Recent PubMed Articles on Gut Motility

A Wireless Implantable System for Facilitating Gastrointestinal Motility.

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A Wireless Implantable System for Facilitating Gastrointestinal Motility.

Micromachines (Basel). 2019 Aug 09;10(8):

Authors: Wang PM, Dubrovsky G, Dunn JCY, Lo YK, Liu W

Abstract
Gastrointestinal (GI) electrical stimulation has been shown in several studies to be a potential treatment option for GI motility disorders. Despite the promising preliminary research progress, however, its clinical applicability and usability are still unknown and limited due to the lack of a miniaturized versatile implantable stimulator supporting the investigation of effective stimulation patterns for facilitating GI dysmotility. In this paper, we present a wireless implantable GI modulation system to fill this technology gap. The system consists of a wireless extraluminal gastrointestinal modulation device (EGMD) performing GI electrical stimulation, and a rendezvous device (RD) and a custom-made graphical user interface (GUI) outside the body to wirelessly power and configure the EGMD to provide the desired stimuli for modulating GI smooth muscle activities. The system prototype was validated in bench-top and in vivo tests. The GI modulation system demonstrated its potential for facilitating intestinal transit in the preliminary in vivo chronic study using porcine models.

PMID: 31395845 [PubMed]

Vibrio parahaemolyticus VopA Is a Potent Inhibitor of Cell Migration and Apoptosis in the Intestinal Epithelium of Drosophila melanogaster.

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Vibrio parahaemolyticus VopA Is a Potent Inhibitor of Cell Migration and Apoptosis in the Intestinal Epithelium of Drosophila melanogaster.

Infect Immun. 2019 03;87(3):

Authors: Luo L, Matthews JD, Robinson BS, Jones RM

Abstract
Animal models have played a key role in providing an understanding of the mechanisms that govern the pathophysiology of intestinal diseases. To expand on the repertoire of organisms available to study enteric diseases, we report on the use of the Drosophila melanogaster model to identify a novel function of an effector protein secreted by Vibrio parahaemolyticus, which is an enteric pathogen found in contaminated seafood. During pathogenesis, V. parahaemolyticus secretes effector proteins that usurp the host's innate immune signaling pathways, thus allowing the bacterium to evade detection by the innate immune system. One secreted effector protein, VopA, has potent inhibitory effects on mitogen-activated protein kinase (MAPK) signaling pathways via the acetylation of critical residues within the catalytic loops of mitogen-activated protein kinase kinases (MAPKKs). Using the Drosophila model and cultured mammalian cells, we show that VopA also has potent modulating activity on focal adhesion complex (FAC) proteins, where VopA markedly reduced the levels of focal adhesion kinase (FAK) phosphorylation at Ser910, whereas the phosphorylation levels of FAK at Tyr397 and Tyr861 were markedly increased. Cultured cells expressing VopA were also impaired in their ability to migrate and repopulate areas subjected to a scratch wound. Consistently, expression of VopA in Drosophila midgut enterocytes disrupted the normal enterocyte arrangement. Finally, VopA inhibited apoptosis in both Drosophila tissues and mammalian cultured cells. Together, our data show that VopA can alter normal intestinal homeostatic processes to facilitate opportunities for V. parahaemolyticus to prolong infection within the host.

PMID: 30617204 [PubMed - indexed for MEDLINE]

Preoperative Evaluation Is Not Predictive of Transpyloric Feeding Conversion in Gastrostomy-dependent Pediatric Patients.

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Preoperative Evaluation Is Not Predictive of Transpyloric Feeding Conversion in Gastrostomy-dependent Pediatric Patients.

J Pediatr Gastroenterol Nutr. 2018 Jun;66(6):887-892

Authors: McSweeney ME, Kerr J, Amirault J, Fishman E, Lurie M, Peinado-Fabregat MI, Mitchell PD, Rosen R

Abstract
OBJECTIVES: Limited literature exists as to whether preoperative gastrostomy (GT) evaluation may predict which patients will go onto require gastrojejunostomy (GJ) tube feeding. The goal of this study was to compare the preoperative evaluations between patients maintained on GT feeds versus patients who required conversion to GJ feeds.
METHODS: We identified patients at Boston Children's Hospital who underwent GT tube placement and required GJ feeding between 2006 and 2012. GT patients were matched according to age, neurologic, and cardiac status with GJ-converted patients. Preoperative characteristics, rates of total hospitalizations, and respiratory-related admissions were reviewed.
RESULTS: A total of 79 GJ patients (median interquartile range (IQR): age 15 (4.3, 55.7) months; weight 8.8 (4.6, 14.5) kg) were matched with 79 GT patients (median (IQR): age 14.6 (4.7, 55.7) months; weight 8.5 (5, 13.6) kg). Median time from GT to GJ conversion was 8 (IQR 3, 16) months. Both groups had similar rates of successful preoperative nasogastric feeding trials (GT (84.5%) versus GJ (83.1%), P = 1.0), upper gastrointestinal series (GT (89.1%) versus GJ (93.2%), P = 0.73), abnormal videofluoroscopic swallow studies (GT (53.8%) versus GJ (62.2%), P = 0.4), and completion of gastric emptying studies (GT (10.1%) versus GJ (5.1%), P = 0.22). No differences were seen in preoperative hospitalization rates (P = 0.25), respiratory admissions (P = 0.36), although GJ patients had a mean reduction in the number of hospitalization of -1.5 ± 0.5 days, P < 0.001, after conversion.
CONCLUSIONS: No differences in preoperative patient characteristics or diagnostic evaluations were seen in GT fed versus GJ converted patients. GJ patients did experience an overall decrease in total admissions after GJ conversion.

PMID: 29261527 [PubMed - indexed for MEDLINE]

Misdiagnosis and pitfalls in Panayiotopoulos syndrome.

Misdiagnosis and pitfalls in Panayiotopoulos syndrome.

Epilepsy Behav. 2019 Jul 29;98(Pt A):124-128

Authors: Graziosi A, Pellegrino N, Di Stefano V, Raucci U, Luchetti A, Parisi P

Abstract
Panayiotopoulos syndrome (PS) is a frequent (6% among children of 1-15 years) and benign epileptic syndrome, characterized by predominantly autonomic symptoms (emesis, pallor, flushing, cyanosis, mydriasis/miosis, cardiorespiratory and thermoregulatory alterations, incontinence of urine and/or feces, hypersalivation, and modifications of intestinal motility) associated with simple motor focal seizures, which can be followed by secondary generalization. Panayiotopoulos syndrome can be extremely insidious, because it can mimic several condition, such as gastroenteritis, gastroesophageal reflux disease, encephalitis, syncope, migraine, sleep disorders, or even metabolic diseases. This peculiar pleiotropism should be kept in mind by child neurologists and pediatricians and general practitioners, because a wrong diagnosis may lead to inappropriate interventions. The consequences are high morbidity, costly mismanagement, and stress for children and their parents. The availability of electroencephalography (EEG) recording in pediatric Emergency Departments might be useful for a prompt and not-cost-consuming diagnosis. On the other hand, it is important to be aware of the possible, multifaceted, clinical presentations of PS and its clinical, radiological, and neurophysiological features in order to improve both recognition and management.

PMID: 31369969 [PubMed - as supplied by publisher]

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 07;157(1):179-192.e2

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 polymerase chain reaction, 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 - indexed for MEDLINE]

Lactobacillus plantarum PS128 ameliorates 2,5-Dimethoxy-4-iodoamphetamine-induced tic-like behaviors via its influences on the microbiota-gut-brain-axis.

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Lactobacillus plantarum PS128 ameliorates 2,5-Dimethoxy-4-iodoamphetamine-induced tic-like behaviors via its influences on the microbiota-gut-brain-axis.

Brain Res Bull. 2019 Jul 25;:

Authors: Liao JF, Cheng YF, Li SW, Lee WT, Hsu CC, Wu CC, Jeng OJ, Wang S, Tsai YC

Abstract
We previously reported a novel psychobiotic strain of Lactobacillus plantarum PS128 (PS128) which could ameliorate anxiety-like& depression-like behaviors and modulate cerebral dopamine (DA) and serotonin (5-HT) in mice. Here, we examine the possibility of using PS128 administration to improve tic-like behaviors by using a 5-HT2A and 5-HT2C receptor agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI). PS128 was orally administered to male Wistar rat for 2 weeks before two daily DOI injections. We recorded the behaviors immediately after the second DOI injection and compared the results with control and haloperidol treatment groups. PS128 significantly reduced tic-like behaviors and pre-pulse inhibition deficit in a threshold-dose of 109 CFU per day. Brain tissue analysis showed that DOI induced abnormal DA efflux in the striatum and prefrontal cortex, while PS128 ingestion improved DA metabolism and increased norepinephrine (NE) levels in these two regions. In addition, PS128 ingestion increased DA transporter and β-arrestin expressions and decreased DOI-induced phosphorylation of DA and cAMP regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) at Thr34 and extracellular regulated protein kinases (ERK). PS128 ingestion also modulated peripheral 5-HT levels and shaped the cecal microbiota composition, which helps to alleviate DOI-induced dysbiosis. These results suggested that PS128 ameliorated DOI-induced tic-like hyper-active behaviors via stabilizing cerebral dopaminergic pathways through its modulation of host's microbiota-gut-brain axis. Thus, we believe there are potentials for utilizing psychobiotics to improve syndromes caused by DA dysregulation in DA-related neurological disorders and movement disorders such as Tourette syndrome.

PMID: 31351942 [PubMed - as supplied by publisher]

The assessment of the esophageal motility of children with esophageal disorders by the detailed observation of the pH-multichannel intraluminal impedance waveform and baseline impedance: screening test potential.

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The assessment of the esophageal motility of children with esophageal disorders by the detailed observation of the pH-multichannel intraluminal impedance waveform and baseline impedance: screening test potential.

Esophagus. 2019 04;16(2):133-140

Authors: Masui D, Fukahori S, Ishii S, Hashizume N, Saikusa N, Yoshida M, Higashidate N, Sakamoto S, Tsuruhisa S, Nakahara H, Tanaka Y, Yagi M

Abstract
BACKGROUND: The present study aimed to evaluate whether the detailed observation of pH/MII waveforms and the analysis of baseline impedance (BI) values could detect esophageal dysmotility in pediatric patients with esophageal disorders.
PATIENTS AND METHODS: Eleven patients with congenital esophageal disorder in whom pH/MII was conducted from April 2011 to June 2015, were enrolled in this study. The diagnoses of the patients were as follows: postoperative esophageal atresia (EA), n = 6; esophageal achalasia (EAch), n = 4; and congenital esophageal stenosis (CES), n = 1. The characteristics of the pH/MII waveform, pathological GERD, BI value, and the average BI value of the 2 distal channels (distal BI; DBI) were analyzed in each disorder.
RESULTS: Two EA (33%) patients and one EAch (25%) patient were diagnosed with GERD. The mean DBI values of the EA, EAch and CES patients was 912 ± 550, 2153 ± 915 and 1392 Ω, respectively. The EA patients showed consistently low DBI values. One CES patient and two infantile EAch patients showed postprandial prolonged low DBI values. Whereas, the pH/MII waveforms of the adolescent EAch patients were difficult to interpret due to their extremely low BI values.
CONCLUSIONS: The present study demonstrated that the detailed observation of the pH/MII waveforms in all channels and the analysis of BI were useful for evaluating esophageal motility in children with congenital esophageal disorders. In particular, infantile patients with EAch showed DBI findings that were distinct from those of adult EAch patients. Considering the difficulty of performing esophageal manometry in young children, the detailed observation of the pH/MII waveform may help in the diagnosis of esophageal dysmotility in children.

PMID: 30145680 [PubMed - indexed for MEDLINE]

Short Bowel Syndrome as the Leading Cause of Intestinal Failure in Early Life: Some Insights into the Management.

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Short Bowel Syndrome as the Leading Cause of Intestinal Failure in Early Life: Some Insights into the Management.

Pediatr Gastroenterol Hepatol Nutr. 2019 Jul;22(4):303-329

Authors: Goulet O, Abi Nader E, Pigneur B, Lambe C

Abstract
Intestinal failure (IF) is the critical reduction of the gut mass or its function below the minimum needed to absorb nutrients and fluids required for adequate growth in children. Severe IF requires parenteral nutrition (PN). Pediatric IF is most commonly due to congenital or neonatal intestinal diseases or malformations divided into 3 groups: 1) reduced intestinal length and consequently reduced absorptive surface, such as in short bowel syndrome (SBS) or extensive aganglionosis; 2) abnormal development of the intestinal mucosa such as congenital diseases of enterocyte development; 3) extensive motility dysfunction such as chronic intestinal pseudo-obstruction syndromes. The leading cause of IF in childhood is the SBS. In clinical practice the degree of IF may be indirectly measured by the level of PN required for normal or catch up growth. Other indicators such as serum citrulline have not proven to be highly reliable prognostic factors in children. The last decades have allowed the development of highly sophisticated nutrient solutions consisting of optimal combinations of macronutrients and micronutrients as well as guidelines, promoting PN as a safe and efficient feeding technique. However, IF that requires long-term PN may be associated with various complications including infections, growth failure, metabolic disorders, and bone disease. IF Associated Liver Disease may be a limiting factor. However, changes in the global management of IF pediatric patients, especially since the setup of intestinal rehabilitation centres did change the prognosis thus limiting "nutritional failure" which is considered as a major indication for intestinal transplantation (ITx) or combined liver-ITx.

PMID: 31338307 [PubMed]

Nutrition Management in Pediatric Gastrointestinal Motility Disorders.

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Nutrition Management in Pediatric Gastrointestinal Motility Disorders.

Nutr Clin Pract. 2019 Jul 18;:

Authors: Krasaelap A, Kovacic K, Goday PS

Abstract
Gastrointestinal (GI) motility disorders are associated with suboptimal nutrition in children, mainly because of malabsorption and symptoms limiting dietary intake. Apart from medical therapy, nutrition support has a crucial role in maintaining growth and improving clinical outcomes in children. Based on recent data and guidelines, this review provides an overview of nutrition assessment and specific interventions for common pediatric GI disorders including gastroesophageal reflux disease, esophageal motility disorders, gastroparesis, chronic intestinal pseudo-obstruction, and constipation. Several approaches including diet modification, enteral nutrition (gastric vs post-pyloric, temporary vs permanent access, bolus vs continuous), and parenteral nutrition need to be tailored based on patient's nutrition and clinical assessment.

PMID: 31321821 [PubMed - as supplied by publisher]

Neuronal Nitric Oxide Mediates the Anti-Inflammatory Effects of Intestinal Ischemic Preconditioning.

Neuronal Nitric Oxide Mediates the Anti-Inflammatory Effects of Intestinal Ischemic Preconditioning.

J Surg Res. 2019 Jul 10;244:241-250

Authors: Varga S, Juhász L, Gál P, Bogáts G, Boros M, Palásthy Z, Szabó A, Kaszaki J

Abstract
BACKGROUND: Ischemic preconditioning (IPC) can provide a defense against ischemia-reperfusion (IR)-induced acute inflammation and barrier dysfunction in many organs. Because nitric oxide (NO) has been implicated as a trigger or mediator in the IPC mechanism and because neuronal NO synthase (nNOS) is a dominant isoform of NOS in the gastrointestinal tract, our aim was to investigate the role of nNOS in IPC-induced protection after mesenteric IR.
MATERIALS AND METHODS: Intestinal IR was induced in sodium pentobarbital-anesthetized dogs by clamping the superior mesenteric artery for 60 min followed by 2 h of reperfusion (IR group; n = 7). In further groups, IPC was used (three cycles of 5-min ischemia/5-min reperfusion periods) before IR in the presence or absence of selective inhibition of nNOS with 7-nitroindazole (5 mg/kg, intravenously, in a bolus 15 min before IPC, n = 6 each). Changes in mesenteric vascular resistance, intramucosal pH (pHi), and small bowel motility were monitored. Plasma nitrite/nitrate levels, intestinal NO synthase activity, leukocyte accumulation, mast cell degranulation, and histologic injury were also determined.
RESULTS: Ischemia significantly decreased mesenteric vascular resistance and pHi, whereas IR induced a temporary bowel hypermotility and acute inflammatory reaction. IPC facilitated pHi recovery, attenuated motility dysfunction, elevated NOS-dependent NO production, and reduced leukocyte accumulation, mast cell degranulation, and mucosal injury. Pretreatment with 7-nitroindazole halted the IPC-induced increase in NO availability, pHi recovery, and the anti-inflammatory and morphologic effects.
CONCLUSIONS: Our data demonstrate that NO generated by intestinal nNOS plays a pivotal role in IPC-linked tissue protection by inhibiting an IR-related acute inflammatory response.

PMID: 31301480 [PubMed - as supplied by publisher]

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.

FASEB J. 2019 Jul 12;:fj201900858R

Authors: Cil O, Anderson MO, Yen R, Kelleher B, Huynh TL, Seo Y, Nilsen SP, Turner JR, Verkman AS

Abstract
Interstitial cells of Cajal, which express the calcium-activated chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestinal (GI) motility. We previously identified the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry, gave analog 2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide (TMinh-23) with 30 nM half-maximal inhibitory concentration. Here, we tested the efficacy of TMinh-23 for inhibition of GI motility in mice. In isolated murine gastric antrum, TMinh-23 strongly inhibited spontaneous and carbachol-stimulated rhythmic contractions. Pharmacokinetic analysis showed predicted therapeutic concentrations of TMinh-23 for at least 4 h following a single oral or intraperitoneal dose at 10 mg/kg. Gastric emptying, as assessed following an oral bolus of phenol red or independently by [99mTc]-diethylenetriamine pentaacetic acid scintigraphy, was reduced by TMinh-23 by ∼60% at 20 min. Interestingly, there was little effect of TMinh-23 on baseline whole-gut transit time or time to diarrhea induced by castor oil. Consequent to the delay in gastric emptying, TMinh-23 administration significantly reduced the elevation in blood sugar in mice following an oral but not intraperitoneal glucose load. These results provide pharmacological evidence for involvement of TMEM16A in gastric emptying and suggest the utility of TMEM16A inhibition in disorders of accelerated gastric emptying, such as dumping syndrome, and potentially for improving glucose tolerance in diabetes mellitus/metabolic syndrome and enhancing satiety in obesity.-Cil, O., Anderson, M. O., Yen, R., Kelleher, B., Huynh, T. L., Seo, Y., Nilsen, S. P., Turner, J. R., Verkman, A. S. Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.

PMID: 31299174 [PubMed - as supplied by publisher]

First translational consensus on terminology and definitions of colonic motility in animals and humans studied by manometric and other techniques.

First translational consensus on terminology and definitions of colonic motility in animals and humans studied by manometric and other techniques.

Nat Rev Gastroenterol Hepatol. 2019 Jul 11;:

Authors: Corsetti M, Costa M, Bassotti G, Bharucha AE, Borrelli O, Dinning P, Di Lorenzo C, Huizinga JD, Jimenez M, Rao S, Spiller R, Spencer NJ, Lentle R, Pannemans J, Thys A, Benninga M, Tack J

Abstract
Alterations in colonic motility are implicated in the pathophysiology of bowel disorders, but high-resolution manometry of human colonic motor function has revealed that our knowledge of normal motor patterns is limited. Furthermore, various terminologies and definitions have been used to describe colonic motor patterns in children, adults and animals. An example is the distinction between the high-amplitude propagating contractions in humans and giant contractions in animals. Harmonized terminology and definitions are required that are applicable to the study of colonic motility performed by basic scientists and clinicians, as well as adult and paediatric gastroenterologists. As clinical studies increasingly require adequate animal models to develop and test new therapies, there is a need for rational use of terminology to describe those motor patterns that are equivalent between animals and humans. This Consensus Statement provides the first harmonized interpretation of commonly used terminology to describe colonic motor function and delineates possible similarities between motor patterns observed in animal models and humans in vitro (ex vivo) and in vivo. The consolidated terminology can be an impetus for new research that will considerably improve our understanding of colonic motor function and will facilitate the development and testing of new therapies for colonic motility disorders.

PMID: 31296967 [PubMed - as supplied by publisher]

The role of mast cells in pediatric gastrointestinal disease.

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The role of mast cells in pediatric gastrointestinal disease.

Ann Gastroenterol. 2019 Jul-Aug;32(4):338-345

Authors: Ravanbakhsh N, Kesavan A

Abstract
Mast cells are granulocytes derived from CD34+ pluripotent progenitor cells that demonstrate plasticity in their development, leaving the bone marrow and differentiating in the tissue where they ultimately reside. They are best known for their role in the allergic response, but also play a prominent immunoregulatory role in other processes, including immune tolerance, the innate immune response, angiogenesis, wound healing and tissue remodeling. Mast cells are found throughout the gastrointestinal tract; their metabolic products influence and regulate intestinal epithelial and endothelial function, gastrointestinal secretion, intestinal motility and absorption, and contribute to host defense. They also play an important role in the development of visceral hypersensitivity through bidirectional interaction with the enteric nervous system. Mast cells have been found to have an increasingly important role in the pathophysiology of a number of pediatric gastrointestinal diseases. This review summarizes the current understanding of the role that mast cells play in the development of pediatric gastrointestinal disorders, including eosinophilic esophagitis, functional dyspepsia, irritable bowel syndrome, celiac disease, inflammatory bowel disease, histologically negative appendicitis, Hirschsprung's disease, intestinal neuronal dysplasia, and food protein-induced enterocolitis syndrome.

PMID: 31263355 [PubMed]

Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms.

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Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms.

Am J Physiol Gastrointest Liver Physiol. 2018 08 01;315(2):G259-G271

Authors: Golden JM, Escobar OH, Nguyen MVL, Mallicote MU, Kavarian P, Frey MR, Gayer CP

Abstract
The intestinal barrier is often disrupted in disease states, and intestinal barrier failure leads to sepsis. Ursodeoxycholic acid (UDCA) is a bile acid that may protect the intestinal barrier. We hypothesized that UDCA would protect the intestinal epithelium in injury models. To test this hypothesis, we utilized an in vitro wound-healing assay and a mouse model of intestinal barrier injury. We found that UDCA stimulates intestinal epithelial cell migration in vitro, and this migration was blocked by inhibition of cyclooxygenase 2 (COX-2), epidermal growth factor receptor (EGFR), or ERK. Furthermore, UDCA stimulated both COX-2 induction and EGFR phosphorylation. In vivo UDCA protected the intestinal barrier from LPS-induced injury as measured by FITC dextran leakage into the serum. Using 5-bromo-2'-deoxyuridine and 5-ethynyl-2'-deoxyuridine injections, we found that UDCA stimulated intestinal epithelial cell migration in these animals. These effects were blocked with either administration of Rofecoxib, a COX-2 inhibitor, or in EGFR-dominant negative Velvet mice, wherein UDCA had no effect on LPS-induced injury. Finally, we found increased COX-2 and phosphorylated ERK levels in LPS animals also treated with UDCA. Taken together, these data suggest that UDCA can stimulate intestinal epithelial cell migration and protect against acute intestinal injury via an EGFR- and COX-2-dependent mechanism. UDCA may be an effective treatment to prevent the early onset of gut-origin sepsis. NEW & NOTEWORTHY In this study, we show that the secondary bile acid ursodeoxycholic acid stimulates intestinal epithelial cell migration after cellular injury and also protects the intestinal barrier in an acute rodent injury model, neither of which has been previously reported. These effects are dependent on epidermal growth factor receptor activation and downstream cyclooxygenase 2 upregulation in the small intestine. This provides a potential treatment for acute, gut-origin sepsis as seen in diseases such as necrotizing enterocolitis.

PMID: 29672156 [PubMed - indexed for MEDLINE]

The recruitment of extra-intestinal cells to the injured mucosa promotes healing in radiation enteritis and chemical colitis in a mouse parabiosis model.

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The recruitment of extra-intestinal cells to the injured mucosa promotes healing in radiation enteritis and chemical colitis in a mouse parabiosis model.

Mucosal Immunol. 2019 03;12(2):503-517

Authors: Sung J, Sodhi CP, Voltaggio L, Hou X, Jia H, Zhou Q, Čiháková D, Hackam DJ

Abstract
Mucosal healing occurs through migration and proliferation of cells within injured epithelium, yet these processes may be inadequate for mucosal healing after significant injury where the mucosa is denuded. We hypothesize that extra-intestinal cells can contribute to mucosal healing after injury to the small and large intestine. We generated parabiotic pairs between wild-type and tdTomato mice, which were then subjected to radiation-induced enteritis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. We now show that as compared with singleton mice, mice with a parabiotic partner were protected against intestinal damage as revealed by significantly reduced weight loss, reduced expression of pro-inflammatory cytokines, reduced enterocyte apoptosis, and improved crypt proliferation. Donor cells expressed CD45-, Sca-1+, c-kit+, and CXCR4+ and accumulated around the injured crypts but did not transdifferentiate into epithelia, suggesting that extra-intestinal cells play a paracrine role in the healing response, while parabiotic pairings with Rag1-/- mice showed improved healing, indicating that adaptive immune cells were dispensable for mucosal healing. Strikingly, ablation of the bone marrow of the donor parabionts removed the protective effects. These findings reveal that the recruitment of extra-intestinal, bone marrow-derived cells into the injured intestinal mucosa can promote mucosal healing, suggesting novel therapeutic approaches for severe intestinal disease.

PMID: 30617302 [PubMed - indexed for MEDLINE]

IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.

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IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.

Mucosal Immunol. 2019 03;12(2):479-490

Authors: Costes LMM, Lindenbergh-Kortleve DJ, van Berkel LA, Veenbergen S, Raatgeep HRC, Simons-Oosterhuis Y, van Haaften DH, Karrich JJ, Escher JC, Groeneweg M, Clausen BE, Cupedo T, Samsom JN

Abstract
Breach of tolerance to gluten leads to the chronic small intestinal enteropathy celiac disease. A key event in celiac disease development is gluten-dependent infiltration of activated cytotoxic intraepithelial lymphocytes (IELs), which cytolyze epithelial cells causing crypt hyperplasia and villous atrophy. The mechanisms leading to gluten-dependent small intestinal IEL infiltration and activation remain elusive. We have demonstrated that under homeostatic conditions in mice, gluten drives the differentiation of anti-inflammatory T cells producing large amounts of the immunosuppressive cytokine interleukin-10 (IL-10). Here we addressed whether this dominant IL-10 axis prevents gluten-dependent infiltration of activated cytotoxic IEL and subsequent small intestinal enteropathy. We demonstrate that IL-10 regulation prevents gluten-induced cytotoxic inflammatory IEL infiltration. In particular, IL-10 suppresses gluten-induced accumulation of a specialized population of cytotoxic CD4+CD8αα+ IEL (CD4+ CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4+CD8α- IEL population expressing Il17a, Il21, and Il10. Concomitantly, IL-10 suppresses gluten-dependent small intestinal epithelial hyperproliferation and upregulation of stress-induced molecules on epithelial cells. Remarkably, frequencies of granzyme B+CD4+CD8α+ IEL are increased in pediatric celiac disease patient biopsies. These findings demonstrate that IL-10 is pivotal to prevent gluten-induced small intestinal inflammation and epithelial damage, and imply that CD4+ CTL are potential new players into these processes.

PMID: 30542112 [PubMed - indexed for MEDLINE]

Tyrosine kinase Pyk2 is involved in colonic smooth muscle contraction via the RhoA/ROCK pathway.

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Tyrosine kinase Pyk2 is involved in colonic smooth muscle contraction via the RhoA/ROCK pathway.

Physiol Res. 2019 03 06;68(1):89-98

Authors: Tong L, Ao JP, Lu HL, Huang X, Zang JY, Liu SH, Song NN, Huang SQ, Lu C, Chen J, Xu WX

Abstract
The contraction of gastrointestinal (GI) smooth muscles is regulated by both Ca(2+)-dependent and Ca(2+) sensitization mechanisms. Proline-rich tyrosine kinase 2 (Pyk2) is involved in the depolarization-induced contraction of vascular smooth muscle via a Ca(2+) sensitization pathway. However, the role of Pyk2 in GI smooth muscle contraction is unclear. The spontaneous contraction of colonic smooth muscle was measured by using isometric force transducers. Protein and phosphorylation levels were determined by using western blotting. Pyk2 protein was expressed in colonic tissue, and spontaneous colonic contractions were inhibited by PF-431396, a Pyk2 inhibitor, in the presence of tetrodotoxin (TTX). In cultured colonic smooth muscle cells (CSMCs), PF-431396 decreased the levels of myosin light chain (MLC20) phosphorylated at Ser19 and ROCK2 protein expression, but myosin light chain kinase (MLCK) expression was not altered. However, Y-27632, a Rho kinase inhibitor, increased phosphorylation of Pyk2 at Tyr402 and concomitantly decreased ROCK2 levels; the expression of MLCK in CSMCs did not change. The expression of P(Tyr402)-Pyk2 and ROCK2 was increased when CSMCs were treated with Ach. Pyk2 is involved in the process of colonic smooth muscle contraction through the RhoA/ROCK pathway. These pathways may provide very important targets for investigating GI motility disorders.

PMID: 30433799 [PubMed - indexed for MEDLINE]

Roles of esophageal manometry study in children with refractory gastroesophageal reflux symptoms.

Roles of esophageal manometry study in children with refractory gastroesophageal reflux symptoms.

Pediatr Int. 2019 Jun 20;:

Authors: Hsing TY, Tsai IJ, Hsu CT, Wu JF

Abstract
BACKGROUND: We investigated the prevalence of psychiatric referral, the frequency of repeat upper gastrointestinal (UGI) contrast studies, and esophagogastroduodenoscopy (EGD) in patients with ineffective esophageal motility (IEM) before diagnosis.
METHODS: A total of 19 patients (9 males and 10 females; mean 13.80 ± 5.10 years of age) with refractory symptoms of gastroesophageal reflux who underwent high-resolution esophageal impedance manometry (HRIM) were enrolled in this retrospective study. Refractory gastroesophageal reflux symptoms was defined as subjects with persist symptoms even under acid-suppression therapy for 8 weeks in this study. Clinical data including age, sex, time from symptom onset to diagnosis, and number of UGI contrast studies and EGD examination before diagnosis were obtained. HRM parameters and the prevalence of psychiatric referral were also analyzed.
RESULTS: A significant proportion of IEM patients were misdiagnosed with psychological problems rather than gastroesophageal reflux disease (GERD) patients (78.57% vs. 20.00%, P = 0.04). Three IEM subjects (21.43%) received antipsychotic and antidepressant agents before diagnosis of IEM, and all of them discontinued these medications after diagnosis. These patients underwent a greater number of UGI contrast studies (1.07 ± 0.92 vs. 0.20 ± 0.45-examinations; P = 0.02) and EGD (2.36 ± 2.50 vs. 0.60 ± 0.55 examinations; P = 0.03) before HRM than GERD patients.
CONCLUSIONS: HRIM for the diagnosis of IEM should be considered in pediatric subjects with refractory gastroesophageal reflux symptoms to acid-suppression therapy for 8 weeks to avoid repeat UGI contrast studies, EGD tests, and psychological therapy. This article is protected by copyright. All rights reserved.

PMID: 31220381 [PubMed - as supplied by publisher]

Long-Chain Fatty Acid Receptors Mediate Relaxation of the Porcine Lower Esophageal Sphincter.

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Long-Chain Fatty Acid Receptors Mediate Relaxation of the Porcine Lower Esophageal Sphincter.

Front Physiol. 2019;10:676

Authors: Tsai CC, Li YC, Chang LC, Tey SL, Lin KJ, Huang SC

Abstract
Long-chain fatty acids activate the free fatty acid receptor 1 (FFA1) and FFA4. In the gastrointestinal system, FFA1 and FFA4 have been found in the pancreas and intestine. Fatty food and decreased lower esophageal sphincter (LES) motility are associated with gastroesophageal reflux disease. The effect of long-chain fatty acids on the esophageal motility is unknown. The purpose of this study is to investigate the effects of long-chain fatty acids on the porcine LES motility ex vivo using isometric transducers. In endothelin 1-precontracted porcine LES strips, the FFA1 selective agonists, fasiglifam, TUG424, and GW9508, caused marked relaxations in a concentration-dependent manner. The relative efficacies to elicit relaxation were GW9508 > TUG424 > fasiglifam in both clasp and sling strips. In contrast, the FFA4 specific agonists, TUG891 and GSK137647, produced mild relaxations. In addition, the endogenous FFA1 agonist DHA caused a mild relaxation whereas GW1100, an FFA1 antagonist, inhibited GW9508 induced relaxation of the porcine LES clasp and sling muscle. Both real-time PCR and immunohistochemistry revealed that FFA1 and FFA4 were expressed in the porcine LES. Real-time PCR analysis showed that the FFA4 expression was much lower than FFA1. Taken together, long-chain fatty acid receptor agonists elicit relaxation of the porcine LES. FFA1 might influence LES motility.

PMID: 31214048 [PubMed]

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