Migrating Motor Complex Research Articles

The influence of gastric motility on the intraluminal behavior of fosamprenavir

In fasting conditions, the gastrointestinal system contracts according to the interdigestive migrating motor complex (MMC), in which phases of quiescence (MMC phase I) alternate with phases of medium (MMC phase II) to very strong (MMC phase III) contractions. The time of drug intake relative to this cyclic motility pattern may cause variations in formulation behavior. To explore this hypothesis, a cross-over study was performed in healthy volunteers with an immediate release tablet of fosamprenavir (Telzir) which was administered in either MMC phase I or MMC phase II, as determined by high-resolution manometry. In the intestinal tract, fosamprenavir is rapidly hydrolyzed to the active compound amprenavir by alkaline phosphatases. Drug concentrations of both prodrug and drug were determined in the stomach and duodenum and linked to simultaneously assessed systemic concentrations. In 5 out of 6 healthy volunteers, the gastric release of fosamprenavir and the systemic uptake of amprenavir were affected by the MMC phase in which the tablet was administered. The intragastric disintegration of the tablet was faster and less variable after administration in MMC phase II, resulting in faster and less variable uptake of amprenavir in the systemic circulation. Mean plasma tmax values were 157 (±72.0) and 73.3 (±27.3) min after administration in MMC phase I and MMC phase II, respectively. The study clearly identified the time of oral drug intake relative to the interdigestive motility pattern as a possible source of variation in gastrointestinal drug behavior and absorption.

Colonic Dysmotility in Murine Partial Colonic Obstruction Due to Functional Changes in Interstitial Cells.

Background/AimsInterstitial cells play important roles in gastrointestinal (GI) neuro-smooth muscle transmission. The underlying mechanisms of colonic dysmotility have not been well illustrated. We established a partial colon obstruction (PCO) mouse model to investigate the changes of interstitial cells and the correlation with colonic motility.MethodsWestern blot technique was employed to observe the protein expressions of Kit, platelet-derived growth factor receptor-α (Pdgfra), Ca2+-activated Cl− (Ano1) channels, and small conductance Ca2+- activated K+ (SK) channels. Colonic migrating motor complexes (CMMCs) and isometric force measurements were employed in control mice and PCO mice.ResultsPCO mice showed distended abdomen and feces excretion was significantly reduced. Anatomically, the colon above the obstructive silicone ring was obviously dilated. Kit and Ano1 proteins in the colonic smooth muscle layer of the PCO colons were significantly decreased, while the expression of Pdgfra and SK3 proteins were significantly increased. The effects of a nitric oxide synthase inhibitor (L-NAME) and an Ano1 channel inhibitor (NPPB) on CMMC and colonic spontaneous contractions were decreased in the proximal and distal colons of PCO mice. The SK agonist, CyPPA and antagonist, apamin in PCO mice showed more effect to the CMMCs and colonic smooth muscle contractions.ConclusionsColonic transit disorder may be due to the downregulation of the Kit and Ano1 channels and the upregulation of SK3 channels in platelet-derived growth factor receptor-α positive (PDGFRα+) cells. The imbalance between interstitial cells of Cajal-Ano1 and PDGFRα-SK3 distribution might be a potential reason for the colonic dysmotility.

Simulated migrating motor complex and its impact on the release properties of hydrophilic matrix systems

Following ingestion, the dosage forms are exposed to high mechanical stresses, mainly due to the movement of gastric musculature and passage through the sphincters. The generated mechanical forces can have a profound impact on the release properties of the mechanically sensitive formulations, which may result in greater in vivo variability. The aim of the study was to prepare a new programme sequence for our bio-relevant in vitro dissolution model, the advanced gastric simulator (AGS), which would closely resemble the four phases of the migrating motor complex (MMC) and to evaluate the influence of the simulated mechanical stress on the drug release rate and the gel layer properties of the model hydrophilic matrix system. For this purpose, two kinds of HPMC matrix tablets were used, which have previously been tested in vivo. In vivo pressure measurements in human fasted stomach were gathered from literature and compared to the measurements obtained with the wireless motility capsule (WMC) in AGS. Dissolution studies conducted in AGS were compared to the experiments performed in USP2. Properties of the gel layer were evaluated with texture analysis and matrix erosion determination. Our in vitro measured pressure profiles of simulated MMC were found to be within the same range as those observed in vivo. The simulated MMC was shown to significantly affect the drug release kinetics from tested hydrophilic matrices. Compared to USP2, the AGS was shown to have a higher discriminatory power in distinguishing the differences in behaviour of the tested formulations, in accordance with in vivo data.

1748 Blood Bezoar: A Rare Complication of Achalasia

INTRODUCTION: Bezoars are retained concretions of indigestible foreign material that accumulate and conglomerate in any part of the GI tract but rarely in the esophagus. Only a few patients with achalasia have been reported to develop esophageal bezoars. CASE DESCRIPTION/METHODS: 76-year-old-man with history of atrial fibrillation on anticoagulation and achalasia s/p Heller myotomy in 1990, endoscopic dilation in 2007 and botox injection in 2015 who presented due to hematemesis after an episode of food binge. An upper endoscopy was performed with evidence of a severely dilated esophagus and presence of a bulky, cylindrical, foreign body composed of digested food and coagulated blood resembling a large blood sausage. The foreign body was removed through upper esophageal sphincter in piecemeal with a polypectomy snare and roth net using an overtube for airway protection. Two endoscopic procedures were necessary to completely remove the huge cylindrical esophageal bezoar. DISCUSSION: Bezoars are retained concretions of indigestible foreign material that accumulate and conglomerate in any part of the GI tract but rarely in the esophagus. They may occur due to ingestion of undigestible material or in patients with impairment in the grinding mechanism and the interdigestive migrating motor complex. Achalasia is an uncommon disorder resulting from progressive degeneration of ganglion cells in the myenteric plexus in the esophageal wall, leading to failure of relaxation of the lower esophageal sphincter accompanied by a loss of peristalsis in the distal esophagus. Dysphagia for solids and liquids and regurgitation of undigested food are the most frequent symptoms, however patients may also present with chest pain, heartburn, and difficulty belching. Only a few patients with achalasia have been reported to develop esophageal bezoars. In such cases, patients may be asymptomatic for years, or present with symptoms like abdominal pain, nausea, vomiting or serious complications like outlet obstruction, perforation and hematemesis. Upper endoscopy is regarded as the mainstay modality for the diagnosis and treatment of esophageal bezoars. In difficult cases, step by step management with N-acetylcysteine and gastrografrin spraying has been reported. Surgery should be reserved for select patients with bezoars if chemical dissolution and endoscopic fragmentation cannot be performed or fail, as well as for patients with significant complications such as obstruction and severe bleeding.

Roles of three distinct neurogenic motor patterns during pellet propulsion in guinea-pig distal colon.

Enteric neural circuits enable isolated preparations of guinea-pig distal colon to propel solid and fluid contents by a self-sustaining neuromechanical loop process. In addition there are at least three neural mechanisms which are not directly involved in propulsion: cyclic motor complexes, transient neural events and distal colon migrating motor complexes. In excised guinea-pig colon we simultaneously recorded high resolution manometry, video-imaging of colonic wall movements and electrophysiological recordings from smooth muscle, which enabled us to identify mechanisms that underlie the propulsion of colonic content. The results show that the intermittent propulsion during emptying of the multiple natural faecal pellets is due to the intermittent activation of cyclic motor complexes and this is facilitated by transient neural events. Loss or dysfunction of these activities is likely to underlie disordered gastrointestinal transit. It is well known that there are different patterns of electrical activity in smooth muscle cells along different regions of the gastrointestinal tract. These different patterns can be generated by myogenic and/or neurogenic mechanisms. However, what patterns of electrical activity underlie the propulsion of natural faecal content remains unknown, particularly along the large intestine, where large quantities of water are reabsorbed and semi-solid faeces form. In this study, we developed a novel approach which enables for the first time the simultaneous recording of high resolution intraluminal manometry, electrophysiology from the smooth muscle, and spatio-temporal video imaging of colonic wall movements. Using this approach we were able to reveal the nature of enteric neuromuscular transmission and patterns of motor activity responsible for the movement of content. Three distinct neurogenic patterns of electrical activity were recorded even in the absence of propulsive movement. These were the cyclic motor complexes (CMCs), the transient neural events (TNEs) and the slowly propagating distal colonic migrating motor complexes (DCMMCs). We present evidence that the initiation of pellet propulsion is due to a cyclic motor complex (CMC) occurring oral to the pellet. Furthermore, we discovered that the intermittent propulsion of natural faecal pellets is generated by intermittent activation of CMCs; and this propulsion is facilitated by hexamethonium-sensitive TNEs. However, TNEs were not required for propulsion. The findings reveal the patterns of electrical activity that underlie propulsion of natural colonic content and demonstrate that propulsion is generated by a complex interplay between distinct enteric neural circuits.

Trimebutine: a state-of-the-art review.

Trimebutine maleate has been used extensively, since the late 1960's, for the treatment of functional gastrointestinal disorders, including irritable bowel syndrome (IBS). It is usually linked to the antispasmodic class of agents, but its properties make trimebutine an unmatched and multi-tasking compound. The efficacy on relieving abdominal pain has been demonstrated in various clinical studies with different protocols of treatment. The main effect was first believed to be merely due to its antispastic activity, but further evidences expanded the acknowledgement of a broader impact on the gastrointestinal tract. The actions of trimebutine are mediated via an agonist effect on peripheral mu, kappa and delta opiate receptors and a modulation of gastrointestinal peptides release. The final motor effects on the gut are summarized in an acceleration of the gastric emptying, an induction of premature phase III of the migrating motor complex in the small intestine and a modulation of the contractile activity of the colon. Moreover, it has been shown to have a role in regulating the visceral sensitivity. It has been observed that this drug is also a multiple-ion channel modulator in the gut. Its function at various levels, from motility to pain control, makes this drug unique and its spectrum of action can be exploited for the treatment of both hypermotility and hypomotility disorders including irritable bowel syndrome and other functional gastrointestinal diseases. This article provides an overview of the current knowledge on the pharmacological mechanisms of trimebutine and its clinical applications in gastrointestinal disorders. Its biochemical properties and the complex mechanisms of action, along with a well-studied pharmacological safety, make this compound still actual and valuable.

Colonic Motility and Jejunal Vagal Afferent Firing Rates Are Decreased in Aged Adult Male Mice and Can Be Restored by an Aminosterol

There is a general decline in gastrointestinal function in old age including decreased intestinal motility, sensory signaling, and afferent sensitivity. There is also increased prevalence of significant constipation in aged populations. We hypothesized this may be linked to reduced colonic motility and alterations in vagal-gut-brain sensory signaling. Using in vitro preparations from young (3 months) and old (18–24 months) male CD1 mice we report functional age-related differences in colonic motility and jejunal mesenteric afferent firing. Furthermore, we tested the effect of the aminosterol squalamine on colonic motility and jejunal vagal firing rate. Old mice had significantly reduced velocity of colonic migrating motor complexes (MMC) by 27% compared to young mice (p = 0.0161). Intraluminal squalamine increased colonic MMC velocity by 31% in old mice (p = 0.0150), which also had significantly reduced mesenteric afferent single-unit firing rates from the jejunum by 51% (p < 0.0001). The jejunal vagal afferent firing rate was reduced in aged mice by 62% (p = 0.0004). While the time to peak response to squalamine was longer in old mice compared to young mice (18.82 ± 1.37 min vs. 12.95 ± 0.99 min; p = 0.0182), it significantly increased vagal afferent firing rate by 36 and 56% in young and old mice, respectively (p = 0.0006, p = 0.0013). Our results show for the first time that the jejunal vagal afferent firing rate is reduced in aged-mice. They also suggest that there is translational potential for the therapeutic use of squalamine in the treatment of age-related constipation and dysmotility.

Patients with dyspepsia have impaired mucosal integrity both in the duodenum and jejunum: in vivo assessment of small bowel mucosal integrity using baseline impedance

BackgroundRecent studies reported that impaired proximal duodenal mucosa, assessed by duodenal biopsy, could play an important role in the development of dyspeptic symptoms. The aims of this study were (a) to develop a method to measure “in vivo” duodenal and jejunal baseline impedance (BI) and (b) to assess small bowel mucosal integrity in patients with functional dyspepsia (FD) and healthy controls (HC).MethodsWe recruited 16 patients with FD and 15 HC. All subjects underwent ambulatory duodeno-jejunal manometry combined with impedance (HRM/Z), BI were determined by measuring impedance immediately after the passage of nocturnal migrating motor complex (MMC) phase IIIs.ResultsThe number of MMC phase IIIs in FD was significantly lower than that in HC (2.6 ± 1.4 vs 4.8 ± 1.7, p < 0.001). The BI in patients was significantly lower than that in HC in D1(164.2 ± 59.8 Ω in FD and 243.1 ± 40.5 Ω in HC, p = 0.0061), D2 (191.2 ± 34.1 and 256.5 ± 91.4 Ω, p = 0.01), D3 (214.0 ± 76.9 and 278.1 ± 45.3 Ω, p = 0.009), D4 (270.8 ± 54.2 and 351.8 ± 50.2 Ω, p < 0.001), and J1 (312.2 ± 55.4 and 379.3 ± 38.3 Ω, p = 0.001).ConclusionsThis is the first study reporting the duodenal and jejunal BI in vivo. The results have shown significantly lowered BI in the proximal small intestine in patients with FD compared to HC. Furthermore it suggests that measurements of small bowel BI could be used as a biomarker for diagnosis and follow up of patients with FD.

Covering the Cover

Covering the Cover

Activity within specific enteric neurochemical subtypes is correlated with distinct patterns of gastrointestinal motility in the murine colon.

The enteric nervous system in the large intestine generates two important patterns relating to motility: 1) propagating rhythmic peristaltic smooth muscle contractions referred to as colonic migrating motor complexes (CMMCs) and 2) tonic inhibition, during which colonic smooth muscle contractions are suppressed. The precise neurobiological substrates underlying each of these patterns are unclear. Using transgenic animals expressing the genetically encoded calcium indicator GCaMP3 to monitor activity or the optogenetic actuator channelrhodopsin (ChR2) to drive activity in defined enteric neuronal subpopulations, we provide evidence that cholinergic and nitrergic neurons play significant roles in mediating CMMCs and tonic inhibition, respectively. Nitrergic neurons [neuronal nitric oxide synthase (nNOS)-positive neurons] expressing GCaMP3 exhibited higher levels of activity during periods of tonic inhibition than during CMMCs. Consistent with these findings, optogenetic activation of ChR2 in nitrergic neurons depressed ongoing CMMCs. Conversely, cholinergic neurons [choline acetyltransferase (ChAT)-positive neurons] expressing GCaMP3 markedly increased their activity during the CMMC. Treatment with the NO synthesis inhibitor Nω-nitro-l-arginine also augmented the activity of ChAT-GCaMP3 neurons, suggesting that the reciprocal patterns of activity exhibited by nitrergic and cholinergic enteric neurons during distinct phases of colonic motility may be related.NEW & NOTEWORTHY Correlating the activity of neuronal populations in the myenteric plexus to distinct periods of gastrointestinal motility is complicated by the difficulty of measuring the activity of specific neuronal subtypes. Here, using mice expressing genetically encoded calcium indicators or the optical actuator channelrhodopsin-2, we provide compelling evidence that cholinergic and nitrergic neurons play important roles in mediating coordinated propagating peristaltic contractions or tonic inhibition, respectively, in the murine colon.

Co-treatment With BGP-15 Exacerbates 5-Fluorouracil-Induced Gastrointestinal Dysfunction.

Gastrointestinal (GI) side-effects of chemotherapy present a constant impediment to efficient and tolerable treatment of cancer. GI symptoms often lead to dose reduction, delays and cessation of treatment. Chemotherapy-induced nausea, bloating, vomiting, constipation, and/or diarrhea can persist up to 10 years post-treatment. We have previously reported that long-term 5-fluorouracil (5-FU) administration results in enteric neuronal loss, acute inflammation and intestinal dysfunction. In this study, we investigated whether the cytoprotectant, BGP-15, has a neuroprotective effect during 5-FU treatment. Balb/c mice received tri-weekly intraperitoneal 5-FU (23 mg/kg/d) administration with and without BGP-15 (15 mg/kg/d) for up to 14 days. GI transit was analyzed via in vivo serial X-ray imaging prior to and following 3, 7, and 14 days of treatment. On day 14, colons were collected for assessment of ex vivo colonic motility, neuronal mitochondrial superoxide, and cytochrome c levels as well as immunohistochemical analysis of myenteric neurons. BGP-15 did not inhibit 5-FU-induced neuronal loss, but significantly increased the number and proportion of choline acetyltransferase (ChAT)-immunoreactive (IR) and neuronal nitric oxide synthase (nNOS)-IR neurons in the myenteric plexus. BGP-15 co-administration significantly increased mitochondrial superoxide production, mitochondrial depolarization and cytochrome c release in myenteric plexus and exacerbated 5-FU-induced colonic inflammation. BGP-15 exacerbated 5-FU-induced colonic dysmotility by reducing the number and proportion of colonic migrating motor complexes and increasing the number and proportion of fragmented contractions and increased fecal water content indicative of diarrhea. Taken together, BGP-15 co-treatment aggravates 5-FU-induced GI side-effects, in contrast with our previous findings that BGP-15 alleviates GI side-effects of oxaliplatin.

Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression.

Mood disorders and constipation are often comorbid, yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Therefore, defects in neuron production of 5-HT might result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%-80% decrease in levels of 5-HT in the central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice, and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT-dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamine-evoked release of endogenous 5-HT. In live mice, we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximodistal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls, and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth CONCLUSIONS: In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.

Colonic Transit Disorder Mediated by Downregulation of Interstitial Cells of Cajal/Anoctamin-1 in Dextran Sodium Sulfate-induced Colitis Mice.

Background/AimsInterstitial cells of Cajal (ICC) and their special calcium-activated chloride channel, anoctamin-1 (ANO1) play pivotal roles in regulating colonic transit. This study is designed to investigate the role of ICC and the ANO1 channel in colonic transit disorder in dextran sodium sulfate (DSS)-treated colitis mice.MethodsColonic transit experiment, colonic migrating motor complexes (CMMCs), smooth muscle spontaneous contractile experiments, intracellular electrical recordings, western blotting analysis, and quantitative polymerase chain reaction were applied in this study.ResultsThe mRNA and protein expressions of c-KIT and ANO1 channels were significantly decreased in the colons of DSS-colitis mice. The colonic artificial fecal-pellet transit experiment in vitro was significantly delayed in DSS-colitis mice. The CMMCs and smooth muscle spontaneous contractions were significantly decreased by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), an ANO1 channel blocker, and NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME), an inhibitor of nitric oxide synthase activity, in DSS-colitis mice compared with that of control mice. Intracellular electrical recordings showed that the amplitude of NPPB-induced hyperpolarization was more positive in DSS-colitis mice. The electric field stimulation-elicited nitric-dependent slow inhibitory junctional potentials were also more positive in DSS-colitis mice than those of control mice.ConclusionThe results suggest that colonic transit disorder is mediated via downregulation of the nitric oxide/ICC/ANO1 signalling pathway in DSS-colitis mice.

Embryogenesis of the peristaltic reflex.

Neurogenic gut movements start after longitudinal smooth muscle differentiation in three species (mouse, zebrafish, chicken), and at E16 in the chicken embryo. The first activity of the chicken enteric nervous system is dominated by inhibitory neurons. The embryonic enteric nervous system electromechanically couples circular and longitudinal spontaneous myogenic contractions, thereby producing a new, rostro-caudally directed bolus transport pattern: the migrating motor complex. The response of the embryonic gut to mechanical stimulation evolves from a symmetric, myogenic response at E12, to a neurally mediated, polarized, descending inhibitory, 'law of the intestine'-like response at E16. High resolution, whole-mount 3D reconstructions are presented of the enteric nervous system of the chicken embryo at the neural-control stage E16 with the iDISCO+ tissue clarification technique. Gut motility is a complex transport phenomenon involving smooth muscle, enteric neurons, glia and interstitial cells of Cajal. Because these different cells differentiate and become active at different times during embryo development, studying the ontogenesis of motility offers a unique opportunity to 'time-reverse-engineer' the peristaltic reflex. Working on chicken embryo intestinal explants in vitro, we found by spatio-temporal mapping and signal processing of diameter and position changes that motility follows a characteristic sequence of increasing complexity: (1) myogenic circular smooth muscle contractions from E6 to E12 that propagate as waves along the intestine, (2) overlapping and independent, myogenic, low-frequency, bulk longitudinal smooth muscle contractions around E14, and (3) tetrodotoxin-sensitive coupling of longitudinal and circular contractions by the enteric nervous system as from E16. Inhibition of nitric oxide synthase neurons shows that the coupling consists in nitric oxide-mediated relaxation of circular smooth muscle when the longitudinal muscle layer is contracted. This mechanosensitive coupling gives rise to a directional, cyclical, propagating bolus transport pattern: the migrating motor complex. We further reveal a transition to a polarized, descending, inhibitory reflex response to mechanical stimulation after neuronal activity sets in at E16. This asymmetric response is the elementary mechanism responsible for peristaltic transport. We finally present unique high-resolution 3D reconstructions of the chicken enteric nervous system at the neural-control stage based on confocal imaging of iDISCO+ clarified tissues. Our study shows that the enteric nervous system gives rise to new peristaltic transport patterns during development by coupling spontaneous circular and longitudinal smooth muscle contraction waves.

Colonic dilation and altered ex vivo gastrointestinal motility in the neuroligin-3 knockout mouse.

Gastrointestinal (GI) dysfunction is commonly reported by people diagnosed with autism spectrum disorder (ASD; autism) but the cause is unknown. Mutations in genes encoding synaptic proteins including Neuroligin‐3 are associated with autism. Mice lacking Neuroligin‐3 (Nlgn3−/−) have altered brain function, but whether the enteric nervous system (ENS) is altered remains unknown. We assessed for changes in GI structure and function in Nlgn3−/− mice. We found no significant morphological differences in villus height or crypt depth in the jejunum or colon between wildtype (WT) and Nlgn3−/− mice. To determine whether deletion of Nlgn3 affects enteric neurons, we stained for neural markers in the myenteric plexus. Nlgn3−/− mice had similar numbers of neurons expressing the pan‐neuronal marker Hu in the jejunum, proximal mid, and distal colon regions. We also found no differences in the number of neuronal nitric oxide synthase (nNOS+) or calretinin (CalR+) motor neurons and interneurons between WT and Nlgn3−/− mice. We used ex vivo video imaging analysis to assess colonic motility under baseline conditions and observed faster colonic migrating motor complexes (CMMCs) and an increased colonic diameter in Nlgn3−/− mice, although CMMC frequency was unchanged. At baseline, CMMCs were faster in Nlgn3−/− mice compared to WT. Although the numbers of neuronal subsets are conserved in Nlgn3−/− mice, these findings suggest that Neuroligin‐3 modulates inhibitory neural pathways in the ENS and may contribute to mechanisms underlying GI disorders in autism. Autism Res 2020, 13: 691–701. © 2019 The Authors. Autism Research published by International Society for Autism Research published byWiley Periodicals, Inc.Lay SummaryPeople with autism commonly experience gut problems. Many gene mutations associated with autism affect neuronal activity. We studied mice in which the autism‐associated Neuroligin‐3 gene is deleted to determine whether this impacts gut neuronal numbers or motility. We found that although mutant mice had similar gut structure and numbers of neurons in all gut regions examined, they had distended colons and faster colonic muscle contractions. Further work is needed to understand how Neuroligin‐3 affects neuron connectivity in the gastrointestinal tract.

Pacemaker network properties determine intestinal motor pattern behaviour.

Pacemaker network properties determine intestinal motor pattern behaviour.

Propagation Characteristics of Fasting Duodeno-Jejunal Contractions in Healthy Controls Measured by Clustered Closely-spaced Manometric Sensors.

Background/AimsHigh-resolution methods have advanced esophageal and anorectal manometry interpretation but are incompletely established for intestinal manometry. We characterized normal fasting duodeno-jejunal manometry parameters not measurable by standard techniques using clustered closely-spaced recordings.MethodsTen fasting recordings were performed in 8 healthy controls using catheters with 3–4 gastrointestinal manometry clusters with 1–2 cm channel spacing. Migrating motor complex phase III characteristics were quantified. Spatial-temporal contour plots measured propagation direction and velocity of individual contractions. Coupling was defined by pressure peak continuity within clusters.ResultsTwenty-three phase III complexes (11 antral, 12 intestinal origin) with 157 (95% CI, 104–211) minute periodicities, 6.99 (6.25–7.74) minute durations, 10.92 (10.68–11.16) cycle/minute frequencies, 73.6 (67.7–79.5) mmHg maximal amplitudes, and 4.20 (3.18–5.22) cm/minute propagation velocities were recorded. Coupling of individual contractions was 39.1% (32.1–46.1); 63.0% (54.4–71.6) of contractions were antegrade and 32.8% (24.1–41.5) were retrograde. Individual phase III contractions propagated > 35 fold faster (2.48 cm/sec; 95% CI, 2.25–2.71) than complexes themselves. Phase III complexes beyond the proximal jejunum were longer in duration (P = 0.025) and had poorer contractile coupling (P = 0.025) than proximal complexes. Coupling was greater with 1 cm channel spacing vs 2 cm (P < 0.001).ConclusionsIntestinal manometry using clustered closely-spaced pressure ports characterizes novel antegrade and retrograde propagation and coupling properties which degrade in more distal jejunal segments. Coupling is greater with more closely-spaced recordings. Applying similar methods to dysmotility syndromes will define the relevance of these methods.

Same day versus next day antroduodenal manometry results in children with upper gastrointestinal symptoms: A prospective study.

We evaluated the changes in antroduodenal manometry (ADM) parameters and interpretation when the test is performed the day of catheter placement and the following day. Catheter was placed endoscopically under anesthesia and recorded on day 1 and repeated on day 2. Study parameters including antrum and small bowel motility index (MI) during fasting, meal, postprandial, erythromycin (EES), and octreotide (OCT) challenge phases, the presence of the phase III of the migrating motor complex (MMC), visual postprandial response, and study interpretation were compared between both days. Twenty patients were studied. Antrum and small bowel MI during fasting, postprandial, and EES challenge phases were significantly higher on day 2 than on day 1 (P<0.05). The proportion of patients having a phase III of the MMC was significantly higher on day 2 compared to day 1 (65% vs 15%; P=0.006). Study interpretation changed from day 1 to day 2. On day 1, 70% of the patients had a normal study and 30% had an abnormal study. On day 2, 67% of the patients with an abnormal study on day 1 changed to normal and 33% remained abnormal. All patients with a normal study on day 1 remained normal on day 2. ADM parameters are affected the day of catheter placement. The MI and presence of the phase III of the MMC were significantly higher on day 2 compared to day 1. Overall, ADM study interpretation changed from day 1 to day 2 in 20% of the patients.

Bowel Sounds Identification and Migrating Motor Complex Detection with Low-Cost Piezoelectric Acoustic Sensing Device.

Interpretation of bowel sounds (BS) provides a convenient and non-invasive technique to aid in the diagnosis of gastrointestinal (GI) conditions. However, the approach’s potential is limited by variation between BS and their irregular occurrence. A short, manual auscultation is sufficient to aid in diagnosis of only a few conditions. A longer recording has the potential to unlock additional understanding of GI physiology and clinical utility. In this paper, a low-cost and straightforward piezoelectric acoustic sensing device was designed and used for long BS recordings. The migrating motor complex (MMC) cycle was detected using this device and the sound index as the biomarker for MMC phases. This cycle of recurring motility is typically measured using expensive and invasive equipment. We also used our recordings to develop an improved categorization system for BS. Five different types of BS were extracted: the single burst, multiple bursts, continuous random sound, harmonic sound, and their combination. Their acoustic characteristics and distribution are described. The quantities of different BS during two-hour recordings varied considerably from person to person, while the proportions of different types were consistent. The sensing devices provide a useful tool for MMC detection and study of GI physiology and function.

Erythromycin and Reflux Events in Premature Neonates: A Randomized Clinical Trial.

Gastroesophageal reflux disease (GERD) in premature neonates may manifest as apnea, bradycardia, growth failure, aspiration, or feeding intolerance. Erythromycin ethylsuccinate (EES), is often used as a pro-kinetic in the management of GERD, despite lack of evidence or safety from randomized controlled trials. We sought to study the efficacy of enteral EES at a dose of 50 mg · kg · day in decreasing the frequency of gastroesophageal reflux events as determined by pH-multichannel intraluminal impedance (pH-MII) monitoring. In a randomized, double-blind, placebo-controlled trial, eligible premature neonates with clinical signs of GERD underwent 24-hour pH-MII monitoring. If >5 reflux events were identified on pH-MII, then subjects were randomized to receive either EES or placebo. Repeat 24-hour pH-MII was performed on day 7 of study treatment and compared to initial pH-MII. Forty-three premature neonates were enrolled. Of those, 31 neonates were randomized, 15 to EES and 16 to placebo with a median (IQR) pretreatment total reflux events per 24 hours of 23 (16-40) and 29 (12-40), respectively. Day 7 total events per 24 hours decreased by 4 events in the EES group to 19 (15-33) and by 10 events in the placebo group to 19 (11-26) (P = 0.09). There were no differences in pretreatment and day 7 acidic and nonacidic reflux, proximal reflux, total or percent reflux time, median or longest bolus clearance time, or nurse-reported apnea events between groups. Enteral EES did not decrease reflux events on 24-hour pH-MII at the dose studied. Therefore, it may be ineffective in the treatment of GERD in premature neonates.