Background Combined pH-impedance monitoring has been suggested as the investigation of choice for diagnosing gastro-oesophageal reflux in children. Although it is superior to oesophageal pH monitoring in detecting all types of reflux episodes (acid, weakly acidic and alkaline) with the ability to evaluate symptom association with reflux events, it is still limited by the lack of true paediatric normal value and the high cost involved (equipment and personnel). Objective To produce a position statement on behalf of the Motility Working Group of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition on the indications and practical application of combined oesophageal pH-impedance monitoring in children. Methods Up-to-date review of available evidence. Results This document provides a practical guide to clinician on indications, methods and results interpretation of paediatric multichannel intraluminal impedance pH (MII-pH). Conclusions MII-pH is increasingly used by paediatricians as the diagnostic tool for assessing gastro-oesophageal reflux disease and symptom association. There is wide variation in paediatric practice and a need for standardised practice.

Intestinal failure (IF), following extensive anatomical or functional loss of small intestine (SI), has debilitating long-term effects on infants and children with this condition. Priority of care is to increase the child’s length of functional intestine, jejunum in particular, to improve nutritional independence. Here we report a robust protocol for reconstruction of autologous intestinal mucosal grafts using primary IF patient materials. Human jejunal intestinal organoids derived from paediatric IF patients can be expanded efficiently in vitro with region-specific markers preserved after long-term culture. Decellularized human intestinal matrix with intact ultrastructure is used as biological scaffolds. Proteomic and Raman spectroscopic analyses reveal highly analogous biochemical composition of decellularized human SI and colon matrix, implying that they can both be utilised as scaffolds for jejunal graft reconstruction. Indeed, seeding of primary human jejunal organoids to either SI or colonic scaffolds in vitro can efficiently reconstruct functional jejunal grafts with persistent disaccharidase activity as early as 4 days after seeding, which can further survive and mature after transplantation in vivo. Our findings pave the way towards regenerative medicine for IF patients.

SummaryThe enteric nervous system (ENS) is derived primarily from the vagal neural crest, a migratory multipotent cell population emerging from the dorsal neural tube between somites 1-7. Defects in the development and function of the ENS give rise to a range of disorders, termed enteric neuropathies and include conditions such as Hirschsprung’s disease. Little is known about the signalling that specifies early ENS progenitors. This has, thus far, limited progress in the generation of enteric neurons from human Pluripotent Stem Cells (hPSCs) that could provide a useful tool for disease modelling and regenerative medicine. We describe the efficient and accelerated generation of ENS progenitors from hPSCs, revealing that retinoic acid is critical for the acquisition of both vagal axial identity and early ENS progenitor specification. These ENS progenitors generate enteric neuronsin vitroand followingin vivotransplantation, achieving long-term colonisation of the ENS in adult mice. Thus, hPSC-derived ENS progenitors may provide the basis for cell therapy for defects in the ENS.

Background ‘Intractable constipation’ (IC) is constipation unresponsive to 3 months of optimal conventional treatment. Colonic manometry (CM) is recommended as a diagnostic modality for evaluation of these children. This study aimed to review outcomes of children with IC who were managed surgically at a single tertiary care center. Methods Records of children with IC who were treated with ACE (antegrade colonic enema), colostomy, or ileostomy (2006–2018) were reviewed. “Success” was defined as adequate evacuation without need for further unplanned surgery. Data are median (range). Results Sixty-seven children underwent surgery, of whom 56 with preoperative CM were included. Age at surgery was 8.6 (3.3–15.1) years. Eight had normal manometry and underwent ACE with 75% success. Thirty-six had left-sided dysfunction and underwent ACE (18), colostomy (14) or ileostomy (4) as initial intervention with 61, 70, and 100% success. Twelve with pancolonic dysfunction underwent ACE (6) or ileostomy (6) with 60 and 100% success. Twenty underwent repeat manometry 2.2 years (10 months–7.6 years) after surgery. Of 18 with stoma, 8 had resolution or improvement and of these, 7 underwent stoma reversal with a simultaneous ACE. Two patients with ACE had improvement, 1 is still on ACE washouts, and 1 is off all treatment. Ten with persistent dysfunction remain diverted. At 3.2 years (4 months–9.9 years) follow-up, 18 remain on ACE washouts, 9 have colostomy, 19 ileostomy, and 10 are off treatment and doing well. Conclusion We present a large series of patients who were surgically managed for IC. CM may guide therapy in these children. Type of study Retrospective comparative study Level of evidence Level III.

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children1. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence2. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.

Defecatory disorders in children, including chronic constipation (CC) and fecal incontinence (FI), are common conditions worldwide and have a significant impact on children, their families, and the healthcare system. Anorectal manometry (ARM) and high-resolution anorectal manometry (HRAM) are relatively novel tools for the assessment of anal sphincter function and rectal sensation and have contributed significantly to improving the understanding of the anorectum as a functional unit. ARM has been recognized as the investigation of choice for adults with symptoms of defecation disorders, including fecal incontinence (FI), evacuation difficulties, and constipation. Although it is the gold standard tool in adults, it has yet to be formally accepted as a standardized diagnostic tool in the pediatric age, with limited knowledge regarding indications, protocol, and normal values. ARM/HRAM is slowly becoming recognized among pediatricians, but given that there are currently no agreed guidelines there is a risk that will lead to diversity in practice. The British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN)-Motility Working Group (MWG) therefore has taken the opportunity to provide guidance on the use of ARM/HRAM in children with CC and/or FI.

Enteric neuropathies, such as Hirschsprung disease (HSCR), comprise a number of severe diseases of the enteric nervous system (ENS) of the gastrointestinal (GI) tract with, as yet, no cures. The replacement of absent or diseased enteric neurons via stem cell transplantation directly into diseased gut represents a novel, curative therapy. This idea is supported by over two decades of preclinical research, carried out mainly in mice, demonstrating that neural crest-derived stem cells can be isolated from the gut, expanded in culture, and transplanted into gut in vivo where they migrate, proliferate, differentiate, and become functionally active. Here, we review some of the learnings from these studies, outlining the diseases potentially amenable to stem cell replacement therapy, the animals used to model disease, the different types of stem cells that could be used for therapy, the methodologies developed to prepare and deliver stem cells to the gut, and cell safety considerations. With the significant progress that has already been made by the field, the aim of developing a curative stem cell therapy for devastating diseases of the enteric nervous system is rapidly approaching reality.

The current increasing survival of children with severe central nervous system damage has created a major challenge for medical care. Gastrointestinal and nutritional problems in neurologically impaired children have been recently recognized as an integral part of their disease, often leading to growth failure and worsened quality of life for both children and caregivers. Nutritional support is essential for the optimal care of these children. Undernourished handicapped children might not respond properly to intercurrent diseases and suffer unnecessarily. On the other hand, restoring a normal nutritional status results in a better quality of life in many. The easiest and least invasive method to increase energy intake is to improve oral intake. However, oral intake can be maintained as long as there is no risk of aspiration, the child is growing well and the time required to feed the child remains within acceptable limits. When oral intake is unsafe, insufficient or too time consuming, enteral nutrition should be initiated. Damage to the developing central nervous system may result in significant dysfunction in the gastrointestinal tract and is reflected in impairment in oral-motor function, rumination, gastro-oesophageal reflux (GER), with or without aspiration, delayed gastric emptying and constipation. These problems can all potentially contribute to feeding difficulty in disabled children, carrying further challenging long-term management issues.

Recurrent abdominal pain (RAP) is a common complaint in children. Previously considered a single entity, RAP is now used as a descriptive term and sub-classified in the recently published Rome IV criteria, into four functional abdominal pain disorders (FAPD), including functional dyspepsia and irritable bowel syndrome. All share common pathogenic mechanisms of visceral hypersensitivity and central hypervigilance, resulting from disruption of the microbiota–gut–brain axis and abnormal enteric neuro–immune interactions. Although FAPDs are benign in nature, the persistence of symptoms and effects on everyday life can have significant secondary effects including psychosocial morbidity. The diagnosis of FAPDs is based on careful history and examination looking for ‘alarm signs', although a limited battery of laboratory investigations to screen for organic disease may be of value. The management of FAPDs should be multidisciplinary and based on the bio-psychosocial model of care with careful education and engagement of patients/parents. There is currently little evidence to support the routine use of pharmacotherapy, probiotics or diet and a significant placebo effect should be considered when assessing treatment effect. Hypnotherapy has been shown to be an effective therapy. Approximately 50% of FAPDs cases will achieve resolution, especially those that have engaged with the appropriate model of management.

The enteric nervous system (ENS) is involved in the regulation of virtually all gut functions. Conditions referred to as enteric neuropathies are the result of various mechanisms including abnormal development, degeneration or loss of enteric neurons that affect the structure and functional integrity of the ENS. In the past decade, clinical and molecular research has led to important conceptual advances in our knowledge of the pathogenetic mechanisms of these disorders. In this review we consider ENS disorders from a clinical perspective and highlight the advancing knowledge regarding their pathophysiology. We also review current therapies for these diseases and present potential novel reparative approaches for their treatment.

Background Colonic manometry is the standard diagnostic modality for evaluating colonic motility in children. Intraluminal bisacodyl is routinely used to trigger high-amplitude propagating contractions (HAPCs), a feature of normal colonic motility. Usually, only a single dose (0.2 mg/kg) is suggested. We retrospectively explored whether the use of an additional higher (0.4 mg/kg) dose of bisacodyl increases the yield of colonic manometry. Methods In 103 children (median age: 8.8 years, range 3.2–15.7 years) with a diagnosis of slow transit constipation, colonic motility was recorded for 1 h before and 1 h after each of two incremental doses of bisacodyl (low, L, dose: 0.2 mg/kg, max 10 mg; high, H, dose: 0.4 mg/kg, max 20 mg) and the characteristics of HAPCs analyzed. Key Results High-amplitude propagating contractions were seen in 85 children. H dose significantly increased the proportion of patients with fully propagated HAPCs (H dose: 57/103 [55%], L dose: 27/103 [26%], p

Abnormal development or disturbed functioning of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is associated with the development of neuropathic gastrointestinal motility disorders. Here, we review the underlying molecular basis of these disorders and hypothesize that many of them have a common defective biological mechanism. Genetic burden and environmental components affecting this common mechanism are ultimately responsible for disease severity and symptom heterogeneity. We believe that they act together as the fulcrum in a seesaw balanced with harmful and protective factors, and are responsible for a continuum of symptoms ranging from neuronal hyperplasia to absence of neurons.