Recent PubMed Articles on Gut Motility

Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes.

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Visceral myopathy: Clinical and molecular survey of a cohort of seven new patients and state of the art of overlapping phenotypes.

Am J Med Genet A. 2016 Nov;170(11):2965-2974

Authors: Moreno CA, Metze K, Lomazi EA, Bertola DR, Barbosa RH, Cosentino V, Sobreira N, Cavalcanti DP

Abstract
Visceral motility dysfunction is a key feature of genetic disorders such as megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS, MIM moved from 249210 to 155310), chronic intestinal pseudo-obstruction (CIPO, MIM609629), and multisystemic smooth muscle dysfunction syndrome (MSMDS, MIM613834). The genetic bases of these conditions recently begun to be clarified with the identification of pathogenic variants in ACTG2, ACTA2, and MYH11 in individuals with visceral motility dysfunction. The MMIHS was associated with the heterozygous variant in ACTG2 and homozygous variant in MYH11, while the heterozygous variant in ACTA2 was observed in patients with MSMDS. In this study, we describe the clinical data as well as the molecular investigation of seven individuals with visceral myopathy phenotypes. Five patients presented with MMIHS, including two siblings from consanguineous parents, one had CIPO, and the other had MSMDS. In three individuals with MMIHS and in one with CIPO we identified heterozygous variant in ACTG2, one being a novel variant (c.584C>T-p.Thr195Ile). In the individual with MSMDS we identified a heterozygous variant in ACTA2. We performed the whole-exome sequencing in one sibling with MMIHS and her parents; however, the pathogenic variant responsible for her phenotype could not be identified. These results reinforce the clinical and genetic heterogeneity of the visceral myopathies. Although many cases of MMIHS are associated with ACTG2 variants, we suggest that other genes, besides MYH11, could cause the MMIHS with autosomal recessive pattern. © 2016 Wiley Periodicals, Inc.

PMID: 27481187 [PubMed - indexed for MEDLINE]

The role of intermediate filaments in maintaining integrity and function of intestinal epithelial cells after massive bowel resection in a rat.

The role of intermediate filaments in maintaining integrity and function of intestinal epithelial cells after massive bowel resection in a rat.

Pediatr Surg Int. 2017 Oct 17;:

Authors: Sukhotnik I, Shahar YB, Pollak Y, Dorfman T, Shefer HK, Assi ZE, Mor-Vaknin N, Coran AG

Abstract
PURPOSE: Intermediate filaments (IFs) are a part of the cytoskeleton that extend throughout the cytoplasm of all cells and function in the maintenance of cell-shape by bearing tension and serving as structural components of the nuclear lamina. In normal intestine, IFs provide a tissue-specific three-dimensional scaffolding with unique context-dependent organizational features. The purpose of this study was to evaluate the role of IFs during intestinal adaptation in a rat model of short bowel syndrome (SBS).
MATERIALS AND METHODS: Male rats were divided into two groups: Sham rats underwent bowel transection and SBS rats underwent a 75% bowel resection. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined 2 weeks after operation. Illumina's Digital Gene Expression (DGE) analysis was used to determine the cytoskeleton-related gene expression profiling. IF-related genes and protein expression were determined using real-time PCR, Western blotting and immunohistochemistry.
RESULTS: Massive small bowel resection resulted in a significant increase in enterocyte proliferation and concomitant increase in cell apoptosis. From the total number of 20,000 probes, 16 cytoskeleton-related genes were investigated. Between these genes, only myosin and tubulin levels were upregulated in SBS compared to sham animals. Between IF-related genes, desmin, vimentin and lamin levels were down-regulated and keratin and neurofilament remain unchanged. The levels of TGF-β, vimentin and desmin gene and protein were down-regulated in resected rats (vs sham animals).
CONCLUSIONS: Two weeks following massive bowel resection in rats, the accelerated cell turnover was accompanied by a stimulated microfilaments and microtubules, and by inhibited intermediate filaments. Resistance to cell compression rather that maintenance of cell-shape by bearing tension are responsible for contraction, motility and postmitotic cell separation in a late stage of intestinal adaptation.

PMID: 29043445 [PubMed - as supplied by publisher]

Serotonergic Mechanisms Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance.

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Serotonergic Mechanisms Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance.

Handb Exp Pharmacol. 2017;239:319-342

Authors: Terry N, Margolis KG

Abstract
Serotonin (5-hydroxytryptamine; 5-HT) is best known as a neurotransmitter critical for central nervous system (CNS) development and function. 95% of the body's serotonin, however, is produced in the intestine where it has been increasingly recognized for its hormonal, autocrine, paracrine, and endocrine actions. This chapter provides the most current knowledge of the critical autocrine and paracrine roles of 5-HT in intestinal motility and inflammation as well as its function as a hormone in osteocyte homeostasis. Therapeutic applications in each of these areas are also discussed.

PMID: 28035530 [PubMed - indexed for MEDLINE]

Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease.

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Early Postnatal Secondhand Smoke Exposure Disrupts Bacterial Clearance and Abolishes Immune Responses in Muco-Obstructive Lung Disease.

J Immunol. 2017 Aug 01;199(3):1170-1183

Authors: Lewis BW, Sultana R, Sharma R, Noël A, Langohr I, Patial S, Penn AL, Saini Y

Abstract
Secondhand smoke (SHS) exposure has been linked to the worsening of ongoing lung diseases. However, whether SHS exposure affects the manifestation and natural history of imminent pediatric muco-obstructive airway diseases such as cystic fibrosis remains unclear. To address these questions, we exposed Scnn1b transgenic (Scnn1b-Tg(+)) mice to SHS from postnatal day (PND) 3-21 and lung phenotypes were examined at PND22. Although a majority of filtered air (FA)-exposed Scnn1b-Tg(+) (FA-Tg(+)) mice successfully cleared spontaneous bacterial infections by PND22, the SHS-exposed Scnn1b-Tg(+) (SHS-Tg(+)) mice failed to resolve these infections. This defect was associated with suppressed antibacterial defenses, i.e., phagocyte recruitment, IgA secretion, and Muc5b expression. Whereas the FA-Tg(+) mice exhibited marked mucus obstruction and Th2 responses, SHS-Tg(+) mice displayed a dramatic suppression of these responses. Mechanistically, downregulated expression of IL-33, a stimulator of type II innate lymphoid cells, in lung epithelial cells was associated with suppression of neutrophil recruitment, IgA secretions, Th2 responses, and delayed bacterial clearance in SHS-Tg(+) mice. Cessation of SHS exposure for 21 d restored previously suppressed responses, including phagocyte recruitment, IgA secretion, and mucous cell metaplasia. However, in contrast with FA-Tg(+) mice, the SHS-Tg(+) mice had pronounced epithelial necrosis, alveolar space consolidation, and lymphoid hyperplasia; indicating lagged unfavorable effects of early postnatal SHS exposure in later life. Collectively, our data show that early postnatal SHS exposure reversibly suppresses IL-33 levels in airspaces which, in turn, results in reduced neutrophil recruitment and diminished Th2 response. Our data indicate that household smoking may predispose neonates with muco-obstructive lung disease to bacterial exacerbations.

PMID: 28667160 [PubMed - indexed for MEDLINE]

Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture.

Understanding Chylomicron Retention Disease Through Sar1b Gtpase Gene Disruption: Insight From Cell Culture.

Arterioscler Thromb Vasc Biol. 2017 Oct 05;:

Authors: Sané AT, Seidman E, Peretti N, Klémé ML, Delvin E, Deslandres C, Garofalo C, Spahis S, Levy E

Abstract
BACKGROUND: Understanding the specific mechanisms of rare autosomal disorders has greatly expanded insights into the complex processes regulating intestinal fat transport. Sar1B GTPase is one of the critical proteins governing chylomicron secretion by the small intestine, and its mutations lead to chylomicron retention disease, despite the presence of Sar1A paralog.
OBJECTIVE: The central aim of this work is to examine the cause-effect relationship between Sar1B expression and chylomicron output and to determine whether Sar1B is obligatory for normal high-density lipoprotein biogenesis.
APPROACH AND RESULTS: The SAR1B gene was totally silenced in Caco-2/15 cells using the zinc finger nuclease technique. SAR1B deletion resulted in significantly decreased secretion of triglycerides (≈40%), apolipoprotein B-48 (≈57%), and chylomicron (≈34.5%). The absence of expected chylomicron production collapse may be because of the compensatory SAR1A elevation observed in our experiments. Therefore, a double knockout of SAR1A and SAR1B was engineered in Caco-2/15 cells, which led to almost complete inhibition of triglycerides, apolipoprotein B-48, and chylomicron output. Further experiments with labeled cholesterol revealed the downregulation of high-density lipoprotein biogenesis in cells deficient in SAR1B or with the double knockout of the 2 SAR1 paralogs. Similarly, there was a fall in the movement of labeled cholesterol from cells to basolateral medium containing apolipoprotein A-I, thereby limiting newly synthesized high-density lipoprotein in genetically modified cells. The decreased cholesterol efflux was associated with impaired expression of ABCA1 (ATP-binding cassette subfamily A member 1).
CONCLUSIONS: These findings demonstrate that the deletion of the 2 SAR1 isoforms is required to fully eliminate the secretion of chylomicron in vitro. They also underscore the limited high-density lipoprotein production by the intestinal cells in response to SAR1 knockout.

PMID: 28982670 [PubMed - as supplied by publisher]

Preliminary identification of key miRNAs, signaling pathways, and genes associated with Hirschsprung's disease by analysis of tissue microRNA expression profiles.

Preliminary identification of key miRNAs, signaling pathways, and genes associated with Hirschsprung's disease by analysis of tissue microRNA expression profiles.

World J Pediatr. 2017 Oct;13(5):489-495

Authors: Gao ZG, Chen QJ, Shao M, Qian YZ, Zhang LF, Zhang YB, Xiong QX

Abstract
BACKGROUND: Hirschsprung's disease (HSCR) is a congenital gut motility disorder of infants, and if left untreated, it is fatal to the affected infants. This study aimed to identify key microRNAs (miRNAs), signaling pathways and genes involved in the pathogenesis of HSCR.
METHODS: The miRNA microarray dataset GSE77296 was downloaded. Nine colon tissue samples were available: six from HSCR patients and three matched control samples. Differentially expressed miRNAs (DEMs) were identified after data preprocessing. Target genes of the selected upregulated and downregulated DEMs were predicted. In addition, functional enrichment analyses for the selected DEMs and target genes were conducted. Finally, interaction networks between the DEMs and target genes were constructed.
RESULTS: A total of 162 DEMs (73 upregulated and 89 downregulated) were obtained. A total of 2511 DEM-target gene pairs for the 40 selected DEMs were identified, including 1645 pairs for the upregulated DEMs and 866 pairs for the downregulated DEMs. The upregulated DEM miR-141-3p and down-regulated DEM miR-30a-3p were identified as key miRNAs by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and network analyses. Besides, KEGG pathway enrichment analysis revealed that pathways in cancer and the mitogen-activated protein kinase (MAPK) signaling pathway were key pathways. The key genes frizzled class receptor 3 (FZD3) and docking protein 6 (DOK6) were obtained through the DEM-target gene interaction networks.
CONCLUSION: Two key miRNAs (miR-141-3p and miR-30a-3p), the MAPK signaling pathway and two key genes (FZD3 and DOK6) were implicated in the pathogenesis of HSCR.

PMID: 28965333 [PubMed - in process]

Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation.

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Prolonged intestinal transit and diarrhea in patients with an activating GUCY2C mutation.

PLoS One. 2017;12(9):e0185496

Authors: von Volkmann HL, Brønstad I, Gilja OH, R Tronstad R, Sangnes DA, Nortvedt R, Hausken T, Dimcevski G, Fiskerstrand T, Nylund K

Abstract
INTRODUCTION: Increased intestinal hydration by activation of the epithelial enzyme linked receptor guanylate cyclase C (GC-C) is a pharmacological principle for treating constipation. Activating mutations in the GUCY2C gene encoding GC-C cause Familial GUCY2C diarrhea syndrome (FGDS) which has been diagnosed with severe dysmotility.
AIM: To investigate gut motility and hormones before and after a meal in FGDS patients and compare with healthy controls (HC).
SUBJECTS AND METHODS: Bristol stool chart and stool frequency was assessed. Before and after a meal occlusive and non-occlusive contractions were obtained using ultrasound. A wireless motility capsule (WMC) recorded gut transit time, pH, contractions and pressure. Plasma levels of selected gut hormones were measured at different time points.
RESULTS: The FGDS patients had 4 (range 1-10) loose stools/day and prolonged total gut transit time compared to HC, 55.5 h vs 28.5 h, respectively,with significantly increased colon transit time. In FGDS patients, pH in duodenum, small bowel and colon was increased and the number of contractions and the intraluminal pressure were significantly decreased, measured by WMC. Ultrasound showed in small bowel increased number of non-occlusive contractions in the FGDS patients. Serotonin (5-HT) plasma levels in the HC peaked 30 min after the meal, while the FGDS patients had no response.
CONCLUSION: Despite having diarrhea, the FGDS patients have prolonged transit time through the gut compared to HC, particularly in colon. The reduced number of intestinal contractions and lack of 5-HT release after a meal in FGDS patients surprisingly resemble colonic motility disturbances seen in patients with constipation.

PMID: 28957388 [PubMed - in process]

Does diverting ileostomy improve the outcome in children with tuberculous small bowel obstruction requiring surgical intervention?

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Does diverting ileostomy improve the outcome in children with tuberculous small bowel obstruction requiring surgical intervention?

Pediatr Surg Int. 2017 Sep 27;:

Authors: Khan RA, Wahab S, Ghani I

Abstract
INTRODUCTION: Abdominal tuberculosis is fairly common in children. The most common clinical presentation is bowel obstruction. Depending upon the presentation, the intestinal obstruction can be either managed conservatively or by operative intervention. There are various options in patients who undergo operative treatment. This study was undertaken to analyze the results of operative intervention with and without ileostomy.
MATERIALS AND METHODS: This is a retrospective study carried out over a period of 10 years on 32 children who were operated for small bowel obstruction due to abdominal tuberculosis. The patients were divided into two groups (A: with ileostomy and B: without ileostomy). The relevant data and the defined outcome measures were statistically analyzed.
RESULTS: A total of 32 children with tuberculous bowel obstruction requiring surgical intervention were studied. The patient of group A had mean duration of postoperative ileus for 2.55 days, restoration of enteral feeding within mean period of 3.55 days and had a primary hospital stay for a mean period of 9.0 days. These outcomes when compared with group B patients were statistically significant.
CONCLUSION: In children with bowel obstruction due to tuberculosis, diverting ileostomy decreases the morbidity by allowing early return of enteral motility, early institution of feeding and first-line ATT and decreasing the primary hospital stay.

PMID: 28956144 [PubMed - as supplied by publisher]

Intestinal Epithelial and Intraepithelial T Cell Crosstalk Mediates a Dynamic Response to Infection.

Intestinal Epithelial and Intraepithelial T Cell Crosstalk Mediates a Dynamic Response to Infection.

Cell. 2017 Sep 16;:

Authors: Hoytema van Konijnenburg DP, Reis BS, Pedicord VA, Farache J, Victora GD, Mucida D

Abstract
Intestinal intraepithelial lymphocytes (IELs) are located at the critical interface between the intestinal lumen, which is chronically exposed to food and microbes, and the core of the body. Using high-resolution microscopy techniques and intersectional genetic tools, we investigated the nature of IEL responses to luminal microbes. We observed that TCRγδ IELs exhibit unique microbiota-dependent location and movement patterns in the epithelial compartment. This behavioral pattern quickly changes upon exposure to different enteric pathogens, resulting in increased interepithelial cell (EC) scanning, expression of antimicrobial genes, and glycolysis. Both dynamic and metabolic changes to γδ IEL depend on pathogen sensing by ECs. Direct modulation of glycolysis is sufficient to change γδ IEL behavior and susceptibility to early pathogen invasion. Our results uncover a coordinated EC-IEL response to enteric infections that modulates lymphocyte energy utilization and dynamics and supports maintenance of the intestinal epithelial barrier.

PMID: 28942917 [PubMed - as supplied by publisher]

Obesity increases the risk of small intestinal bacterial overgrowth (SIBO).

Obesity increases the risk of small intestinal bacterial overgrowth (SIBO).

Neurogastroenterol Motil. 2017 Sep 21;:

Authors: Roland BC, Lee D, Miller LS, Vegesna A, Yolken R, Severance E, Prandovszky E, Zheng XE, Mullin GE

Abstract
BACKGROUND: Small intestinal bacterial overgrowth (SIBO) has been associated with anatomical and motility-related abnormalities. Specifically, obesity has been postulated to alter small bowel motility, leading to SIBO.
AIMS: (i) Assess the prevalence of SIBO in obesity; (ii) determine the relationship of obesity and SIBO, using small bowel transit time (SBTT) and pH; (iii) profile the gut microbiome in obese and non-obese patients with SIBO.
METHODS: Thirty consecutive participants referred for SIBO underwent lactulose breath tests (LBTs) and wireless motility capsule (WMC) studies. Composition of the intestinal microbiome was assessed by analyzing samples from three different gastrointestinal sites via 16S rRNA gene-sequencing.
KEY RESULTS: SIBO was more frequent among obese patients vs non-obese patients (88.9% vs 42.9%, P < .05). Obesity did not correlate with small bowel transit time (SBTT), gastric pH, and small bowel pH. In patients with normal SBTT, obesity was associated with an 11-fold increase (P = .05) in the risk of SIBO. Whereas in those with prolonged SBTT, there was no correlation between obesity and SIBO. Obese vs non-obese patients exhibited significant differences in microbiome diversity in rectal samples. Obesity was associated with increased odds of developing SIBO (P = .04) in multivariate regression analyses.
CONCLUSIONS AND INFERENCES: While obesity was significantly associated with SIBO, our findings suggest that alterations in gut pH, SBTT, and decline in species richness do not account for the obesity-SIBO relationship.

PMID: 28940740 [PubMed - as supplied by publisher]

Motility disorders in infants.

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Motility disorders in infants.

Early Hum Dev. 2017 Sep 16;:

Authors: Koppen IJN, Benninga MA, Singendonk MMJ

Abstract
Gastrointestinal motility disorders are common in the pediatric population and may affect the entire gastrointestinal tract and can vary from mild to severe conditions. They may clinically manifest as gastro-esophageal reflux symptoms, feeding difficulties and failure to thrive, constipation and diarrhea amongst others. This review first highlights the embryologic development of the gastrointestinal tract, after which the prenatal and neonatal development of gastrointestinal motility is discussed. Normal motility patterns as seen in (preterm) infants are described as a background for the discussion of the most common congenital and acquired motility disorders in infancy. This review specifically focuses on the role of preterm birth on the development of these disorders.

PMID: 28927754 [PubMed - as supplied by publisher]

Tumour-associated changes in intestinal epithelial cells cause local accumulation of KLRG1(+) GATA3(+) regulatory T cells in mice.

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Tumour-associated changes in intestinal epithelial cells cause local accumulation of KLRG1(+) GATA3(+) regulatory T cells in mice.

Immunology. 2017 Sep;152(1):74-88

Authors: Meinicke H, Bremser A, Brack M, Akeus P, Pearson C, Bullers S, Hoffmeyer K, Stemmler MP, Quiding-Järbrink M, Izcue A

Abstract
CD4(+) Foxp3(+) regulatory T (Treg) cells include differentiated populations of effector Treg cells characterized by the expression of specific transcription factors. Tumours, including intestinal malignancies, often present with local accumulation of Treg cells that can prevent tumour clearance, but how tumour progression leads to Treg cell accumulation is incompletely understood. Here using genetically modified mouse models we show that ablation of E-cadherin, a process associated with epithelial to mesenchymal transition and tumour progression, promotes the accumulation of intestinal Treg cells by the specific accumulation of the KLRG1(+) GATA3(+) Treg subset. Epithelial E-cadherin ablation activates the β-catenin pathway, and we find that increasing β-catenin signals in intestinal epithelial cells also boosts Treg cell frequencies through local accumulation of KLRG1(+) GATA3(+) Treg cells. Both E-cadherin ablation and increased β-catenin signals resulted in epithelial cells with higher levels of interleukin-33, a cytokine that preferentially expands KLRG1(+) GATA3(+) Treg cells. Tumours often present reduced E-cadherin expression and increased β-catenin signalling and interleukin-33 production. Accordingly, Treg cell accumulation in intestinal tumours from APC(min/+) mice was exclusively due to the increase in KLRG1(+) GATA3(+) Treg cells. Our data identify a novel axis through which epithelial cells control local Treg cell subsets, which may be activated during intestinal tumorigenesis.

PMID: 28437001 [PubMed - indexed for MEDLINE]

The Low FODMAP Diet: Many Question Marks for a Catchy Acronym.

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The Low FODMAP Diet: Many Question Marks for a Catchy Acronym.

Nutrients. 2017 Mar 16;9(3):

Authors: Catassi G, Lionetti E, Gatti S, Catassi C

Abstract
FODMAP, "Fermentable Oligo-, Di- and Mono-saccharides And Polyols", is a heterogeneous group of highly fermentable but poorly absorbed short-chain carbohydrates and polyols. Dietary FODMAPs might exacerbate intestinal symptoms by increasing small intestinal water volume, colonic gas production, and intestinal motility. In recent years the low-FODMAP diet for treatment of irritable bowel syndrome (IBS) has gained increasing popularity. In the present review we aim to summarize the physiological, clinical, and nutritional issues, suggesting caution in the prolonged use of this dietary treatment on the basis of the existing literature. The criteria for inclusion in the FODMAPs list are not fully defined. Although the low-FODMAP diet can have a positive impact on the symptoms of IBS, particularly bloating and diarrhea, the quality of the evidence is lower than optimal, due to frequent methodological flaws, particularly lack of a proper control group and/or lack of blinding. In particular, it remains to be proven whether this regimen is superior to conventional IBS diets. The drastic reduction of FODMAP intake has physiological consequences, e.g., on the intestinal microbiome and colonocyte metabolism, which are still poorly understood. A low-FODMAP diet imposes an important restriction of dietary choices due to the elimination of some staple foods, such as wheat derivatives, lactose-containing dairy products, many vegetables and pulses, and several types of fruits. For this reason, patients may be at risk of reduced intake of fiber, calcium, iron, zinc, folate, B and D vitamins, and natural antioxidants. The nutritional risk of the low-FODMAP diet may be higher in persons with limited access to the expensive, alternative dietary items included in the low-FODMAP diet.

PMID: 28300773 [PubMed - indexed for MEDLINE]

Platelet-derived growth factor receptor alpha-positive cells: a new cell type in the human ureteropelvic junction.

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Platelet-derived growth factor receptor alpha-positive cells: a new cell type in the human ureteropelvic junction.

Pediatr Res. 2017 Sep 13;:

Authors: Hunziker M, O'Donnell AM, Puri P

Abstract
BACKGROUND: Ureteropelvic junction (UPJ) obstruction is the most common cause of congenital hydronephrosis. Normal ureteral motility requires coordinated interaction between neurons, smooth muscle cells (SMCs), and interstitial Cajal-like cells (IC-LCs). Recently, a new type of interstitial cell, platelet-derived growth factor receptor α-positive (PDGFRα(+)) cells, was discovered in the gastrointestinal tract and bladder.MethodsWe used immunohistochemistry to study PDGFRα protein distribution in normal human UPJ and congenital UPJ obstruction. Western blot and real-time PCR (RT-PCR) were used to study PDGFRα protein and gene expression levels. In addition, closely associated cells and small conductance Ca(2+)-activated K(+) (SK) channels were investigated.ResultsPDGFRα(+) cells were distinct from IC-LCs and SMCs and were in close proximity to nerve fibers. PDGFRα(+) cells expressed SK3 channels, which are thought to mediate purinergic inhibitory neurotransmission in SMCs. The distribution of PDGFRα(+) cells was similar in UPJ obstruction vs.
CONTROLS: However, the expression of SK3 channels in PDGFRα(+) cells was decreased in UPJ obstruction vs.
CONTROLS: ConclusionThis study shows, for the first time, the PDGFRα(+) cell expression in the human UPJ. Altered SK3 channel expression observed in PDGFRα(+) cells in UPJ obstruction suggests that the impairment of SK3 activity across the UPJ may perturb upper urinary tract peristalsis in this urological condition.Pediatric Research advance online publication, 13 September 2017; doi:10.1038/pr.2017.193.

PMID: 28902181 [PubMed - as supplied by publisher]

Role of ghrelin in small intestinal motility following pediatric intracerebral hemorrhage in mice.

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Role of ghrelin in small intestinal motility following pediatric intracerebral hemorrhage in mice.

Mol Med Rep. 2017 Sep 12;:

Authors: Zan J, Song L, Wang J, Zou R, Hong F, Zhao J, Cheng Y, Xu M

Abstract
Small intestinal motility (SIM) disorder is a common complication following pediatric intracerebral hemorrhage (ICH), leading to a poor prognosis in patients. Previous studies have shown that ghrelin is involved in SIM in various diseases; however, the role of ghrelin in pediatric ICH‑induced SIM disorder remains to be elucidated. The present study was designed to investigate the association between ghrelin and SIM post‑ICH, and to examine the effect of exogenous ghrelin administration on SIM in vivo. An ICH model was induced in mice by autologous blood infusion. Neurobehavioral deficits were evaluated using a Rotarod test, forelimb placing test, and corner turn test. Intestinal mucosal damage was examined using hematoxylin and eosin staining. SIM was measured using charcoal meal staining. An enzyme‑linked immunosorbent assay was used to evaluate serum levels of ghrelin and nitric oxide (NO). Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were performed to determine the levels of inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) at the mRNA and protein levels. Nω‑nitro‑L‑arginine methyl ester hydrochloride (L‑NAME), L‑arginine, atropine, phentolamine and propranolol were used to manipulate the putative pathways induced by ghrelin. Neurological dysfunction was observed post‑ICH. ICH caused damage to the intestinal mucosa and delayed SIM. Serum levels of ghrelin increased between 3 h and 3 days, peaking at 12 h, and showed a significant negative correlation with SIM post‑ICH. Ghrelin administration dose‑dependently attenua-ted ICH‑induced SIM disorder. Ghrelin also decreased NO levels by downregulating the mRNA and protein expression levels of iNOS, but not those of nNOS or eNOS, post‑ICH. Consistently, the effect was enhanced by L‑NAME and weakened by L‑arginine, respectively. The protective effect of ghrelin was eradicated by atropine, but not phentolamine or propranolol. These findings suggested that ghrelin ameliorated SIM disorder by downregulating iNOS/NO via the cholinergic pathway. Therefore, ghrelin may serve as a potential biomarker and useful target in ICH‑induced SIM disorder.

PMID: 28901462 [PubMed - as supplied by publisher]

Oncogenic β-catenin and PIK3CA instruct network states and cancer phenotypes in intestinal organoids.

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Oncogenic β-catenin and PIK3CA instruct network states and cancer phenotypes in intestinal organoids.

J Cell Biol. 2017 Jun 05;216(6):1567-1577

Authors: Riemer P, Rydenfelt M, Marks M, van Eunen K, Thedieck K, Herrmann BG, Blüthgen N, Sers C, Morkel M

Abstract
Colorectal cancer is driven by cooperating oncogenic mutations. In this study, we use organotypic cultures derived from transgenic mice inducibly expressing oncogenic β-catenin and/or PIK3CA(H1047R) to follow sequential changes in cancer-related signaling networks, intestinal cell metabolism, and physiology in a three-dimensional environment mimicking tissue architecture. Activation of β-catenin alone results in the formation of highly clonogenic cells that are nonmotile and prone to undergo apoptosis. In contrast, coexpression of stabilized β-catenin and PIK3CA(H1047R) gives rise to intestinal cells that are apoptosis-resistant, proliferative, stem cell-like, and motile. Systematic inhibitor treatments of organoids followed by quantitative phenotyping and phosphoprotein analyses uncover key changes in the signaling network topology of intestinal cells after induction of stabilized β-catenin and PIK3CA(H1047R) We find that survival and motility of organoid cells are associated with 4EBP1 and AKT phosphorylation, respectively. Our work defines phenotypes, signaling network states, and vulnerabilities of transgenic intestinal organoids as a novel approach to understanding oncogene activities and guiding the development of targeted therapies.

PMID: 28442534 [PubMed - indexed for MEDLINE]

Perceived medication adherence barriers mediating effects between gastrointestinal symptoms and health-related quality of life in pediatric inflammatory bowel disease.

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Perceived medication adherence barriers mediating effects between gastrointestinal symptoms and health-related quality of life in pediatric inflammatory bowel disease.

Qual Life Res. 2017 Sep 08;:

Authors: Varni JW, Shulman RJ, Self MM, Saeed SA, Zacur GM, Patel AS, Nurko S, Neigut DA, Franciosi JP, Saps M, Denham JM, Dark CV, Bendo CB, Pohl JF, Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms Module Testing Study Consortium

Abstract
OBJECTIVES: The primary objective was to investigate the mediating effects of patient-perceived medication adherence barriers in the relationship between gastrointestinal symptoms and generic health-related quality of life (HRQOL) in adolescents with inflammatory bowel disease (IBD). The secondary objective explored patient health communication and gastrointestinal worry as additional mediators with medication adherence barriers in a serial multiple mediator model.
METHODS: The Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms, Medicines, Communication, Gastrointestinal Worry, and Generic Core Scales were completed in a 9-site study by 172 adolescents with IBD. Gastrointestinal Symptoms Scales measuring stomach pain, constipation, or diarrhea and perceived medication adherence barriers were tested for bivariate and multivariate linear associations with HRQOL. Mediational analyses were conducted to test the hypothesized mediating effects of perceived medication adherence barriers as an intervening variable between gastrointestinal symptoms and HRQOL.
RESULTS: The predictive effects of gastrointestinal symptoms on HRQOL were mediated in part by perceived medication adherence barriers. Patient health communication was a significant additional mediator. In predictive analytics models utilizing multiple regression analyses, demographic variables, gastrointestinal symptoms (stomach pain, constipation, or diarrhea), and perceived medication adherence barriers significantly accounted for 45, 38, and 29 percent of the variance in HRQOL (all Ps < 0.001), respectively, demonstrating large effect sizes.
CONCLUSIONS: Perceived medication adherence barriers explain in part the effects of gastrointestinal symptoms on HRQOL in adolescents with IBD. Patient health communication to healthcare providers and significant others further explain the mechanism in the relationship between gastrointestinal symptoms, perceived medication adherence barriers, and HRQOL.

PMID: 28887749 [PubMed - as supplied by publisher]

Hypoxia-inducible factor-2α plays a role in mediating oesophagitis in GORD.

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Hypoxia-inducible factor-2α plays a role in mediating oesophagitis in GORD.

Gut. 2017 Sep;66(9):1542-1554

Authors: Huo X, Agoston AT, Dunbar KB, Cipher DJ, Zhang X, Yu C, Cheng E, Zhang Q, Pham TH, Tambar UK, Bruick RK, Wang DH, Odze RD, Spechler SJ, Souza RF

Abstract
OBJECTIVE: In an earlier study wherein we induced acute reflux by interrupting proton pump inhibitor (PPI) therapy in patients with reflux oesophagitis (RO) healed by PPIs, we refuted the traditional concept that RO develops as an acid burn. The present study explored our alternative hypothesis that RO results from reflux-stimulated production of pro-inflammatory molecules mediated by hypoxia-inducible factors (HIFs).
DESIGN: Using oesophageal biopsies taken from patients in our earlier study at baseline and at 1 and 2 weeks off PPIs, we immunostained for HIF-1α, HIF-2α and phospho-p65, and measured pro-inflammatory molecule mRNAs. We exposed human oesophageal squamous cell lines to acidic bile salts, and evaluated effects on HIF activation, p65 function, pro-inflammatory molecule production and immune cell migration.
RESULTS: In patient biopsies, increased immunostaining for HIF-2α and phospho-p65, and increased pro-inflammatory molecule mRNA levels were seen when RO redeveloped 1 or 2 weeks after stopping PPIs. In oesophageal cells, exposure to acidic bile salts increased intracellular reactive oxygen species, which decreased prolyl hydroxylase function and stabilised HIF-2α, causing a p65-dependent increase in pro-inflammatory molecules; conditioned media from these cells increased T cell migration rates. HIF-2α inhibition by small hairpin RNA or selective small molecule antagonist blocked the increases in pro-inflammatory molecule expression and T cell migration induced by acidic bile salts.
CONCLUSIONS: In patients developing RO, increases in oesophageal HIF-2α correlate with increased pro-inflammatory molecule expression. In oesophageal epithelial cells, acidic bile salts stabilise HIF-2α, which mediates expression of pro-inflammatory molecules. HIF-2α appears to have a role in RO pathogenesis.
TRIAL REGISTRATION NUMBER: NCT01733810; Results.

PMID: 27694141 [PubMed - indexed for MEDLINE]

Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine.

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Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine.

Sci Rep. 2017 Sep 04;7(1):10322

Authors: Cao H, Liu X, An Y, Zhou G, Liu Y, Xu M, Dong W, Wang S, Yan F, Jiang K, Wang B

Abstract
Chronic constipation is a prevalent functional gastrointestinal disorder accompanied with intestinal dysbiosis. However, causal relationship between dysbiosis and constipation remains poorly understood. Serotonin transporter (SERT) is a transmembrane transport protein which re-uptakes excessive 5-hydroxytryptamine (5-HT) from effective location to terminate its physiological effects and involves in regulating gastrointestinal motility. In this study, fecal microbiota from patients with constipation and healthy controls were transplanted into the antibiotic depletion mice model. The mice which received fecal microbiota from patients with constipation presented a reducing in intestinal peristalsis and abnormal defecation parameters including the frequency of pellet expulsion, fecal weight and fecal water content. After fecal microbiota transplantation, the SERT expression in the colonic tissue was significantly upregulated, and the content of 5-HT was decreased which negatively correlated with the gastrointestinal transit time. Moverover, fecal microbiota from the mice which received fecal microbiota from patients with constipation also upregulated SERT in Caco-2 cells. Besides, this process accompanied with the decreased abundance of Clostridium, Lactobacillus, Desulfovibrio, and Methylobacterium and an increased tend of Bacteroides and Akkermansia, which also involved in the impairment of intestinal barrier after FMT. Taken together, intestinal dysbiosis may upregulate the SERT expression and contribute to the development of chronic constipation.

PMID: 28871143 [PubMed - in process]

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