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 Pten was conditionally ablated, (1) in glia (Plp1-expressing cells) and (2) in neurons (Calb2-expressing cells). Tamoxifen-treated adult (7-12 weeks of age; n = 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). We investigated gut motility and evaluated the enteric nervous system. Pten inhibition in Plp1-expressing cells elicited gliogenesis at baseline and post-DSS (early and late) in the colon, and neurogenesis post-DSS late in the proximal colon. They also exhibited an increased frequency of colonic migrating motor complexes (CMMC) and slower whole gut transit times. Pten inhibition in Calb2-expressing cells did not induce enteric neuro- or gliogenesis, and no alterations were detected in CMMC or whole gut transit times when compared to the control at baseline or post-DSS (early and late). Our results merit further research into Pten modulation where increased glia and/or slower intestinal transit times are desired (e.g., short-bowel syndrome and rapid-transit disorders).

Efficacy of an Enterotoxigenic Escherichia coli (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. Fecal samples were collected upon arrival, departure, and during TD for pathogen identification. Serum was collected in a subset of subjects to determine IgA cholera toxin B subunit (CTB) antibody titers upon their arrival in the country. The ETEC vaccine's efficacy, utilizing a TD severity score and other alternative endpoints, including the relationship between antibody levels and TD risk, was assessed and compared to the per-protocol primary efficacy endpoint. A total of 1435 subjects completed 7-28 days of follow-up and had available data. Vaccine efficacy was higher against more severe (≥5 unformed stools/24 h) ETEC-attributable TD and when accounting for immunologic take (PE ≥ 50%; p < 0.05). The vaccine protected against less severe (3 and 4 unformed stools/24 h) ETEC-attributable TD when accounting for symptom severity or change in activity (PE = 76.3%, p = 0.01). Immunologic take of the vaccine was associated with a reduced risk of infection with ETEC and other enteric pathogens, and with lower TD severity. Clear efficacy was observed among vaccinees with a TD score of ≥4 or ≥5, regardless of immunologic take (PE = 72.0% and 79.0%, respectively, p ≤ 0.03). The vaccine reduced the incidence and severity of ETEC, and this warrants accelerated evaluation of the improved formulation (designated ETVAX), currently undergoing advanced field testing. Subjects with serum IgA titers to CTB had a lower risk of infection with ETEC and Campylobacter jejuni/coli. Furthermore, the TD severity score provided a more robust descriptor of disease severity and should be included as an endpoint in future studies.

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. To interrogate the role of Plp1 in enteric glia, we investigated gut motility, secretomotor function and permeability, and evaluated the ENS in mice lacking Plp1. We studied two time points: ∼3 mo (young) and >1 yr (old). Old Plp1 null mice exhibited increased fecal output, decreased fecal water content, faster whole gut transit times, reduced intestinal permeability, and faster colonic migrating motor complexes. Interestingly, in both young and old mice, the ENS exhibited normal glial and neuronal numbers as well as glial arborization density in the absence of Plp1. As Plp1-associated functions involve mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Mapk/Erk1/2) signaling and Mapk/Erk1/2 are reported to have a regulatory role in intestinal motility, we measured protein expression of Erk1/2 and its active form in the small intestine. Old Plp1 null mice had reduced levels of phosphorylated-Erk1/2. Although Plp1 is not required for the normal appearance of enteric glial cells, it has a regulatory role in intestinal motility and barrier function. Our results suggest that functional changes mediated by Plp1-expressing enteric glia may involve Erk1/2 activation.NEW & NOTEWORTHY Here, we describe that Plp1 regulates gut motility and barrier function. The functional effects of Plp1 eradication are only seen in old mice, not young. The effects of Plp1 appear to be mediated through the Erk1/2 pathway.

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. These symptoms are particularly difficult to treat when there is comorbid dysautonomia, usually manifesting as postural orthostatic tachycardia syndrome. Here, we describe a successful trial of multidisciplinary rehabilitative interventions to avoid placement of a surgical feeding tube in such a patient. Main components of intervention were intensive pelvic floor physiotherapy and biofeedback, occupational therapy focused on coping with feeding-related symptoms, psychology support, and medications targeting histamine blockade and enhancing intestinal motility.

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. Using a mouse model of antibiotic (Abx)-induced bacterial depletion, we sought to determine the molecular mechanisms of microbial regulation of intestinal function and the integrity of the ENS. Spontaneous reconstitution of the Abx-depleted microbiota was used to assess the plasticity of structure and function of the GI tract and ENS. Microbiota-dependent molecular mechanisms of ENS neuronal survival and neurogenesis were also assessed. RESULTS: Adult male and female Abx-treated mice exhibited alterations in GI structure and function, including a longer small intestine, slower transit time, increased carbachol-stimulated ion secretion, and increased intestinal permeability. These alterations were accompanied by the loss of enteric neurons in the ileum and proximal colon in both submucosal and myenteric plexuses. A reduction in the number of enteric glia was only observed in the ileal myenteric plexus. Recovery of the microbiota restored intestinal function and stimulated enteric neurogenesis leading to increases in the number of enteric glia and neurons. Lipopolysaccharide (LPS) supplementation enhanced neuronal survival alongside bacterial depletion, but had no effect on neuronal recovery once the Abx-induced neuronal loss was established. In contrast, short-chain fatty acids (SCFA) were able to restore neuronal numbers after Abx-induced neuronal loss, demonstrating that SCFA stimulate enteric neurogenesis in vivo. CONCLUSIONS: Our results demonstrate a role for the gut microbiota in regulating the structure and function of the GI tract in a sex-independent manner. Moreover, the microbiota is essential for the maintenance of ENS integrity, by regulating enteric neuronal survival and promoting neurogenesis. Molecular determinants of the microbiota, LPS and SCFA, regulate enteric neuronal survival, while SCFA also stimulates neurogenesis. Our data reveal new insights into the role of the gut microbiota that could lead to therapeutic developments for the treatment of enteric neuropathies. Video abstract.

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). METHODS: We analyzed distal rectal tissue taken at autopsy from 10 children with normal GI tracts and resected rectal specimens in 48 cases of ARM. Of these specimens, 6 had neurons within the extrinsic rectal innervation. These were further investigated with immunohistochemistry for neuronal and SC/glial markers. KEY RESULTS: Perirectal tissue from control and ARM contained GLUT1-positive extrinsic nerves, many containing neurons. SC/glial markers (SOX10, CDH19, and PLP1) were expressed by glia in the enteric nervous system and perirectal nerves, while MPZ predominated only in glia of perirectal nerves, in both control and ARM. Neurons in perirectal nerves were 61% larger in ARM samples and co-expressed SOX10 (81%), PLP1 (73%), and CDH19 (56%). In ARM, cytoplasmic SOX10 was co-expressed with neuronal antigens in ~57% of submucosal and myenteric neurons, vs. ~3% in control. Furthermore, intrinsic gut neurons in ARM specimens co-expressed PLP1 (18%) and CDH19 (18%); however, neuronal co-expression of PLP1 and CDH19 was rarely (<2%) observed in controls. CONCLUSIONS & INFERENCES: Dual expression of glial and neuronal markers in rectal and perirectal neurons support a model of Schwann cell-derived neurogenesis in the innervation of the human GI tract.

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.

ABSTRACT: 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). Members of the joint task force applied their expertise to identify the components of knowledge, skills, and management, which are expected of NGM consultants. The clinical knowledge, skills and management elements of the NGM curriculum are divided into domains based on anatomic regions including esophagus, stomach, small bowel, colon and anorectum. In addition, dedicated sections on pediatric functional gastrointestinal (GI) disorders, research and collaborative approach, role of behavioral health and surgical approaches to NGM disorders and transition from pediatric to adult neurogastroenterology are included in this document. Members of the NASPGHAN-ANMS task force anticipate that this document will serve as a resource to break existing barriers to pursuing a career in NGM and provide a framework towards uniform training expectations at 3 hierarchical tiers corresponding to EPA levels.

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. An investigation was started to seek the origin and possible management of this condition. METHODS: Medical and radiologic records were reviewed retrospectively, with emphasis on the type and ingredients of enemas used, the duration the patients had been receiving enemas, and their original diagnosis. A literature review was done on previous reports of this condition and publications related to long-term use of enemas. RESULTS: This series included 22 patients (average age, 19.6 years; range, 8-54) with fecal incontinence due to anorectal malformations (10 cases), myelomeningocele (5), cloaca (2), severe colonic dysmotility (2), Hirschsprung's disease (2), and sacrococcygeal teratoma (1). The average duration of enema use was 13.7 years (range, 4-45). The composition of the enemas included saline/glycerin (six cases), only saline solution (five), saline/glycerin/soap (four), plain water (three), and one case each of molasses/milk, saline/glycerin/soap/phosphate, saline/phosphate, and only phosphate. The enemas were performed in an antegrade fashion in 21 cases and rectally in 1. All patients had a dilated right colon and a narrow, spastic, left, transverse, and descending colon. Four patients underwent colonoscopy, colonic manometry, and mucosal biopsies, which did not help in explaining the etiology of the problem. In the literature, 43 reports mentioned a "long-term follow-up" for the administration of enemas, but we could not find a description of symptoms, such as in our cases. CONCLUSIONS: An intriguing and, to our knowledge, previously unreported complication of chronic enema use is presented. We call attention to an overly concerning complication and report our findings in the hope that they will aid and stimulate more investigations into this condition. Several hypotheses to explain the cause are presented, as well as potential treatment options.

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. Patient and test characteristics were summarized using descriptive statistics. Results from patients who had both TBE and high-resolution esophageal manometry (HRM) were used to generate ROC curves for TBE to identify esophageal emptying disorders. RESULTS: Twenty-two patients underwent 25 TBE. Fourteen of 23 (61%) received 150 mL barium volume per protocol. Nearly half (42%) of subjects could tolerate ingesting barium within 20 seconds. Nine individuals underwent HRM. The sensitivity of standard adult TBE criteria (1 cm barium column height at 5 minutes) to detect emptying disorder was 100%, specificity 40%. A modified diagnostic cutoff (1.6 cm height at 5 minutes) offered 100% sensitivity, 80% specificity. CONCLUSIONS: TBE is feasible and should be considered an adjunctive noninvasive screen for impaired esophageal emptying in children. There was heterogeneous adherence to protocol for timing and volume of barium; however, studies remained interpretable. This population may benefit from different diagnostic cutoffs than adults, and clinical judgment should be used until specific diagnostic cutoffs are determined in children.

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. METHODS: The symposium brought together leading experts throughout North America to review the state of the art in the diagnosis and management of motility and functional disorders in children. Presentations were divided into esophageal, antral duodenal, and colorectal modules. Each module included oral presentations by experts in the respective fields, leading to thought-provoking discussions. There were 2 breakout sessions with small group discussions on select topics, focusing on defining scientific insights into the diagnosis and management of pediatric functional gastrointestinal and motility disorders in a systematic, segment-based approach. CONCLUSIONS: The field of neurogastroenterology has made remarkable progress in the last decade. The current report summarizes the major learning points from the symposium highlighting the diagnosis and promising therapies on the horizon for pediatric neurogastrointestinal and motility disorders.

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. We compared the clinical outcome of patients who underwent PFPT (n = 49) to control patients (n = 20) whom received only medical treatment (laxatives/stool softeners). Additionally, characteristics of the treatment group were analyzed in relation to therapeutic response. RESULTS: Thirty-seven (76%) of the patients who received physical therapy had improvement in constipation symptoms, compared to 5 (25%) of the patients on conservative treatment (p < 0.01). Additionally, patients who received pelvic physical therapy had fewer hospitalizations for cleanouts (4 vs. 25%, p = 0.01) and -colonic surgery than those that were treated with medical therapy exclusively (0 vs. 10%, p = 0.03). Among the patients who received physical therapy, those that suffered from anxiety and/or low muscle tone had a higher response rate (100%). There were no adverse effects from the intervention. CONCLUSION: The new field of pediatric PFPT is a safe and effective intervention for children with dyssynergic defecation causing or contributing to chronic constipation, particularly in children whose comorbidities include anxiety and low -muscle tone.

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. Recent evidence suggests that changes in the enteric microenvironment due to injury-associated increases in glial cell-derived neurotrophic factor (GDNF), serotonin (5-hydroxytryptamine [HT]), products from the gut microbiome, and possibly endocannabinoids may lead to the transdifferentiation of mature enteric glia and may reprogram recruited Schwann cells. Targeting neurogenic pathways presents a promising avenue toward the development of new and innovative treatments for acquired damage to the ENS. In this review, we discuss potential sources of newly generated adult enteric neurons, the involvement of GDNF, 5-HT, endocannabinoids, and lipopolysaccharide, as well as therapeutic applications of this evolving work. Stem Cells 2019;37:1136-1143.

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. Eighty-one pediatric gastroenterology fellows responded to the anonymous survey. RESULTS: A total of 53.1% of the fellows reported interest in NGM; however, 75.1% of the fellows believed they had not been adequately trained in NGM during their fellowship. Eighty percent of fellows with 2 weeks or less of dedicated motility training reported that they received inadequate NGM training, compared to 46.2% fellows who received 1 or more months of dedicated motility training (P = 0.0148). The majority of fellows reported not being comfortable in performing gastrointestinal (GI) motility studies. The majority of fellows also reported not being comfortable in interpreting GI motility studies. CONCLUSIONS: Although most pediatric gastroenterology fellows expressed interest in NGM, the lack of exposure and dedicated training in motility during fellowship were identified as barriers to pursuing motility-focused careers. Furthermore, most fellows reported limited comfort with performing and/or interpreting motility studies. Changes are needed to encourage fellows to develop their interest and expertise in NGM.

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. METHODS: Retrospective study of 164 children receiving sphincter BT for severe constipation unresponsive to medication management. Charts reviewed for symptoms, anorectal manometry (ARM) findings and response defined by decreased pain or increased defecation. Patients were grouped: normal sphincter pressure (≤50 mmHg), elevated (>50 mmHg), normal and abnormal rectoanal inhibitory reflex (RAIR). RESULTS: There were 142 analyzed and 124 completed ARMs; 98 (70%) had positive response with 57% lasting greater than 6 months. 36 had normal sphincter pressure with 24 (69%) responding. 88 had elevated pressure with 60 (68%) responding (p=0.87). 90 normal RAIRs with 64 (71%) responding. 34 abnormal RAIRs with 22 (64%) responding (p=0.41). With logistic regression, fecal incontinence prior to BT was a predictor of poor response (p= 0.02). The most common side effect was fecal incontinence typically resolving within week with equal frequency regardless of sphincter dynamics. CONCLUSIONS: BT is effective for children with chronic constipation. Patients with fecal incontinence are less likely to respond. More than half had prolonged beneficial response. Those with normal and abnormal sphincter dynamics had similar responses and without differences in side effects. Therefore, injection may be considered in patients with intractable constipation unresponsive to medication, regardless of anal sphincter dynamics. LEVEL OF EVIDENCE: Level III (Treatment Study: Retrospective comparative study).

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. Sox2GFP and PLP1GFP mice confirmed the cell-type specificity of these markers. Sox2CreER:YFP and PLP1creER:tdT mice were used to determine the fate of these cells after colitis. Sox2 expression was investigated in colonic neurons of human patients with Clostridium difficile or ulcerative colitis. Both DSS and CC led to increased colonic neurons. Following colitis in adult Sox2CreER:YFP mice, YFP initially expressed predominantly by glia becomes expressed by neurons following colitis, without observable DNA replication. Similarly in PLP1CreER:tdT mice, PLP1 cells that co-express S100b but not RET also give rise to neurons following colitis. In human colitis, Sox2-expressing neurons increase from 1-2% to an average 14% in colitis. The new neurons predominantly express calretinin, thus appear to be excitatory. These results suggest that colitis promotes rapid enteric neurogenesis in adult mice and humans through differentiation of Sox2- and PLP1-expressing cells, which represent enteric glia and/or neural progenitors. Further defining neurogenesis will improve understanding and treatment of injury-associated intestinal motility/sensory disorders.

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. Of the 531 cases with functional abdominal pain, 192 initiated SSRIs or TCAs while followed by gastroenterology. Charts reviewed for symptoms, adverse effects, and response: decreased pain or increased daily functioning. RESULTS: Sixty-three of 84 (75%) SSRI patients improved, 56 of 92 (61%) TCA patients improved (P = 0.03). Logistic regression controlling for psychiatric factors: SSRI remained significant over TCA (P = 0.04). Thirty-two of 67 (48%) patients with constipation received TCAs and 26 of 45 (58%) patients with diarrhea received SSRIs (P = 0.64). Three SSRI patients reported gastrointestinal effects, all diarrheal-type symptoms, and 2 TCA patients reported gastrointestinal effects, both constipation, in all it led to discontinuation. Thirteen (29%) of diarrheal-type patients reported adverse effects causing discontinuation as compared to 7 (8%) in the constipation group (P = .01). Twenty-one (25%) SSRI patients reported adverse effects with 5 (6%) mood disturbances. Twenty (22%) TCA patients reported adverse effects, 13 (14%) with mood disturbances (P = .07). Overall, 12 (14%) SSRI patients discontinued medication due to adverse effects, whereas 16 (17%) TCA patients (P = 0.24) did. CONCLUSIONS: Patients had significantly greater response to SSRIs than TCAs, remaining significant after controlling for psychiatric factors. Little significance is given to patient's associated gastrointestinal symptoms, frequently resulting in adverse effects and termination of medication.

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. Neuronal differentiation and proliferation of ENSCs from submucosal and myenteric plexuses from patients with and without HSCR were characterized. ENSC migration and differentiation were studied following transplantation into embryonic chick neural crest, embryonic chick hindgut, and postnatal mouse aganglionic colon. RESULTS: The proliferative and neurogenic potential of ENSCs from HSCR intestine is equivalent to that of non-HSCR controls. Similarly, no difference was observed between myenteric- and submucosal-derived ENSCs. Postnatal ENSCs transplanted to embryonic neural crest pathways and to aneural hindgut migrate normally and differentiate into appropriate neural crest-derived cell types. ENSCs in postnatal mouse aganglionic colon differentiate into neurons and glia both ex vivo and in vivo. CONCLUSIONS: ENSCs isolated from the postnatal intestine of patients with and without HSCR can behave like embryonic neural crest-derived cells. These results support the feasibility of cell-based therapy for future treatment of neurointestinal disease.