Recent PubMed Articles on Gut Motility

Per-oral endoscopic myotomy (POEM): a new endoscopic treatment for achalasia.

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Per-oral endoscopic myotomy (POEM): a new endoscopic treatment for achalasia.

Rev Esp Enferm Dig. 2017 Oct;109(10):719-726

Authors: Miranda García P, Casals Seoane F, Gonzalez JM, Barthet M, Santander Vaquero C

Abstract
BACKGROUND/AIMS: Per-oral endoscopic myotomy (POEM) is a new minimally invasive technique to treat achalasia.
METHODS: We performed a review of the literature of POEM with a special focus on technical details and the results obtained with this technique in patients with achalasia and other esophageal motility disorders.
RESULTS: Thousands of POEM procedures have been performed worldwide since its introduction in 2008. The procedure is based on the creation of a mucosal entry point in the proximal esophagus to reach the cardia through a submucosal tunnel and then perform a myotomy of the muscular layers of the cardia, esophagogastric junction and distal esophagus, as performed in a Heller myotomy. The clinical remission rate ranges from 82 to 100%. Although no randomized studies exist and available data are from single-center studies, no differences have been found between laparoscopic Heller myotomy (LHM) and POEM in terms of perioperative outcomes, short-term outcomes (12 months) and long-term outcomes (up to three years). Procedure time and length of hospital stay were lower for POEM. Post-POEM reflux is a concern, and controversial data have been reported compared to LHM. The technique is safe, with no reported deaths related to the procedure and an adverse event rate comparable to surgery. Potential complications include bleeding, perforation, aspiration and insufflation-related adverse events. Thus, this is a complex technique that needs specific training even in expert hands. The indication for this procedure is widening and other motor hypercontractil esophageal disorders have been treated by POEM with promising results. POEM can be performed in complicated situations such as in pediatric patients, sigmoid achalasia or after failure of previous treatments.
CONCLUSIONS: POEM is an effective treatment for achalasia and is a promising tool for other motor esophageal disorders. It is a safe procedure but, due to its technical difficulty and possible associated complications, the procedure should be performed in referral centers by trained endoscopists.

PMID: 28724307 [PubMed - indexed for MEDLINE]

Saturated long-chain fatty acid-producing bacteria contribute to enhanced colonic motility in rats.

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Saturated long-chain fatty acid-producing bacteria contribute to enhanced colonic motility in rats.

Microbiome. 2018 Jun 14;6(1):107

Authors: Zhao L, Huang Y, Lu L, Yang W, Huang T, Lin Z, Lin C, Kwan H, Wong HLX, Chen Y, Sun S, Xie X, Fang X, Yang H, Wang J, Zhu L, Bian Z

Abstract
BACKGROUND: The gut microbiota is closely associated with gastrointestinal (GI) motility disorder, but the mechanism(s) by which bacteria interact with and affect host GI motility remains unclear. In this study, through using metabolomic and metagenomic analyses, an animal model of neonatal maternal separation (NMS) characterized by accelerated colonic motility and gut dysbiosis was used to investigate the mechanism underlying microbiota-driven motility dysfunction.
RESULTS: An excess of intracolonic saturated long-chain fatty acids (SLCFAs) was associated with enhanced bowel motility in NMS rats. Heptadecanoic acid (C17:0) and stearic acid (C18:0), as the most abundant odd- and even-numbered carbon SLCFAs in the colon lumen, can promote rat colonic muscle contraction and increase stool frequency. Increase of SLCFAs was positively correlated with elevated abundances of Prevotella, Lactobacillus, and Alistipes. Functional annotation found that the level of bacterial LCFA biosynthesis was highly enriched in NMS group. Essential synthetic genes Fabs were largely identified from the genera Prevotella, Lactobacillus, and Alistipes. Pseudo germ-free (GF) rats receiving fecal microbiota from NMS donors exhibited increased defecation frequency and upregulated bacterial production of intracolonic SLCFAs. Modulation of gut dysbiosis by neomycin effectively attenuated GI motility and reduced bacterial SLCFA generation in the colon lumen of NMS rats.
CONCLUSIONS: These findings reveal a previously unknown relationship between gut bacteria, intracolonic SLCFAs, and host GI motility, suggesting the importance of SLCFA-producing bacteria in GI motility disorders. Further exploration of this relationship could lead to a precise medication targeting the gut microbiota for treating GI motility disorders.

PMID: 29903041 [PubMed - in process]

Pharmacokinetic drug evaluation of rifaximin for treatment of diarrhea-predominant irritable bowel syndrome.

Pharmacokinetic drug evaluation of rifaximin for treatment of diarrhea-predominant irritable bowel syndrome.

Expert Opin Drug Metab Toxicol. 2018 Jun 13;:

Authors: Bruzzese E, Pesce M, Sarnelli G, Guarino A

Abstract
INTRODUCTION: Rifaximin is a poorly absorbable antibiotic with a broad-spectrum activity against both Gram-negative and -positive bacteria. It is active in the small intestine due to its high bile solubility, whereas in the aqueous environment of the colon, it shows limited efficacy against highly susceptible bacteria. These unique pharmacokinetic properties limit its systemic effects and can correct gut microflora imbalances. Thus, rifaximin has become a major therapeutic agent in several gastrointestinal diseases in which an imbalance in gut microflora may play a role, including diarrhea predominant irritable bowel syndrome (IBS-D).
AREA COVERED: This is an up-to-date review focusing on the efficacy of rifaximin in the treatment of IBS-D in both adult and pediatric populations. We will review the pharmacokinetic properties of rifaximin, including its absorption in health and disease, mechanisms of action, and interactions with other drugs.
EXPERT OPINION: Given its safety profile and its negligible absorption, rifaximin is a suitable treatment forIBS-D, in both adults and children. The possibility of modulating gut microbiota composition without side effects has made this drug an appealing therapeutic agent in highly prevalent gastrointestinal diseases. However, to date, monitoring for the development of resistant bacterial strains during long-term rifaximin use is still lacking.

PMID: 29897844 [PubMed - as supplied by publisher]

Down-regulation of circ-PRKCI inhibits cell migration and proliferation in Hirschsprung disease by suppressing the expression of miR-1324 target PLCB1.

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Down-regulation of circ-PRKCI inhibits cell migration and proliferation in Hirschsprung disease by suppressing the expression of miR-1324 target PLCB1.

Cell Cycle. 2018 Jun 12;:

Authors: Zhou L, Li Y, Jiang W, Zhang H, Wen Z, Su Y, Wu F, Zhi Z, Shen Q, Li H, Xu X, Tang W

Abstract
Circular RNAs (circRNAs) are a novel class of noncoding RNAs (ncRNAs), which have been shown to participate in intracellular RNA regulatory networks and play vital roles in many pathological processes. Recently, circular RNA_PRKCI (circ-PRKCI) has been reported to regulate cell proliferation, migration and invasion in several human cancers. Hirschsprung disease (HSCR) is a well-known congenital gut motility disorder which roots in the aberrance of cranial-caudal neural crest cell migration. In this study, we investigated whether circ-PRKCI may affect cell migration and proliferation in HSCR. Quantitative reverse transcription PCR (qRT-PCR) was performed to detect the expression of circ-PRKCI in 48 HSCR aganglionic tissues and 48 normal bowel tissues. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay verified the direct interaction between miR-1324 and PLCB1 or circ-PRKCI. Cell counting Kit-8 (CCK-8) and Ethynyldeoxyuridine (EdU) assays were employed to appraise the effects of miR-1324 or circ-PRKCI on cell proliferative potential, while transwell was performed to detect the migration in vitro. We found that circ-PRKCI was significantly down-regulated in HSCR aganglionic tissues. Morever, knockdown of circ-PRKCI suppressed cell proliferation and migration in vitro. Mechanistically, we confirmed that circ-PRKCI functioned as a molecular sponge for miR-1324 to upregulate the expression of PLCB1. In conclusion, our present study revealed the important role of circ-PRKCI-miR-1324-PLCB1 regulatory network in HSCR, providing a novel insight for the pathogenesis of HSCR.

PMID: 29895226 [PubMed - as supplied by publisher]

Analgesic effect of ADX71441, a positive allosteric modulator (PAM) of GABAB receptor in a rat model of bladder pain.

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Analgesic effect of ADX71441, a positive allosteric modulator (PAM) of GABAB receptor in a rat model of bladder pain.

Neuropharmacology. 2017 Nov;126:1-11

Authors: Kannampalli P, Poli SM, Boléa C, Sengupta JN

Abstract
Therapeutic use of GABAB receptor agonists for conditions like chronic abdominal pain, overactive bladder (OAB) and gastroesophageal reflux disease (GERD) is severely affected by poor blood-brain barrier permeability and potential side effects. ADX71441 is a novel positive allosteric modulator (PAM) of the GABAB receptor that has shown encouraging results in pre-clinical models of anxiety, pain, OAB and alcohol addiction. The present study investigates the analgesic effect of ADX71441 to noxious stimulation of the urinary bladder and colon in rats. In female Sprague-Dawley rats, systemic (i.p), but not intrathecal (i.t), administration of ADX71441 produced a dose-dependent decrease in viscero-motor response (VMR) to graded urinary bladder distension (UBD) and colorectal distension (CRD). Additionally, intra-cerebroventricular (i.c.v.) administration of ADX71441 significantly decreased the VMRs to noxious UBD. In electrophysiology experiments, the drug did not attenuate the responses of UBD-sensitive pelvic nerve afferent (PNA) fibers to UBD. In contrast, ADX71441 significantly decreased the responses of UBD-responsive lumbosacral (LS) spinal neurons in spinal intact rats. However, ADX71441 did not attenuate these LS neurons in cervical (C1-C2) spinal transected rats. During cystometrogram (CMG) recordings, ADX71441 (i.p.) significantly decreased the VMR to slow infusion without affecting the number of voiding contraction. These results indicate that ADX71441 modulate bladder nociception via its effect at the supra-spinal sites without affecting the normal bladder motility and micturition reflex in naïve adult rats.

PMID: 28823612 [PubMed - indexed for MEDLINE]

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 Nov;33(11):1215-1219

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 - indexed for MEDLINE]

Intra- and interrater reliability of the Chicago Classification of achalasia subtypes in pediatric high-resolution esophageal manometry (HRM) recordings.

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Intra- and interrater reliability of the Chicago Classification of achalasia subtypes in pediatric high-resolution esophageal manometry (HRM) recordings.

Neurogastroenterol Motil. 2017 Nov;29(11):

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

Abstract
BACKGROUND: Subtyping achalasia by high-resolution manometry (HRM) is clinically relevant as response to therapy and prognosis have shown to vary accordingly. The aim of this study was to assess inter- and intrarater reliability of diagnosing achalasia and achalasia subtyping in children using the Chicago Classification (CC) V3.0.
METHODS: Six observers analyzed 40 pediatric HRM recordings (22 achalasia and 18 non-achalasia) twice by using dedicated analysis software (ManoView 3.0, Given Imaging, Los Angeles, CA, USA). Integrated relaxation pressure (IRP4s), distal contractile integral (DCI), intrabolus pressurization pattern (IBP), and distal latency (DL) were extracted and analyzed hierarchically. Cohen's κ (2 raters) and Fleiss' κ (>2 raters) and the intraclass correlation coefficient (ICC) were used for categorical and ordinal data, respectively.
RESULTS: Based on the results of dedicated analysis software only, intra- and interrater reliability was excellent and moderate (κ=0.89 and κ=0.52, respectively) for differentiating achalasia from non-achalasia. For subtyping achalasia, reliability decreased to substantial and fair (κ=0.72 and κ=0.28, respectively). When observers were allowed to change the software-driven diagnosis according to their own interpretation of the manometric patterns, intra- and interrater reliability increased for diagnosing achalasia (κ=0.98 and κ=0.92, respectively) and for subtyping achalasia (κ=0.79 and κ=0.58, respectively).
CONCLUSIONS: Intra- and interrater agreement for diagnosing achalasia when using HRM and the CC was very good to excellent when results of automated analysis software were interpreted by experienced observers. More variability was seen when relying solely on the software-driven diagnosis and for subtyping achalasia. Therefore, diagnosing and subtyping achalasia should be performed in pediatric motility centers with significant expertise.

PMID: 28585270 [PubMed - indexed for MEDLINE]

MicroRNA-7-5p regulates the proliferation and migration of intestinal epithelial cells by targeting trefoil factor 3 via inhibiting the phosphoinositide 3-kinase/Akt signalling pathway.

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MicroRNA-7-5p regulates the proliferation and migration of intestinal epithelial cells by targeting trefoil factor 3 via inhibiting the phosphoinositide 3-kinase/Akt signalling pathway.

Int J Mol Med. 2017 Nov;40(5):1435-1443

Authors: Guo J, Xu L, Teng X, Sun M

Abstract
Trefoil factor 3 (TFF3) reconstructs the epithelial barrier by stimulating epithelial cell migration and proliferation, and significantly contributes to intestinal mucosal damage and healing. In a previous study, TFF3 was identified as a novel target of microRNA-7-5p (miR-7-5p). The aim of the present study was to investigate the roles and mechanisms of miR-7-5p in the proliferation and migration of intestinal epithelial cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression level of miR-7-5p in the experimental groups. In addition, western blot analysis was performed to examine the expression levels of TFF3, phosphoinositide 3-kinase (PI3K), Akt and phosphorylated (p)-AKT when miR-7-5p or TFF3 was overexpressed, and the effects of miR-7-5p and TFF3 on LS174T cell proliferation and migration were simultaneously investigated. miR-7-5p was demonstrated to decrease the expression level of TFF3, and inhibit LS174T cell proliferation and migration, which was accompanied by decreased expression levels of PI3K and p-Akt. miR-7-5p was decreased following combined treatment with the TFF3 plasmid and miR‑7-5p mimics, compared with treatment with miR-7-5p mimics alone, which was accompanied by increased expression levels of TFF3, PI3K and p-Akt, and enhanced LS174T cell proliferation and migration effects. The expression levels of miR-7-5p in the miRNA negative control (NC) + LY294002 group, the miR‑7-5p mimic + LY294002 group, and the miR-7-5p mimic + TFF3 plasmid + LY294002 group were higher than those in the NC group, the miR-7-5p mimic group and the miR-7-5p mimic + TFF3 plasmid group, respectively. Accordingly, the expression level of TFF3 was downregulated and the proliferation and migration ability of the cells was downregulated. The present study demonstrates that overexpressed miR-7-5p may inhibit the proliferation and migration of LS174T cells by targeting the expression of TFF3 via inhibiting the PI3K/Akt signalling pathway. The PI3K/Akt signalling pathway may exert a feedback regulation effect on miR-7-5p, inhibiting the activity of this signalling pathway, which increases the miR-7-5p expression levels and further enhances the effects of miR-7-5p on cell proliferation and migration.

PMID: 28901375 [PubMed - indexed for MEDLINE]

Efficacy of peroral endoscopic myotomy compared with other invasive treatment options for the different esophageal motor disorders.

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Efficacy of peroral endoscopic myotomy compared with other invasive treatment options for the different esophageal motor disorders.

Rev Esp Enferm Dig. 2017 08;109(8):578-586

Authors: Estremera-Arévalo F, Albéniz E, Rullán M, Areste I, Iglesias R, Vila JJ

Abstract
INTRODUCTION: Peroral endoscopic myotomy (POEM) has been performed since 2008 on more than 5,000 patients. It has proven to be highly effective in the treatment of achalasia and has shown promising outcomes for other esophageal motility spastic disorders.
METHODS: A literature review of the efficacy of POEM compared to the previous invasive treatments for different esophageal motility disorders was performed. The application in the pediatric and elderly populations and its role as a rescue therapy after other procedures are also outlined.
RESULTS: Short-term outcomes are similar to laparoscopic Heller myotomy (LHM) and pneumatic endoscopic dilation (PD) (clinical success > 90%) for achalasia subtypes I and II. Mid-term outcomes are comparable to LHM and overcome the results obtained after PD (> 90% vs ~50%). With regard to type III achalasia, POEM efficacy is 98% compared to 80.8% for LHM and the PD success remains at 40%. With regard to spastic esophageal disorders (SED), POEM has an effectiveness of 88% and 70% for distal esophageal spasm (DES) and jackhammer esophagus (JE) respectively. A response of 95% in patients with sigmoid esophagus has been reported. POEM has been performed in pediatric and elderly populations and has obtained a higher efficacy than PD in pediatric series (100% vs 33%) without greater adverse events. Previous treatments do not seem to hinder POEM results with excellent response rates, including 97% in post LHM and 100% in a re-POEM series. Final considerations: POEM has shown excellent short and mid-term results for all subtypes of achalasia but long-term results are not yet available. The promising results in SED may make POEM the first-line treatment for SED. A high-safety profile and efficacy have been shown in elderly and pediatric populations. Previous treatments do not seem to diminish the success rate of POEM. Core tip: POEM has emerged as an efficient treatment option for all subtypes of achalasia and other scenarios (including previous treatments and elderly and pediatric populations). Short and mid-term results are comparable to LHM and are better than PD data. The clinical response rate of DES and JE may make POEM the first-line treatment for SED.

PMID: 28617027 [PubMed - indexed for MEDLINE]

Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids.

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Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids.

Proc Natl Acad Sci U S A. 2017 03 21;114(12):E2357-E2364

Authors: Fumagalli A, Drost J, Suijkerbuijk SJ, van Boxtel R, de Ligt J, Offerhaus GJ, Begthel H, Beerling E, Tan EH, Sansom OJ, Cuppen E, Clevers H, van Rheenen J

Abstract
In the adenoma-carcinoma sequence, it is proposed that intestinal polyps evolve through a set of defined mutations toward metastatic colorectal cancer (CRC). Here, we dissect this adenoma-carcinoma sequence in vivo by using an orthotopic organoid transplantation model of human colon organoids engineered to harbor different CRC mutation combinations. We demonstrate that sequential accumulation of oncogenic mutations in Wnt, EGFR, P53, and TGF-β signaling pathways facilitates efficient tumor growth, migration, and metastatic colonization. We show that reconstitution of specific niche signals can restore metastatic growth potential of tumor cells lacking one of the oncogenic mutations. Our findings imply that the ability to metastasize-i.e., to colonize distant sites-is the direct consequence of the loss of dependency on specific niche signals.

PMID: 28270604 [PubMed - indexed for MEDLINE]

Variants in ACTG2 underlie a substantial number of Australasian patients with primary chronic intestinal pseudo-obstruction.

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Variants in ACTG2 underlie a substantial number of Australasian patients with primary chronic intestinal pseudo-obstruction.

Neurogastroenterol Motil. 2018 May 21;:e13371

Authors: Ravenscroft G, Pannell S, O'Grady G, Ong R, Ee HC, Faiz F, Marns L, Goel H, Kumarasinghe P, Sollis E, Sivadorai P, Wilson M, Magoffin A, Nightingale S, Freckmann ML, Kirk EP, Sachdev R, Lemberg DA, Delatycki MB, Kamm MA, Basnayake C, Lamont PJ, Amor DJ, Jones K, Schilperoort J, Davis MR, Laing NG

Abstract
BACKGROUND: Primary chronic intestinal pseudo-obstruction (CIPO) is a rare, potentially life-threatening disorder characterized by severely impaired gastrointestinal motility. The objective of this study was to examine the contribution of ACTG2, LMOD1, MYH11, and MYLK mutations in an Australasian cohort of patients with a diagnosis of primary CIPO associated with visceral myopathy.
METHODS: Pediatric and adult patients with primary CIPO and suspected visceral myopathy were recruited from across Australia and New Zealand. Sanger sequencing of the genes encoding enteric gamma-actin (ACTG2) and smooth muscle leiomodin (LMOD1) was performed on DNA from patients, and their relatives, where available. MYH11 and MYLK were screened by next-generation sequencing.
KEY RESULTS: We identified heterozygous missense variants in ACTG2 in 7 of 17 families (~41%) diagnosed with CIPO and its associated conditions. We also identified a previously unpublished missense mutation (c.443C>T, p.Arg148Leu) in one family. One case presented with megacystis-microcolon-intestinal hypoperistalsis syndrome in utero with subsequent termination of pregnancy at 28 weeks' gestation. All of the substitutions identified occurred at arginine residues. No likely pathogenic variants in LMOD1, MYH11, or MYLK were identified within our cohort.
CONCLUSIONS AND INFERENCES: ACTG2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG2 sequencing should be considered in cases presenting with hypoperistalsis phenotypes with suspected visceral myopathy. It is likely that variants in other genes encoding enteric smooth muscle contractile proteins will contribute further to the genetic heterogeneity of hypoperistalsis phenotypes.

PMID: 29781137 [PubMed - as supplied by publisher]

Collagen 18 and agrin are secreted by neural crest cells to remodel their microenvironment and regulate their migration during enteric nervous system development.

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Collagen 18 and agrin are secreted by neural crest cells to remodel their microenvironment and regulate their migration during enteric nervous system development.

Development. 2018 05 08;145(9):

Authors: Nagy N, Barad C, Hotta R, Bhave S, Arciero E, Dora D, Goldstein AM

Abstract
The enteric nervous system (ENS) arises from neural crest cells that migrate, proliferate, and differentiate into enteric neurons and glia within the intestinal wall. Many extracellular matrix (ECM) components are present in the embryonic gut, but their role in regulating ENS development is largely unknown. Here, we identify heparan sulfate proteoglycan proteins, including collagen XVIII (Col18) and agrin, as important regulators of enteric neural crest-derived cell (ENCDC) development. In developing avian hindgut, Col18 is expressed at the ENCDC wavefront, while agrin expression occurs later. Both proteins are normally present around enteric ganglia, but are absent in aganglionic gut. Using chick-mouse intestinal chimeras and enteric neurospheres, we show that vagal- and sacral-derived ENCDCs from both species secrete Col18 and agrin. Whereas glia express Col18 and agrin, enteric neurons only express the latter. Functional studies demonstrate that Col18 is permissive whereas agrin is strongly inhibitory to ENCDC migration, consistent with the timing of their expression during ENS development. We conclude that ENCDCs govern their own migration by actively remodeling their microenvironment through secretion of ECM proteins.

PMID: 29678817 [PubMed - indexed for MEDLINE]

LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR.

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LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR.

Int J Med Sci. 2017;14(10):1022-1030

Authors: Chen G, Peng L, Zhu Z, Du C, Shen Z, Zang R, Su Y, Xia Y, Tang W

Abstract
Background: Long noncoding RNAs (lncRNAs) have recently emerged as important regulators in a broad spectrum of cellular processes including development and disease. Despite the known engagement of the AFAP1-AS in several human diseases, its biological function in Hirschsprung disease (HSCR) remains elusive. Methods: We used qRT-PCR to detect the relative expression of AFAP1-AS in 64 HSCR bowel tissues and matched normal intestinal tissues. The effects of AFAP1-AS on cell proliferation, migration, cell cycle, apoptosis and cytoskeletal organization were evaluated using CCK-8, transwell assay, flow cytometer analysis and immunofluorescence, in 293T and SH-SY5Y cell lines, respectively. Moreover, the competing endogenous RNA (ceRNA) activity of AFAP1-AS on miR-181a was investigated via luciferase reporter assay and immunoblot analysis. Results: Aberrant inhibition of AFAP1-AS was observed in HSCR tissues. Knockdown of AFAP1-AS in 293T and SH-SY5Y cells suppressed cell proliferation, migration, and induced the loss of cell stress filament integrity, possibly due to AFAP1-AS sequestering miR-181a in HSCR cells. Furthermore, AFAP1-AS could down-regulate RAP1B via its competing endogenous RNA (ceRNA) activity on miR-181a. Conclusions: These findings suggest that aberrant expression of lncRNA AFAP1-AS, a ceRNA of miR-181a, may involve in the onset and progression of HSCR by augmenting the miR-181a target gene, RAP1B.

PMID: 28924375 [PubMed - indexed for MEDLINE]

Probiotic Supplementation in Preterm: Feeding Intolerance and Hospital Cost.

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Probiotic Supplementation in Preterm: Feeding Intolerance and Hospital Cost.

Nutrients. 2017 Aug 31;9(9):

Authors: Indrio F, Riezzo G, Tafuri S, Ficarella M, Carlucci B, Bisceglia M, Polimeno L, Francavilla R

Abstract
We hypothesized that giving the probiotic strain Lactobacillus reuteri (L. reuteri) DSM 17938 to preterm, formula-fed infants would prevent an early traumatic intestinal inflammatory insult modulating intestinal cytokine profile and reducing the onset of feeding intolerance. Newborn were randomly allocated during the first 48 h of life to receive either daily probiotic (10⁸ colony forming units (CFUs) of L. reuteri DSM 17938) or placebo for one month. All the newborns underwent to gastric ultrasound for the measurement of gastric emptying time. Fecal samples were collected for the evaluation of fecal cytokines. Clinical data on feeding intolerance and weight gain were collected. The costs of hospital stays were calculated. The results showed that the newborns receiving L. reuteri DSM 17938 had a significant decrease in the number of days needed to reach full enteral feeding (p < 0.01), days of hospital stay (p < 0.01), and days of antibiotic treatment (p < 0.01). Statistically significant differences were observed in pattern of fecal cytokine profiles. The anti-inflammatory cytokine interleukin (IL)-10, was increased in newborns receiving L. reuteri DSM 17938. Pro-inflammatory cytokines: IL-17, IL-8, and tumor necrosis factor (TNF)-alpha levels were increased in newborns given placebo. Differences in the gastric emptying and fasting antral area (FAA) were also observed. Our study demonstrates an effective role for L. reuteri DSM 17938 supplementation in preventing feeding intolerance and improving gut motor and immune function development in bottle-fed stable preterm newborns. Another benefit from the use of probiotics is the reducing cost for the Health Care service.

PMID: 28858247 [PubMed - indexed for MEDLINE]

Screening Endoscopy Contributes to Relevant Modifications of Therapeutic Regimen in Children with Intestinal Failure.

Screening Endoscopy Contributes to Relevant Modifications of Therapeutic Regimen in Children with Intestinal Failure.

J Pediatr Gastroenterol Nutr. 2018 May 09;:

Authors: Busch A, Sturm E

Abstract
OBJECTIVE: The role of endoscopy in the diagnostic work-up of children with intestinal failure (IF) is not well defined. It is unclear whether endoscopies should be performed as a screening procedure or only upon manifestation of symptoms. The aim of this study is to evaluate, whether performing screening endoscopy contributes to clinical management in children with IF.
METHODS: Comparative retrospective case-series study in children with IF (mean age 70,4 months ± 58,4 months) presenting for diagnostic work-up in a single intestinal rehabilitation center. Endoscopies were performed either as a screening procedure (Group 1, n = 45) or as indicated by symptoms of gastrointestinal dysfunction (Group 2, n = 11).
RESULTS: A total of 92 endoscopies (56 esophagogastroduodenoscopies; 12 enteroscopies; 24 colonoscopies) were performed in 56 children. IF etiology included short bowel syndrome (n = 37), motility disorder (n = 16) and mucosal enteropathy (n = 3). Comparing Group 1 with Group 2 abnormal endoscopic findings were detected in 66,7 % vs. 81,8 %. Findings led to adaptation of therapeutic regimes in 64,7 % vs. 85,7 %. We detected a higher rate of erosive and ulcerative gastritis and duodenitis, enteritis and colitis in Group 1 compared to Group 2.
CONCLUSION: Endoscopy in children with IF frequently reveals abnormal findings, leading to recommendations for treatment adaptation in the majority of cases, irrespective of whether endoscopy has been performed as a screening procedure or as indicated by symptoms. Using endoscopy as a screening tool may improve both, the detection of gastrointestinal pathology and the clinical management of children with IF.

PMID: 29746341 [PubMed - as supplied by publisher]

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice.

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Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice.

Proc Natl Acad Sci U S A. 2017 03 28;114(13):E2739-E2747

Authors: Halim D, Wilson MP, Oliver D, Brosens E, Verheij JB, Han Y, Nanda V, Lyu Q, Doukas M, Stoop H, Brouwer RW, van IJcken WF, Slivano OJ, Burns AJ, Christie CK, de Mesy Bentley KL, Brooks AS, Tibboel D, Xu S, Jin ZG, Djuwantono T, Yan W, Alves MM, Hofstra RM, Miano JM

Abstract
Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon in Leiomodin1 (LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing of Lmod1 to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal-contractile coupling.

PMID: 28292896 [PubMed - indexed for MEDLINE]

Spherical nucleic acid targeting microRNA-99b enhances intestinal MFG-E8 gene expression and restores enterocyte migration in lipopolysaccharide-induced septic mice.

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Spherical nucleic acid targeting microRNA-99b enhances intestinal MFG-E8 gene expression and restores enterocyte migration in lipopolysaccharide-induced septic mice.

Sci Rep. 2016 08 19;6:31687

Authors: Wang X, Hao L, Bu HF, Scott AW, Tian K, Liu F, De Plaen IG, Liu Y, Mirkin CA, Tan XD

Abstract
Milk fat globule-EGF factor 8 (MFG-E8) maintains the intestinal homeostasis by enhancing enterocyte migration and attenuating inflammation. We previously reported that sepsis is associated with down-regulation of intestinal MFG-E8 and impairment of enterocyte migration. Here, we showed that impairment of intestinal epithelial cell migration occurred in lipopolysaccharide (LPS)-induced septic mice. Treatment of RAW264.7 cells (a murine macrophage-like cell line) with LPS increased expression of miR-99b, a microRNA that is predicted to target mouse MFG-E8 3'UTR. Using a luciferase assay, we showed that miR-99b mimic suppressed the activity of a reporter containing MFG-E8 3'UTR. This suggests the role of miR-99b in inhibition of MFG-E8 gene expression. In addition, we developed an anti-miR99b spherical nucleic acid nanoparticle conjugate (SNA-NC(anti-miR99b)). Treatment of both naïve and LPS-challenged cells with SNA-NC(anti-miR99b) enhanced MFG-E8 expression in the cells. Administration of SNA-NC(anti-miR99b) rescued intestinal MFG-E8 expression in LPS-induced septic mice and attenuated LPS inhibitory effects on intestinal epithelial cell migration along the crypt-villus axis. Collectively, our study suggests that LPS represses MFG-E8 expression and disrupts enterocyte migration via a miR-99b dependent mechanism. Furthermore, this work shows that SNA-NC(anti-miR99b) is a novel nanoparticle-conjugate capable of rescuing MFG-E8 gene expression and maintaining intestinal epithelial homeostasis in sepsis.

PMID: 27538453 [PubMed - indexed for MEDLINE]

Adult Intestinal Transplantation.

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Adult Intestinal Transplantation.

Gastroenterol Clin North Am. 2018 Jun;47(2):341-354

Authors: Matsumoto CS, Subramanian S, Fishbein TM

Abstract
Adult intestinal transplantation differs significantly from pediatric intestinal transplantation. While indications have remained largely consistent since 2000, indications for adults have expanded over the last two decades to include motility disorders and desmoid tumors. Graft type in adult recipients depends on the distinct anatomic characteristics of the adult recipient. Colonic inclusion, while initially speculated to portend unfavorable outcomes due to complex host-bacterial interactions has increased over the past two decades with superior graft survival and improved patient quality of life. Overall, outcomes have steadily improved. For adult intestinal transplant candidates, intestinal transplantation remains a mainstay therapy for complicated intestinal failure and is a promising option for other life threatening and debilitating conditions.

PMID: 29735028 [PubMed - in process]

Bioengineered intestinal muscularis complexes with long-term spontaneous and periodic contractions.

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Bioengineered intestinal muscularis complexes with long-term spontaneous and periodic contractions.

PLoS One. 2018;13(5):e0195315

Authors: Wang Q, Wang K, Solorzano-Vargas RS, Lin PY, Walthers CM, Thomas AL, Martín MG, Dunn JCY

Abstract
Although critical for studies of gut motility and intestinal regeneration, the in vitro culture of intestinal muscularis with peristaltic function remains a significant challenge. Periodic contractions of intestinal muscularis result from the coordinated activity of smooth muscle cells (SMC), the enteric nervous system (ENS), and interstitial cells of Cajal (ICC). Reproducing this activity requires the preservation of all these cells in one system. Here we report the first serum-free culture methodology that consistently maintains spontaneous and periodic contractions of murine and human intestinal muscularis cells for months. In this system, SMC expressed the mature marker myosin heavy chain, and multipolar/dipolar ICC, uniaxonal/multipolar neurons and glial cells were present. Furthermore, drugs affecting neural signals, ICC or SMC altered the contractions. Combining this method with scaffolds, contracting cell sheets were formed with organized architecture. With the addition of intestinal epithelial cells, this platform enabled up to 11 types of cells from mucosa, muscularis and serosa to coexist and epithelial cells were stretched by the contracting muscularis cells. The method constitutes a powerful tool for mechanistic studies of gut motility disorders and the functional regeneration of the engineered intestine.

PMID: 29718926 [PubMed - in process]

Pediatric Intestinal Failure: The Key Outcomes for the First 100 Patients Treated in a National Tertiary Referral Center During 1984-2017.

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Pediatric Intestinal Failure: The Key Outcomes for the First 100 Patients Treated in a National Tertiary Referral Center During 1984-2017.

JPEN J Parenter Enteral Nutr. 2018 Apr 27;:

Authors: Merras-Salmio L, Mutanen A, Ylinen E, Rintala R, Koivusalo A, Pakarinen MP

Abstract
BACKGROUND: Pediatric-onset intestinal failure (IF) remains a severe illness with life-threatening consequences. In this study, we analyzed a single center's outcomes of IF over 3 decades.
METHODS: All children with IF who required parenteral nutrition (PN) >2 months or small-intestinal resection ≥50% managed since 1984 were included for retrospective outcome analyses.
RESULTS: In total, 100 patients with median PN duration of 1.2 (interquartile range, 0.4-3.5) years were identified. Causes of IF were short bowel syndrome (SBS; n = 78), primary intestinal motility disorders (n = 14), and congenital intestinopathies (n = 8). Patients with SBS had median 40 (25-60) cm of small bowel remaining. Overall, Kaplan-Meier 5- and 10-year weaning-off estimates were 67% (95% CI, 57-77) and 73% (95% CI, 63-84), respectively. Weaning off PN was predicted by remaining bowel anatomy, multidisciplinary treatment era, and absence of immune deficiency. Catheter-related bloodstream infections decreased from 1.4 to 0.6/1000 PN days (P = .0003) with systematic use of taurolidine locks. None had progressive liver disease. Thirty-one percent of patients with SBS underwent autologous intestinal reconstructive surgery. Five patients received and 2 were listed for isolated intestinal transplantation. Eight patients died, and overall 15-year survival rate estimate was 91% (95% CI, 85-98).
CONCLUSIONS: Despite reassuring rates of survival and weaning off PN, long-term PN failed in 14% of patients solely because of catheter complications in the recent era. Achievement of enteral autonomy in those with the shortest remaining small bowel and functional cause of IF remains challenging.

PMID: 29701871 [PubMed - as supplied by publisher]

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