Recent PubMed Articles on Gut Motility

Oesophageal atresia.

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Oesophageal atresia.

Nat Rev Dis Primers. 2019 Apr 18;5(1):26

Authors: van Lennep M, Singendonk MMJ, Dall'Oglio L, Gottrand F, Krishnan U, Terheggen-Lagro SWJ, Omari TI, Benninga MA, van Wijk MP

Abstract
Oesophageal atresia (EA) is a congenital abnormality of the oesophagus that is caused by incomplete embryonic compartmentalization of the foregut. EA commonly occurs with a tracheo-oesophageal fistula (TEF). Associated birth defects or anomalies, such as VACTERL association, trisomy 18 or 21 and CHARGE syndrome, occur in the majority of patients born with EA. Although several studies have revealed signalling pathways and genes potentially involved in the development of EA, our understanding of the pathophysiology of EA lags behind the improvements in surgical and clinical care of patients born with this anomaly. EA is treated surgically to restore the oesophageal interruption and, if present, ligate and divide the TEF. Survival is now ~90% in those born with EA with severe associated anomalies and even higher in those born with EA alone. Despite these achievements, long-term gastrointestinal and respiratory complications and comorbidities in patients born with EA are common and lead to decreased quality of life. Oesophageal motility disorders are probably ubiquitous in patients after undergoing EA repair and often underlie these complications and comorbidities. The implementation of several new diagnostic and screening tools in clinical care, including high-resolution impedance manometry, pH-multichannel intraluminal impedance testing and disease-specific quality of life questionnaires now provide better insight into these problems and may contribute to better long-term outcomes in the future.

PMID: 31000707 [PubMed - in process]

Small intestinal bacterial overgrowth in systemic sclerosis: a review of the literature.

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Small intestinal bacterial overgrowth in systemic sclerosis: a review of the literature.

Arch Dermatol Res. 2019 Jan;311(1):1-8

Authors: Polkowska-Pruszyńska B, Gerkowicz A, Szczepanik-Kułak P, Krasowska D

Abstract
Systemic sclerosis (SSc) is a chronic, connective tissue disease with an autoimmune pattern characterized by inflammation, fibrosis and microcirculation changes leading to internal organs malfunctions. Recently, the presence of uncharacteristic gastrointestinal symptoms in the course of SSc has been underlined. The possible cause of such clinical presentation is the small intestinal bacterial overgrowth (SIBO). Nevertheless, these manifestations resulting from gastrointestinal tract hypomotility may occur in numerous disease entities. The systematic review of the literature was performed on MEDLINE database using the relevant MeSH terms including all sub-headings. After further investigation, the initial number of 56 records was limited to 7 results. The study analysis showed an increased presence of SIBO in 39% of patients suffering from SSc. The average SSc duration was longer in SSc patients with coexisting SIBO. SIBO remains a diagnostic and therapeutic challenge and therefore is a significant clinical problem among patients suffering from SSc.

PMID: 30382339 [PubMed - indexed for MEDLINE]

Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and...

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Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

J Pediatr Gastroenterol Nutr. 2018 03;66(3):516-554

Authors: Rosen R, Vandenplas Y, Singendonk M, Cabana M, DiLorenzo C, Gottrand F, Gupta S, Langendam M, Staiano A, Thapar N, Tipnis N, Tabbers M

Abstract
This document serves as an update of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2009 clinical guidelines for the diagnosis and management of gastroesophageal reflux disease (GERD) in infants and children and is intended to be applied in daily practice and as a basis for clinical trials. Eight clinical questions addressing diagnostic, therapeutic and prognostic topics were formulated. A systematic literature search was performed from October 1, 2008 (if the question was addressed by 2009 guidelines) or from inception to June 1, 2015 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Clinical Trials. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to define and prioritize outcomes. For therapeutic questions, the quality of evidence was also assessed using GRADE. Grading the quality of evidence for other questions was performed according to the Quality Assessment of Studies of Diagnostic Accuracy (QUADAS) and Quality in Prognostic Studies (QUIPS) tools. During a 3-day consensus meeting, all recommendations were discussed and finalized. In cases where no randomized controlled trials (RCT; therapeutic questions) or diagnostic accuracy studies were available to support the recommendations, expert opinion was used. The group members voted on each recommendation, using the nominal voting technique. With this approach, recommendations regarding evaluation and management of infants and children with GERD to standardize and improve quality of care were formulated. Additionally, 2 algorithms were developed, 1 for infants <12 months of age and the other for older infants and children.

PMID: 29470322 [PubMed - indexed for MEDLINE]

A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation.

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A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation.

Sci Rep. 2019 Apr 12;9(1):5987

Authors: Walker SJ, Langefeld CD, Zimmerman K, Schwartz MZ, Krigsman A

Abstract
In children with autism spectrum disorder (ASD) who present to the gastroenterologist with chronic constipation on a background of colonic inflammation, we have identified two distinct clinical subtypes: (1) patients who experience a sustained state of GI symptomatic remission while on maintenance anti-inflammatory therapy (fast responders) and, (2) those with recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis (slow responders). We hypothesized that a detailed molecular analysis of tissue from the affected region of the colon would provide mechanistic insights regarding the fast versus slow response to anti-inflammatory therapy. To test this, ascending colon biopsy tissues from 35 children with ASD (20 slow responders and 15 fast responders) were analyzed by RNAseq. Hierarchical cluster analysis was performed to assign samples to clusters and gene expression analysis was performed to identify differentially expressed transcripts (DETs) between samples within the clusters. Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction). Regression analysis identified a single long non-coding RNA that could predict cluster assignment with a high specificity (0.88), sensitivity (0.89) and accuracy (0.89). Comparison of gene expression profiles in the ascending colon from a subset of patients with ASD, chronic right-sided fecal loading constipation and a slow versus fast response to therapy has identified molecular mechanisms that likely contribute to this differential response following the primary therapeutic intervention (i.e. treatment for colonic inflammation with brief induction immunosuppression followed by maintenance non-steroidal anti-inflammatory therapy). Importantly, we have identified a transcript that, if validated, may provide a biomarker that can predict from the outset which patients will be slow responders who would benefit from an alternate therapeutic strategy in treating their constipation.

PMID: 30979947 [PubMed - in process]

Pre-operative pediatric cardiac surgery: enema Versus not enema.

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Pre-operative pediatric cardiac surgery: enema Versus not enema.

Acta Biomed. 2019 Mar 28;90(4-S):74-78

Authors: Prendin A, Sansone V, Brugnaro L, De Barbieri I

Abstract
BACKGROUND AND AIM OF THE WORK: There is evidence in adult literature that the enema in the preoperative of thoracic surgery can be dismissed without disadvantage. However, there is a gap of articles about enema in childhood for thoracic surgeries. The aim of the work is  to investigate whether the administration of enema in the preparation for cardiac surgery, the use of different analgosedation drugs and the Extracorporeal Circulation influence the children's intestinal motility in the post-operative period.
METHODS: A retrospective study was carried out comparing the data between users subjected to saline solution enema, originating from the U.O.C. of Pediatric Cardiology and Pediatric Cardiac Surgery and Congenital Heart Disease and users not subjected to such procedure, coming from the U.O.S.D. Pediatric Intensive Care. The data collected will evaluate the intestinal motility in the post-operative cardiac surgery.
RESULTS: The following three variables were analyzed: interval of post-operative evacuation days (mean 2.14, median 2.00, standard deviation 1.525 in non-enema children; mean 2.76, median 2.00, standard deviation 1.318 in enema children), administered analgosedation drugs and use of Extracorporeal Circulation - for which the Pearson Test was used. A sampling bias is also reported from the analysis of the data. The study did not show a statistical significance correlates the variables analyzed to intestinal motility in post-operative period.
CONCLUSION: The sampling bias emerged could reflect the diversity of the catchment area in the two Wards. The study - in agreement with the literature concerning the adult user - proves that the practice of enema evacuation pre-operative cardiac surgery in the pediatric user is unnecessary and does not influence intestinal transit in the post-operative period.

PMID: 30977751 [PubMed - in process]

Novel Pressure-Impedance Parameters for Evaluating Esophageal Function in Pediatric Achalasia.

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Novel Pressure-Impedance Parameters for Evaluating Esophageal Function in Pediatric Achalasia.

J Pediatr Gastroenterol Nutr. 2018 01;66(1):37-42

Authors: Singendonk MMJ, Omari TI, Rommel N, van Wijk MP, Benninga MA, Rosen R, Nurko S

Abstract
OBJECTIVE: In achalasia, absent peristalsis and reduced esophagogastric junction (EGJ) relaxation and compliance underlie dysphagia symptoms. Novel high-resolution impedance manometry variables, that is, bolus presence time (BPT) and trans-EGJ-bolus flow time (BFT) have been developed to estimate the duration of EGJ opening and trans-EGJ bolus flow. The aim of this study was to evaluate esophageal motor function and bolus flow in children diagnosed with achalasia using these variables.
METHODS: High-resolution impedance manometry recordings from 20 children who fulfilled the Chicago Classification (V3) criteria for achalasia were compared with recordings of 15 children with normal esophageal high-resolution manometry findings and no other evidence suggestive of achalasia. Matlab-based analysis software was used to calculate BPT and BFT.
RESULTS: Both BPT and BFT were significantly reduced in achalasia patients compared with children with normal esophageal motility (BPT 3.3 s vs 5.1 s P < 0.01; BFT 1.4 s vs 4.3 s P < 0.001). BFT was significantly lower than BPT (achalasia difference 1.9 s ± 1.3 s, P = 0.001 and normal difference 0.9 ± 0.3 s, P = 0.001). Overall, there was a significant correlation between BPT and BFT (r = 0.825, P < 0.001). We observed a 2-way differentiation of achalasia patients; those in whom the BPT and BFT were proportional, but significantly lower than in patients with normal peristalsis, and those in whom BFT was disproportionately lower than BPT.
CONCLUSIONS: Calculation of BPT and BFT may help determine whether esophageal bolus transport to the EGJ and/or esophageal emptying through the EGJ are aberrant. For achalasia, this may detect flow resistance at the EGJ, potentially improving both diagnosis and objective assessment of therapeutic effects.

PMID: 28604515 [PubMed - indexed for MEDLINE]

Nausea exacerbates symptom burden, quality of life, and functioning in adolescents with functional abdominal pain disorders.

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Nausea exacerbates symptom burden, quality of life, and functioning in adolescents with functional abdominal pain disorders.

Neurogastroenterol Motil. 2019 Apr 07;:e13595

Authors: Kovacic K, Kapavarapu PK, Sood MR, Li BUK, Nugent M, Simpson P, Miranda A

Abstract
BACKGROUND: Nausea frequently co-exists with functional abdominal pain disorders (FAPDs) and may be linked to a higher disease burden. This study aimed to prospectively compare multisystem symptoms, quality of life, and functioning in FAPDs with and without nausea.
METHODS: Adolescents ages 11-18 years fulfilling Rome III criteria for a FAPD were grouped by the presence or absence of chronic nausea. Subjects completed validated instruments assessing nausea (Nausea Profile Questionnaire = NPQ), quality of life (Patient-Reported Outcome Measurement Information System), functioning (Functional Disability Inventory), and anxiety (State-Trait Anxiety Inventory for Children). Group comparisons were performed for instruments, multisystem symptoms, school absences, and clinical diagnoses.
KEY RESULTS: A total of 112 subjects were included; 71% reported chronic nausea. Patients with Nausea compared to No Nausea had higher NPQ scores (P ≤ 0.001), worse quality of life (P = 0.004), and greater disability (P = 0.02). State and trait anxiety scores were similar (P = 0.57, P = 0.25). A higher NPQ score correlated with poorer quality of life, more disability, and higher anxiety. Specific comorbidities were more common in Nausea vs No Nausea group: dizziness (81% vs 41%; P ≤ 0.001), concentrating difficulties (68% vs 27%; P ≤ 0.001), chronic fatigue (58% vs 20%; P = 0.01), and sleep disturbances (73% vs 48%; P = 0.02). The Nausea group reported more school absences (P = 0.001) and more commonly met criteria for functional dyspepsia (P = 0.034).
CONCLUSION AND INFERENCES: Nausea co-existing with FAPDs is associated with a higher extra-intestinal symptom burden, worse quality of life, and impaired functioning in children. Assessing and targeting nausea therapeutically is essential to improve outcomes in FAPDs.

PMID: 30957319 [PubMed - as supplied by publisher]

MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function.

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MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function.

J Immunol. 2018 06 15;200(12):4170-4179

Authors: Zitzer NC, Snyder K, Meng X, Taylor PA, Efebera YA, Devine SM, Blazar BR, Garzon R, Ranganathan P

Abstract
MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155-/-) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8+ T cells and conventional CD4+ CD25- T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8+ donor T cells and promoting exhaustion in donor CD4+ T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155-/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration.

PMID: 29720426 [PubMed - indexed for MEDLINE]

Interactions Between Commensal Bacteria and Enteric Neurons, via FPR1 Induction of ROS, Increase Gastrointestinal Motility in Mice.

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Interactions Between Commensal Bacteria and Enteric Neurons, via FPR1 Induction of ROS, Increase Gastrointestinal Motility in Mice.

Gastroenterology. 2019 Mar 28;:

Authors: Chandrasekharan B, Saeedi BJ, Alam A, Houser M, Srinivasan S, Tansey M, Jones R, Nusrat A, Neish AS

Abstract
BACKGROUND & AIMS: Reduced gastrointestinal (GI) motility is a feature of disorders associated with intestinal dysbiosis and loss of beneficial microbes. It is not clear how consumption of beneficial commensal microbes, marketed as probiotics, affects the enteric nervous system (ENS). We studied the effects of the widely used probiotic and the commensal Lactobacillus rhamnosus GG (LGG) on ENS and GI motility in mice.
METHODS: Conventional and germ-free C57B6 mice were gavaged with LGG and intestinal tissues were collected; changes in the enteric neuronal subtypes were assessed by real-time PCR, immunoblots and immunostaining. Production of reactive oxygen species (ROS) in the jejunal myenteric plexi and phosphorylation (p) of mitogen-activated protein kinase 1 (MAPK1) in the enteric ganglia were assessed by immunoblots and immunostaining. Fluorescence in situ hybridization was performed on jejunal cryosections with probes to detect formyl peptide receptor 1 (FPR1). GI motility in conventional mice was assessed after daily gavage of LGG for 1 week.
RESULTS: Feeding of LGG to mice stimulated myenteric production of ROS, increased levels of phosphorylated MAPK1, and increased expression of choline acetyl transferase by neurons (P<.001). These effects were not observed in mice given N-acetyl cysteine (a ROS inhibitor) or LGGΩSpaC (an adhesion-mutant strain of LGG) or FPR1-knockout mice. Gavage of mice with LGG for 1 week significantly increased stool frequency, reduced total GI transit time, and increased contractions of ileal circular muscle strips in ex vivo experiments (P<.05).
CONCLUSIONS: Using mouse models, we found that LGG-mediated signaling in the ENS requires bacterial adhesion, redox mechanisms, and FPR1. This pathway might be activated to increase GI motility in patients.

PMID: 30930024 [PubMed - as supplied by publisher]

Etiology and functional validation of gastrointestinal motility dysfunction in a zebrafish model of CHARGE syndrome.

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Etiology and functional validation of gastrointestinal motility dysfunction in a zebrafish model of CHARGE syndrome.

FEBS J. 2018 06;285(11):2125-2140

Authors: Cloney K, Steele SL, Stoyek MR, Croll RP, Smith FM, Prykhozhij SV, Brown MM, Midgen C, Blake K, Berman JN

Abstract
CHARGE syndrome is linked to autosomal-dominant mutations in the CHD7 gene and results in a number of physiological and structural abnormalities, including heart defects, hearing and vision loss, and gastrointestinal (GI) problems. Of these challenges, GI problems have a profound impact throughout an individual's life, resulting in increased morbidity and mortality. A homolog of CHD7 has been identified in the zebrafish, the loss of which recapitulates many of the features of the human disease. Using a morpholino chd7 knockdown model complemented by a chd7 null mutant zebrafish line, we examined GI structure, innervation, and motility in larval zebrafish. Loss of chd7 resulted in physically smaller GI tracts with normal epithelial and muscular histology, but decreased and disorganized vagal projections, particularly in the foregut. chd7 morphant larvae had significantly less ability to empty their GI tract of gavaged fluorescent beads, and this condition was only minimally improved by the prokinetic agents, domperidone and erythromycin, in keeping with mixed responses to these agents in patients with CHARGE syndrome. The conserved genetics and transparency of the zebrafish have provided new insights into the consequences of chd7 gene dysfunction on the GI system and cranial nerve patterning. These findings highlight the opportunity of the zebrafish to serve as a preclinical model for studying compounds that may improve GI motility in individuals with CHARGE syndrome.

PMID: 29660852 [PubMed - indexed for MEDLINE]

A descriptive model for a multidisciplinary unit for colorectal and pelvic malformations.

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A descriptive model for a multidisciplinary unit for colorectal and pelvic malformations.

J Pediatr Surg. 2019 Mar;54(3):479-485

Authors: Vilanova-Sanchez A, Halleran DR, Reck-Burneo CA, Gasior AC, Weaver L, Fisher M, Wagner A, Nash O, Booth K, Peters K, Williams C, Brown SM, Lu P, Fuchs M, Diefenbach K, Leonard JR, Hewitt G, McCracken K, Di Lorenzo C, Wood RJ, Levitt MA

Abstract
INTRODUCTION: Patients with anorectal malformations (ARM), Hirschsprung disease (HD), and colonic motility disorders often require care from specialists across a variety of fields, including colorectal surgery, urology, gynecology, and GI motility. We sought to describe the process of creating a collaborative process for the care of these complex patients.
METHODS: We developed a model of a devoted center for these conditions that includes physicians, psychologists, social workers, nurses, and advanced practice nurses. Our weekly planning strategy includes a meeting with representatives of all specialties to review all patients prior to evaluation in our multidisciplinary clinic, followed by combined exams under anesthesia or surgical intervention as needed.
RESULTS: There are 31 people working directly in the Center at present. From the Center's start in 2014 until 2017, 1258 patients were cared for from all 50 United States and 62 countries. 360 patients had an ARM (110 had a cloacal malformation, 11 had cloacal exstrophy), 223 presented with HD, 71 had a spinal malformation or injury causing neurogenic bowel, 321 had severe functional constipation or colonic dysmotility, and 162 had other diagnoses including familial polyposis, Crohn's disease, or ulcerative colitis. We have had 170 multidisciplinary meetings, 170 multispecialty outpatient, and 52 nurse practitioner clinics. In our bowel management program we have seen a total of 514 patients in 36 sessions.
CONCLUSION: This is the first report describing the design of a multidisciplinary team approach for patients with colorectal and complex pelvic malformations. We found that approaching these patients in a collaborative way allows for combined medical and surgical decisions with many providers simultaneously, facilitates therapy, and can potentially improve patient outcomes. We hope that this model will help establish new-devoted centers in other locations to encourage centralized care for these rare malformations.
LEVEL OF EVIDENCE: IV.

PMID: 29778545 [PubMed - indexed for MEDLINE]

Ophthalmoplegia in Mitochondrial Disease.

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Ophthalmoplegia in Mitochondrial Disease.

Yonsei Med J. 2018 Dec;59(10):1190-1196

Authors: Lee SJ, Na JH, Han J, Lee YM

Abstract
PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease.
MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO).
RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p<0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group.
CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.

PMID: 30450853 [PubMed - indexed for MEDLINE]

Stress Adaptation Upregulates Oxytocin within Hypothalamo-Vagal Neurocircuits.

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Stress Adaptation Upregulates Oxytocin within Hypothalamo-Vagal Neurocircuits.

Neuroscience. 2018 10 15;390:198-205

Authors: Jiang Y, Coleman FH, Kopenhaver Doheny K, Travagli RA

Abstract
Stress plays a pivotal role in the development and/or exacerbation of functional gastrointestinal (GI) disorders. The paraventricular nucleus of the hypothalamus (PVN) contains neurons that are part of the hypothalamic-pituitary-adrenal axis as well as preautonomic neurons innervating, among other areas, gastric-projecting preganglionic neurons of the dorsal vagal complex (DVC). The aim of the present study was to test the hypothesis that stress adaptation upregulates oxytocin (OXT) within PVN-brainstem vagal neurocircuitry. The retrograde tracer cholera toxin B (CTB) was injected into the DVC of rats which, after post-surgical recovery, were pair-housed and exposed to either homo- or heterotypic stress for five consecutive days. Fecal pellets were counted at the end of each stress load. Two hours after the last stressor, the whole brain was excised. Brainstem and hypothalamic nuclei were analyzed immunohistochemically for the presence of both OXT-immunopositive cells in identified preautonomic PVN neurons as well as OXT fibers in the DVC. Rats exposed to chronic homotypic, but not chronic heterotypic stress, had a significant increase in both number of CTB+ OXT co-localized neurons in the PVN as well as density of OXT-positive fibers in the DVC compared to control rats. These data suggest that preautonomic OXT PVN neurons and their projections to the DVC increase following adaptation to stress, and suggest that the possible up-regulation of OXT within PVN-brainstem vagal neurocircuitry may play a role in the adaptation of GI responses to stress.

PMID: 30176320 [PubMed - indexed for MEDLINE]

Deletion of choline acetyltransferase in enteric neurons results in postnatal intestinal dysmotility and dysbiosis.

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Deletion of choline acetyltransferase in enteric neurons results in postnatal intestinal dysmotility and dysbiosis.

FASEB J. 2018 09;32(9):4744-4752

Authors: Johnson CD, Barlow-Anacker AJ, Pierre JF, Touw K, Erickson CS, Furness JB, Epstein ML, Gosain A

Abstract
Acetylcholine (ACh)-synthesizing neurons are major components of the enteric nervous system (ENS). They release ACh and peptidergic neurotransmitters onto enteric neurons and muscle. However, pharmacological interrogation has proven inadequate to demonstrate an essential role for ACh. Our objective was to determine whether elimination of ACh synthesis during embryogenesis alters prenatal viability, intestinal function, the neurotransmitter complement, and the microbiome. Conditional deletion of choline acetyltransferase ( ChAT), the ACh synthetic enzyme, in neural crest-derived neurons ( ChAT-Null) was performed. Survival, ChAT activity, gut motility, and the microbiome were studied. ChAT was conditionally deleted in ENS neural crest-derived cells. Despite ChAT absence, mice were born live and survived the first 2 wk. They failed to gain significant weight in the third postnatal week, dying between postnatal d 18 and 30. Small intestinal transit of carmine red was 50% slower in ChAT-Nulls vs. WT and ChAT- Het. The colons of many neonatal ChAT-Null mice contained compacted feces, suggesting dysmotility. Microbiome analysis revealed dysbiosis in ChAT-Null mice. Developmental deletion of ChAT activity in enteric neurons results in proximal gastrointestinal tract dysmotility, critically diminished colonic transit, failure to thrive, intestinal dysbiosis, and death. ACh is necessary for sustained gut motility and survival of neonatal mice after weaning.-Johnson, C. D., Barlow-Anacker, A. J., Pierre, J. F., Touw, K., Erickson, C. S., Furness, J. B., Epstein, M. L., Gosain, A. Deletion of choline acetyltransferase in enteric neurons results in postnatal intestinal dysmotility and dysbiosis.

PMID: 29570391 [PubMed - indexed for MEDLINE]

Species-specific enhancement of enterohemorrhagic E. coli pathogenesis mediated by microbiome metabolites.

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Species-specific enhancement of enterohemorrhagic E. coli pathogenesis mediated by microbiome metabolites.

Microbiome. 2019 Mar 20;7(1):43

Authors: Tovaglieri A, Sontheimer-Phelps A, Geirnaert A, Prantil-Baun R, Camacho DM, Chou DB, Jalili-Firoozinezhad S, de Wouters T, Kasendra M, Super M, Cartwright MJ, Richmond CA, Breault DT, Lacroix C, Ingber DE

Abstract
BACKGROUND: Species-specific differences in tolerance to infection are exemplified by the high susceptibility of humans to enterohemorrhagic Escherichia coli (EHEC) infection, whereas mice are relatively resistant to this pathogen. This intrinsic species-specific difference in EHEC infection limits the translation of murine research to human. Furthermore, studying the mechanisms underlying this differential susceptibility is a difficult problem due to complex in vivo interactions between the host, pathogen, and disparate commensal microbial communities.
RESULTS: We utilize organ-on-a-chip (Organ Chip) microfluidic culture technology to model damage of the human colonic epithelium induced by EHEC infection, and show that epithelial injury is greater when exposed to metabolites derived from the human gut microbiome compared to mouse. Using a multi-omics approach, we discovered four human microbiome metabolites-4-methyl benzoic acid, 3,4-dimethylbenzoic acid, hexanoic acid, and heptanoic acid-that are sufficient to mediate this effect. The active human microbiome metabolites preferentially induce expression of flagellin, a bacterial protein associated with motility of EHEC and increased epithelial injury. Thus, the decreased tolerance to infection observed in humans versus other species may be due in part to the presence of compounds produced by the human intestinal microbiome that actively promote bacterial pathogenicity.
CONCLUSION: Organ-on-chip technology allowed the identification of specific human microbiome metabolites modulating EHEC pathogenesis. These identified metabolites are sufficient to increase susceptibility to EHEC in our human Colon Chip model and they contribute to species-specific tolerance. This work suggests that higher concentrations of these metabolites could be the reason for higher susceptibility to EHEC infection in certain human populations, such as children. Furthermore, this research lays the foundation for therapeutic-modulation of microbe products in order to prevent and treat human bacterial infection.

PMID: 30890187 [PubMed - in process]

Gastrointestinal Neuropathies: New Insights and Emerging Therapies.

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Gastrointestinal Neuropathies: New Insights and Emerging Therapies.

Gastroenterol Clin North Am. 2018 12;47(4):877-894

Authors: Pesce M, Borrelli O, Saliakellis E, Thapar N

Abstract
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.

PMID: 30337038 [PubMed - indexed for MEDLINE]

Gastrointestinal Development: Implications for Management of Preterm and Term Infants.

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Gastrointestinal Development: Implications for Management of Preterm and Term Infants.

Gastroenterol Clin North Am. 2018 12;47(4):773-791

Authors: Lenfestey MW, Neu J

Abstract
The gastrointestinal (GI) system provides digestive, absorptive, neuroendocrine, and immunologic functions to support overall health. If normal development is interrupted, a variety of complications and disease can arise. This article explores normal development of the GI tract and specific clinical challenges pertinent to preterm and term infants. Specific topics include abnormal motility, gastroesophageal reflux, current feeding recommendations for preterm infants, effects of parenteral nutrition, and the relationship between the GI tract and the immune system.

PMID: 30337032 [PubMed - indexed for MEDLINE]

Prevalence of Pediatric Functional Gastrointestinal Disorders Utilizing the Rome IV Criteria.

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Prevalence of Pediatric Functional Gastrointestinal Disorders Utilizing the Rome IV Criteria.

J Pediatr. 2018 04;195:134-139

Authors: Robin SG, Keller C, Zwiener R, Hyman PE, Nurko S, Saps M, Di Lorenzo C, Shulman RJ, Hyams JS, Palsson O, van Tilburg MAL

Abstract
OBJECTIVE: To assess the prevalence of functional gastrointestinal (GI) disorders in children 0-18 years old according to the newly established Rome IV diagnostic criteria as reported by parents in a representative community sample.
STUDY DESIGN: A cross-sectional study in which mothers (n = 1255) of children aged 0-18 years old in the US were recruited to complete an online survey about their child's GI symptoms, quality of life (QoL), and other health conditions.
RESULTS: Based on the Rome IV criteria, 24.7% of infants and toddlers aged 0-3 years and 25.0% of children and adolescents aged 4-18 years fulfilled symptom-based criteria for a functional GI disorder. The most common functional GI disorders were infant regurgitation among infants (24.1%) and functional constipation among both toddlers (18.5%) and children and adolescents (14.1%). QoL was diminished in pediatric patients with functional GI disorders (median = 71.69 vs median = 87.60; z = -11.41; P  < .001). Children were more likely to qualify for a functional GI disorder if their parent qualified for a functional GI disorder (35.4% vs 23.0%; P < .001).
CONCLUSIONS: Based on Rome IV criteria, functional GI disorders are common in pediatric populations of all ages and are associated with decreased QoL.

PMID: 29398057 [PubMed - indexed for MEDLINE]

Diagnostic Role of Anal Sphincter Relaxation Integral in High-Resolution Anorectal Manometry for Hirschsprung Disease in Infants.

Related Articles

Diagnostic Role of Anal Sphincter Relaxation Integral in High-Resolution Anorectal Manometry for Hirschsprung Disease in Infants.

J Pediatr. 2018 03;194:136-141.e2

Authors: Wu JF, Lu CH, Yang CH, Tsai IJ

Abstract
OBJECTIVE: To investigate the possible diagnostic role of anal sphincter relaxation integral (ASRI) in high-resolution anorectal manometry (HRAM) for Hirschsprung disease.
STUDY DESIGN: We performed conventional anorectal manometry (ARM) in 24 infants (8 with Hirschsprung disease and 16 without Hirschsprung disease) and HRAM in another 21 infants (9 with Hirschsprung disease and 12 without Hirschsprung disease) before and after October 2014. All infants underwent rectal suction biopsy for confirmation of Hirschsprung disease. We quantified rectoanal inhibitory reflex (RAIR) adequacy by calculating the ASRI in HRAM study at pressure cutoffs of less than 10, 15, and 20 mm Hg (ASRI10, ASRI15, and ASRI20, respectively) and investigated the diagnostic utility.
RESULTS: Patients with Hirschsprung disease who underwent HRAM had significantly lower ASRI10, ASRI15, and ASRI20 values than did infants without Hirschsprung disease (P = .0002, .0002, and .0003, respectively), indicating significant difference in internal anal sphincter relaxation during RAIR test between these 2 groups. ASRI10 exhibited a greater diagnostic accuracy, area under the curve, sensitivity, and specificity than did ASRI15 and ASRI20 for Hirschsprung disease. Moreover, the diagnostic accuracy of HRAM for Hirschsprung disease based on ASRI10 <7 mm Hg.s.cm was significantly greater than that of conventional ARM (P = .02).
CONCLUSIONS: ASRI10 may be indicative of the adequacy of RAIR by HRAM in infants, thus assisting the diagnosis of Hirschsprung disease. The diagnostic accuracy of HRAM (based on the ASRI10 value) is greater than that of conventional ARM for Hirschsprung disease. ASRI10 may be used in an automatic HRAM analysis system for the diagnosis of anorectal motility disorders.

PMID: 29212617 [PubMed - indexed for MEDLINE]

Characterization of Esophageal Motility in Infants with Congenital Diaphragmatic Hernia using High Resolution Manometry.

Characterization of Esophageal Motility in Infants with Congenital Diaphragmatic Hernia using High Resolution Manometry.

J Pediatr Gastroenterol Nutr. 2019 Mar 05;:

Authors: Rayyan M, Omari T, Debeer A, Decaluwe H, Deprest J, Allegaert K, Rommel N

Abstract
OBJECTIVES: To characterize esophageal motility and esophago-gastric junction (EGJ) function in infants who underwent repair of an isolated congenital diaphragmatic hernia (iCDH).
METHODS: High Resolution Manometry with impedance was used to investigate esophageal motility and EGJ function after diaphragmatic repair in 12 infants with iCDH (11 left-sided; 9 patch repair). They had esophageal motility studies during neonatal admission (n = 12), at 6 months (n = 10) and at 12 months of life (n = 7). Swallows were analyzed using conventional esophageal pressure topography and pressure-flow analysis and were compared with 11 healthy preterm born infants at near-term age.
RESULTS: Esophageal peristaltic motor patterns in iCDH patients were comparable to controls. EGJ end-expiratory pressure was higher in patients with patch repair versus controls (p = 0.050) and those without patch (p = 0.009). The difference between inspiratory and expiratory pressures at the EGJ was lower in iCDH patients with patch (p = 0.045) compared to patients without. iCDH patients with patch showed increased Pressure Flow Index (PFI), resistance of bolus flow at the EGJ, compared to controls (p = 0.043).
CONCLUSIONS: Normal esophageal wave patterns are present in the investigated patients with iCDH. EGJ end-expiratory pressure seems lower in iCDH patients without patch suggesting a decreased EGJ barrier function hence increased vulnerability to gastro-esophageal reflux. Patch repair appears to increase end-expiratory pressure at the EGJ above that of controls suggesting that patch surgery tightens the EGJ, thereby increasing flow resistance. This is in line with the increased PFI. In infants with a patch, the inspiration-expiration pressure difference is lower, reflecting diminished activity of the crural diaphragm.

PMID: 30889138 [PubMed - as supplied by publisher]

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