Phosphatase and Tensin Homolog Inhibition in Proteolipid Protein 1-Expressing Cells Stimulates Neurogenesis and Gliogenesis in the Postnatal Enteric Nervous System.

Phosphatase and tensin homolog (Pten) is a key regulator of cell proliferation and a potential target to stimulate postnatal enteric neuro- and/or gliogenesis. To investigate this, we generated two tamoxifen-inducible Cre recombinase murine models in which was conditionally ablated, (1) in glia (-expressing cells) and (2) in neurons (-expressing cells). Tamoxifen-treated adult (7-12 weeks of age; = 4-15) mice were given DSS to induce colitis, EdU to monitor cell proliferation, and were evaluated at two timepoints: (1) early (3-4 days post-DSS) and (2) late (3-4 weeks post-DSS).

Efficacy of an Enterotoxigenic (ETEC) Vaccine on the Incidence and Severity of Traveler's Diarrhea (TD): Evaluation of Alternative Endpoints and a TD Severity Score.

The efficacy of an Oral Whole Cell ETEC Vaccine (OEV) against Travelers' Diarrhea (TD) was reexamined using novel outcome and immunologic measures. More specifically, a recently developed disease severity score and alternative clinical endpoints were evaluated as part of an initial validation effort to access the efficacy of a vaccine intervention for the first time in travelers to an ETEC endemic area. A randomized, double-blind, placebo-controlled trial followed travelers to Guatemala or Mexico up to 28 days after arrival in the country following vaccination (two doses two weeks apart) with an ETEC vaccine.

Proteolipid protein 1 is involved in the regulation of intestinal motility and barrier function in the mouse.

Proteolipid protein 1 (Plp1) is highly expressed in enteric glia, labeling cells throughout the mucosa, muscularis, and the extrinsic innervation. Plp1 is a major constituent of myelin in the central and peripheral nervous systems, but the absence of myelin in the enteric nervous system (ENS) suggests another role for Plp1 in the gut. Although the functions of enteric glia are still being established, there is strong evidence that they regulate intestinal motility and permeability.

EDS-related Feeding Difficulties: Preventing the Placement of a Surgical Feeding Tube.

Feeding difficulties due to functional gastrointestinal (GI) symptoms (i.e., nausea, pain, and bloating) are well described in patients with hypermobile-type Ehlers-Danlos Syndrome.

Intestinal microbiota shapes gut physiology and regulates enteric neurons and glia.

Background: The intestinal microbiota plays an important role in regulating gastrointestinal (GI) physiology in part through interactions with the enteric nervous system (ENS). Alterations in the gut microbiome frequently occur together with disturbances in enteric neural control in pathophysiological conditions. However, the mechanisms by which the microbiota regulates GI function and the structure of the ENS are incompletely understood.

Neurons populating the rectal extrinsic nerves in humans express neuronal and Schwann cell markers.

Background: In mice, Schwann cell (SC) progenitors give rise to autonomic ganglion cells and migrate into the gut to become enteric neurons. It is unknown whether SC progenitors have a similar fate in humans. In search of evidence for human SC-derived neurogenesis in the gastrointestinal (GI) tract, we studied the rectums from cadaveric controls and children with anorectal malformations (ARM).

Enema-Induced spastic left colon syndrome: An unintended consequence of chronic enema use.

Background/purpose: Enemas have become a common practice for treating fecal incontinence and severe constipation. Several patients receiving enemas complained of severe, colicky, abdominal pain during enema administration and complained that the duration for fluid to pass was progressively increasing. Contrast studies showed a startling picture of severe right colon dilatation and a spastic, narrow, left colon.

Development of Entrustable Professional Activities and Standards in Training in Pediatric Neurogastroenterology and Motility: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and American Neurogastroenterology and Motility Society Position Paper.

Neurogastroenterology and motility (NGM) disorders are common in childhood and are often very debilitating. Although pediatric gastroenterology fellows are expected to obtain training in the diagnosis and management of patients with these disorders, there is an ongoing concern for unmet needs and lack of exposure and standardized curriculum. In the context of tailoring training components, outcome and expressed needs of pediatric gastroenterology fellows and programs, members of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) and American Neurogastroenterology and Motility Society (ANMS) developed guidelines for NGM training in North America in line with specific expectations and goals of training as delineated through already established entrustable professional activities (EPAs).

Implementation of a Timed Barium Esophagram Protocol for Assessment of Esophageal Function in Children.

Objectives: Timed barium esophagram (TBE) is a fluoroscopic study that is widely employed as an adjunctive tool for diagnosing esophageal emptying disorders in adults (eg, achalasia, esophagogastric junction outflow obstruction [EGJOO]) and for following response to treatment. We aimed to describe the characteristics and feasibility of a pediatric TBE protocol and provide a first report of the potential value of TBE for assessment of esophageal emptying in the pediatric population.

Methods: Retrospective chart review of pediatric patients at a tertiary pediatric hospital who underwent TBE from October 2017 to October 2019.

Proceedings of the 2018 Advances In Motility and In NeuroGastroenterology: AIMING for the Future Single Topic Symposium.

Objectives: Motility and functional disorders are common in children and often debilitating, yet these disorders remain challenging to treat effectively. At the 2018 Annual North American Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting, the Neurogastroenterology and Motility Committee held a full day symposium entitled, 2018 Advances In Motility and In NeuroGastroenterology - AIMING for the future. The symposium aimed to explore clinical paradigms in pediatric gastrointestinal motility disorders and provided a foundation for advancing new scientific and therapeutic research strategies.

Concise Review: Cellular and Molecular Mechanisms of Postnatal Injury-Induced Enteric Neurogenesis.

Although still controversial, there is increasing agreement that postnatal neurogenesis occurs in the enteric nervous system (ENS) in response to injury. Following acute colitis, there is significant cell death of enteric neurons and evidence suggests that subsequent neural regeneration follows. An enteric neural stem/progenitor cell population with neurogenic potential has been identified in culture; in vivo, compensatory neurogenesis is driven by enteric glia and may also include de-differentiated Schwann cells.

Benefit of Pelvic Floor Physical Therapy in Pediatric Patients with Dyssynergic Defecation Constipation.

Objectives: Chronic constipation is a common childhood problem and often caused or worsened by abnormal dynamics of defecation. The aim of this study was to assess the benefit of pelvic floor physical therapy (PFPT), a novel treatment in pediatrics for the treatment of chronic constipation with dyssynergic defecation.

Methods: This was a retrospective study of 69 children seen at a pediatric neurogastroenterology program of a large tertiary referral center for chronic constipation and dyssynergic defecation, determined by anorectal manometry and balloon expulsion testing.

Barriers in Neurogastroenterology and Motility Training Experience for Pediatric Gastroenterology Fellows.

Background: Neurogastroenterology and motility (NGM) disorders are common and have a high health care burden. Although pediatric gastroenterology fellows are expected to obtain comprehensive training in the diagnosis and management of NGM disorders, there is ongoing concern for unmet training needs and lack of exposure in treating patients who suffer from NGM problems.

Methods: We conducted a cross-section survey of trainees listed as pediatric gastroenterology fellows in North American training programs in 2018 via direct E-mail and the pediatric gastroenterology listserv.

Botulinum toxin injection for childhood constipation is safe and can be effective regardless of anal sphincter dynamics.

Background: Childhood constipation is common. Previously, internal anal sphincterotomy has been used for hypertensive/non-relaxing sphincters; however, recent benefit has been shown with Botulinum Toxin (BT) injections. The aim is to investigate BT, including response duration, symptom association and effectiveness in relation to sphincter dynamics.

Treatment of Functional Abdominal Pain With Antidepressants: Benefits, Adverse Effects, and the Gastroenterologist's Role.

Objectives: Pediatric functional abdominal pain is often treated with tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). The aim is investigating antidepressant use for treatment efficacy, correlation of response to psychiatric factors, and impact of adverse effects in regard to physicians' prescribing patterns.

Methods: Retrospective review (2005-2013) children (5-21 years old) with functional abdominal pain treated with SSRI or TCA.

Colitis promotes neuronal differentiation of Sox2+ and PLP1+ enteric cells.

Mechanisms mediating adult enteric neurogenesis are largely unknown. Using inflammation-associated neurogenesis models and a transgenic approach, we aimed to understand the cell-source for new neurons in infectious and inflammatory colitis. Dextran sodium sulfate (DSS) and Citrobacter rodentium colitis (CC) was induced in adult mice and colonic neurons were quantified.

Postnatal human enteric neuronal progenitors can migrate, differentiate, and proliferate in embryonic and postnatal aganglionic gut environments.

Background: Enteric neural stem/progenitor cells (ENSCs) offer an innovative approach to treating Hirschsprung disease (HSCR) and other enteric neuropathies. However, postnatal-derived human ENSCs have not been thoroughly characterized and their behavior in the embryonic and postnatal intestinal environment is unknown.

Methods: ENSCs were isolated from the intestines of 25 patients undergoing bowel resection, including 7 children with HSCR.

White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies.

Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts' views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function.

Delivery of enteric neural progenitors with 5-HT4 agonist-loaded nanoparticles and thermosensitive hydrogel enhances cell proliferation and differentiation following transplantation in vivo.

Cell therapy offers an innovative approach for treating enteric neuropathies. Postnatal gut-derived enteric neural stem/progenitor cells (ENSCs) represent a potential autologous source, but have a limited capacity for proliferation and neuronal differentiation. Since serotonin (5-HT) promotes enteric neuronal growth during embryonic development, we hypothesized that serotonin receptor agonism would augment growth of neurons from transplanted ENSCs.

Engraftment of enteric neural progenitor cells into the injured adult brain.

Background: A major area of unmet need is the development of strategies to restore neuronal network systems and to recover brain function in patients with neurological disease. The use of cell-based therapies remains an attractive approach, but its application has been challenging due to the lack of suitable cell sources, ethical concerns, and immune-mediated tissue rejection. We propose an innovative approach that utilizes gut-derived neural tissue for cell-based therapies following focal or diffuse central nervous system injury.

Isogenic enteric neural progenitor cells can replace missing neurons and glia in mice with Hirschsprung disease.

Background: Transplanting autologous patient-derived enteric neuronal stem/progenitor cells (ENSCs) is an innovative approach to replacing missing enteric neurons in patients with Hirschsprung disease (HSCR). Using autologous cells eliminates immunologic and ethical concerns raised by other cell sources. However, whether postnatal aganglionic bowel is permissive for transplanted ENSCs and whether ENSCs from HSCR patients can be successfully isolated, cultured, and transplanted in vivo remains unknown.

Need for Rectal Biopsy for Childhood Constipation Predicts Severity of Illness and Need for Laxatives.

Objectives: This study aimed to examine the long-term clinical outcomes of children with severe constipation, as defined by need for rectal biopsy (RB), and to determine which baseline characteristics were predictors of successful outcome.

Methods: Children with severe constipation who underwent RB for evaluation of Hirschsprung disease at a tertiary medical center were eligible. A cohort of children with constipation without a history of RB served as controls (matched 2:1 by sex and age).