Search

Disrupted gastrointestinal (GI) motility is highly prevalent in patients with inflammatory bowel disease (IBD), but its potential causative role remains unknown. Herein, the role and the mechanism of impaired GI motility in colitis pathogenesis are investigated. Increased colonic mucosal inflammation is found in patients with chronic constipation (CC). Mice with GI dysmotility induced by genetic mutation or chemical insult exhibit increased susceptibility to colitis, dependent on the gut microbiota. GI dysmotility markedly decreases the abundance of Lactobacillus animlalis and increases the abundance of Akkermansia muciniphila. The reduction in L. animlalis, leads to the accumulation of linoleic acid due to compromised conversion to conjugated linoleic acid. The accumulation of linoleic acid inhibits Treg cell differentiation and increases colitis susceptibility via inducing macrophage infiltration and proinflammatory cytokine expression in macrophage. Lactobacillus and A. muciniphila abnormalities are also observed in CC and IBD patients, and mice receiving fecal microbiota from CC patients displayed an increased susceptibility to colitis. These findings suggest that GI dysmotility predisposes host to colitis development by modulating the composition of microbiota and facilitating linoleic acid accumulation. Targeted modulation of microbiota and linoleic acid metabolism may be promising to protect patients with motility disorder from intestinal inflammation. [ABSTRACT FROM AUTHOR]

Background: Zebrafish larvae are translucent, allowing in vivo analysis of gut development and physiology, including gut motility. While recent progress has been made in measuring gut motility in larvae, challenges remain which can influence results, such as how data are interpreted, opportunities for technical user error, and inconsistencies in methods. Methods: To overcome these challenges, we noninvasively introduced Nile Red fluorescent dye to fill the intraluminal gut space in zebrafish larvae and collected serial confocal microscopic images of gut fluorescence. We automated the detection of fluorescent‐contrasted contraction events against the median‐subtracted signal and compared it to manually annotated gut contraction events across anatomically defined gut regions. Supervised machine learning (multiple logistic regression) was then used to discriminate between true contraction events and noise. To demonstrate, we analyzed motility in larvae under control and reserpine‐treated conditions. We also used automated event detection analysis to compare unfed and fed larvae. Key Results: Automated analysis retained event features for proximal midgut‐originating retrograde and anterograde contractions and anorectal‐originating retrograde contractions. While manual annotation showed reserpine disrupted gut motility, machine learning only achieved equivalent contraction discrimination in controls and failed to accurately identify contractions after reserpine due to insufficient intraluminal fluorescence. Automated analysis also showed feeding had no effect on the frequency of anorectal‐originating contractions. Conclusions & Inferences: Automated event detection analysis rapidly and accurately annotated contraction events, including the previously neglected phenomenon of anorectal contractions. However, challenges remain to discriminate contraction events based on intraluminal fluorescence under treatment conditions that disrupt functional motility. [ABSTRACT FROM AUTHOR]

Background: Gut dysmotility is common after ischemic stroke, but the mechanism underlying this response is unknown. Under homeostasis, gut motility is regulated by the neurons of the enteric nervous system that control contractile/relaxation activity of muscle cells in the gut wall. More recently, studies of gut inflammation revealed interactions of macrophages with enteric neurons are also involved in modulating gut motility. However, whether poststroke gut dysmotility is mediated by direct signaling to the enteric nervous system or indirectly via inflammatory macrophages is unknown., Methods and Results: We examined these hypotheses by using a clinically relevant permanent intraluminal midcerebral artery occlusion experimental model of stroke. At 24 hours after stroke, we performed in vivo and ex vivo gut motility assays, flow cytometry, immunofluorescence, and transcriptomic analysis. Stroke-induced gut dysmotility was associated with recruitment of muscularis macrophages into the gastrointestinal tract and redistribution of muscularis macrophages away from myenteric ganglia. The permanent intraluminal midcerebral artery occlusion model caused changes in gene expression in muscularis macrophages consistent with an altered phenotype. While the size of myenteric ganglia after stroke was not altered, myenteric neurons from post-permanent intraluminal midcerebral artery occlusion mice showed a reduction in neuronal nitric oxide synthase expression, and this response was associated with enhanced intestinal smooth muscle contraction ex vivo. Finally, chemical sympathectomy with 6-hydroxydopamine prevented the loss of myenteric neuronal nitric oxide synthase expression and stroke-induced slowed gut transit., Conclusions: Our findings demonstrate that activation of the sympathetic nervous system after stroke is associated with reduced neuronal nitric oxide synthase expression in myenteric neurons, resulting in impaired smooth muscle relaxation and dysregulation of gut transit.

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 Summary: People 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. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin‐3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin‐3 R451C missense mutation (NL3R451C). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3R451C compared to wild‐type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABAA receptor modulation in NL3R451C mice, a well‐established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3R451C mice. Although we observed altered sensitivity to GABAA receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA‐immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3R451C mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3R451C mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043–1056. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary: People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism‐associated R451C mutation encoding the neuroligin‐3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin‐3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication. [ABSTRACT FROM AUTHOR]

Abstract: Background: We previously reported that intrathecal injection of noradrenaline or dopamine causes enhancement of colorectal motility. As these monoamines are neurotransmitters of descending pain inhibitory pathways in the spinal cord, we hypothesized that serotonin, which is one of the neurotransmitters involved in descending pain inhibition, also influences the lumbosacral defecation center. Therefore, we examined whether serotonin acting on the spinal defecation center enhances colorectal motility. Methods: Colorectal intraluminal pressure and propelled liquid volume were recorded in vivo in anesthetized rats. Key Results: Intrathecal injection of serotonin into the L6‐S1 spinal cord elicited periodic increases in colorectal intraluminal pressure, being associated with increases in liquid output. Pharmacological experiments revealed that the effect of serotonin is mediated by both 5‐HT2 and 5‐HT3 receptors. The serotonin‐induced enhancement of colorectal motility was unaffected even after disconnection of the defecation center from supraspinal regions by cutting the T8 spinal cord, while transection of the parasympathetic pelvic nerves prevented the colokinetic effect of serotonin. Finally, we investigated interactions among serotonin, noradrenaline and dopamine. Simultaneous administration of sub‐effective doses of these monoamine neurotransmitters into the spinal cord caused propulsive colorectal motility slightly but substantially. Conclusions and Inferences: These results demonstrate that exogenous serotonin acts on 5‐HT2 and 5‐HT3 receptors in the lumbosacral defecation center and activates the parasympathetic nervous system to enhance colorectal motility in cooperation with noradrenaline and dopamine. [ABSTRACT FROM AUTHOR]

Abstract: The enteric nervous system (ENS) is the largest part of the peripheral nervous system and is entirely neural crest–derived. It provides the intrinsic innervation of the gut, controlling different aspects of gut function, such as motility. In this review, we will discuss key points of Zebrafish ENS development, genes, and signaling pathways regulating ENS development, as well as contributions of the Zebrafish model system to better understand ENS disorders. During their migration, enteric progenitor cells (EPCs) display a gradient of developmental states based on their proliferative and migratory characteristics, and show spatiotemporal heterogeneity based on gene expression patterns. Many genes and signaling pathways that regulate the migration and proliferation of EPCs have been identified, but later stages of ENS development, especially steps of neuronal and glial differentiation, remain poorly understood. In recent years, Zebrafish have become increasingly important to test candidate genes for ENS disorders (e.g., from genome‐wide association studies), to identify environmental influences on ENS development (e.g., through large‐scale drug screens), and to investigate the role the gut microbiota play in ENS development and disease. With its unique advantages as a model organism, Zebrafish will continue to contribute to a better understanding of ENS development, function, and disease. Developmental Dynamics 247:268–278, 2018. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Stress-induced chronic neuropsychiatric conditions such as anxiety are often co-morbid with gastrointestinal malfunctions. While we find enduring anxiety-like symptoms following minimal traumatic brain injury ( MTBI) in rats, gastrointestinal consequences of MTBI remain elusive. Methods In this study, we examined the effects of MTBI on a major gut peptide, neuropeptide Y ( NPY) and gut motility. DNA methylation was studied as a possible epigenetic mechanism operative in the regulation of NPY expression in the gut. Key Results Minimal traumatic brain injury reduced the gut motility 48 hours and 30 days after trauma. The expression of DNA methyltransferase isoforms ( DNMT1, DNMT3a, and DNMT3b) was altered in the jejunum 48 hours and 30 days after MTBI. However, the mRNA levels of growth arrest and DNA damage 45 ( GADD45) isoforms, GADD45a, and GADD45b, which are believed to be involved in active DNA demethylation, initially decreased at 48 hours but subsequently increased after 30 days of trauma. Similarly, DNA hypomethylation at the NPY promoter region in the jejunum was correlated with the increase in NPY mRNA and protein levels 30 days post-trauma. On the other hand, DNA hypomethylation at 48 hours was associated with a decline in NPY expression. Treatment with 5-azacytidine (5-AzaC), a DNMT inhibitor, retarded DNA methylation and restored the NPY mRNA levels in the jejunum of MTBI-induced rats. Conclusions & Inferences These results suggest that DNA demethylation could be operative as an epigenetic mechanism in the long-term regulation of NPY gene expression to alter the gut motility during traumatic stress. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of this study? What are the dynamical rules governing interstitial cell of Cajal (ICC)-generated slow wave contractions in the small intestine, as reflected in their phase response curve and state space?, What is the main finding and its importance? The phase response curve has a region of phase advance surrounding a phase delay peak. This pattern is important in generating a stable synchrony within the ICC network and is related to the state space of the ICC; in particular, the phase delay peak corresponds to the unstable equilibrium point that threads the ICC's limit cycle., Interstitial cells of Cajal (ICCs) generate electrical oscillations in the gut. Synchronization of the ICC population is required for generation of coherent electrical waves ('slow waves') that cause muscular contraction and thereby move gut content. The phase response curve (PRC) is an experimental measure of the dynamical rules governing a population of oscillators that determine their synchrony and gives an experimental window onto the state space of the oscillator, its dynamical landscape. We measured the PRC of slow wave contractions in the mouse small intestine by the novel combination of diameter mapping and single pulse electrical field stimulation. Phase change (τ) was measured as a function of old phase (ϕ) and distance from the stimulation electrode ( d). Plots of τ(ϕ, d) showed an arrowhead-shaped region of phase advance enclosing at its base a phase delay peak. The phase change mirrored the perturbed pattern of contraction waves in response to a pulse. The (ϕ, d) plane is the surface of a displacement tube extending from the limit cycle through state space. To visualize the state space vector field on this tube, latent phase (ϕlat) was calculated from τ. At the transition from advance to delay, isochrons made boomerang turns before tightening and winding around the phase delay peak corresponding to the unstable equilibrium point that threads the limit cycle. This isochron foliation had previously been observed in oscillator models such as the Fitzhugh-Nagumo but has not been demonstrated experimentally. The spatial extension of the PRC afforded by diameter mapping allows a better understanding of the dynamical properties of ICCs and how they synchronize as a population. [ABSTRACT FROM AUTHOR]

Background Gastrointestinal symptoms are common in the general population and may originate from disturbances in gut motility. However, fundamental mechanistic understanding of motility remains inadequate, especially of the less accessible regions of the small bowel and colon. Hence, refinement and validation of objective methods to evaluate motility of the whole gut is important. Such techniques may be applied in clinical settings as diagnostic tools, in research to elucidate underlying mechanisms of diseases, and to evaluate how the gut responds to various drugs. A wide array of such methods exists; however, a limited number are used universally due to drawbacks like radiation exposure, lack of standardization, and difficulties interpreting data. In recent years, several new methods such as the 3D-Transit system and magnetic resonance imaging assessments on small bowel and colonic motility have emerged, with the advantages that they are less invasive, use no radiation, and provide much more detailed information. Purpose This review outlines well-established and emerging methods to evaluate small bowel and colonic motility in clinical settings and in research. The latter include the 3D-Transit system, magnetic resonance imaging assessments, and high-resolution manometry. Procedures, indications, and the relative strengths and weaknesses of each method are summarized. [ABSTRACT FROM AUTHOR]

Background Antipsychotics are essential for the treatment of schizophrenia. However, due to side effects, both continuity of treatment and patients' general health can be jeopardized. Some of these drugs, especially clozapine, have a class of side effects attributed to their antimuscarinic properties, such as dysmotility, a condition in which muscles of the digestive system become impaired. Dysmotility may also alter the speed, strength or coordination of the digestive organs, causing distention, disturbing gastrointestinal transit, leading to symptoms such as bloating, nausea, vomiting, and even malnutrition. In this study, our aim was to develop an in vivo assay capable of identifying and studying the antimuscarinic effects of antipsychotics in a zebrafish model. Methods We performed video recordings of in vivo 5-day postfertilization (dpf) zebrafish larvae gastrointestinal tracts and analyzed the frequency of spontaneous and regular cycles of contractions of the gut. Key Results The assay was first validated with treatment with atropine. We showed that this antimuscarinic drug reduces peristaltic cycles. Subsequently, the larvae were treated with the antipsychotics haloperidol, risperidone, and clozapine. Neither haloperidol nor risperidone reduced gut motility, but clozapine significantly reduced the frequency of cycles of contractions ( P<.0001), which confirms the existing clinical data. Conclusions & Inferences We conclude that this zebrafish assay efficiently identifies anticholinergic side effects of antipsychotics, and can thus be a quick and useful way to screen for this property in new drugs. [ABSTRACT FROM AUTHOR]

Background Bilateral subthalamic nucleus ( STN) stimulation is used to alleviate Parkinson's disease ( PD) motor symptoms. Recently, it has been shown that this therapeutic also increased gut cholinergic contractions. We therefore investigated the effect of STN stimulation on esophageal motility in an interventional randomized study. Methods Sixteen humans PD patients (4 women, 12 men; age: 62.4 ± 9.3-years old) who underwent STN stimulation for at least 6 months were randomly evaluated with either stimulator turned OFF then ON, or inversely. Esophageal high resolution manometry was performed at the end of each ON and OFF period, with a 5 min resting period followed by ten swallows of 5 mL. Key Results During the ON, an increase in the distal contractility index was found ( OFF: 1750 ± 629 vs ON: 2171 ± 755 mmHg/cm/s; p = 0.03), with no difference in the distal front velocity. A decrease in the integrative relaxation pressure of the lower esophageal sphincter ( LES) was noted ( OFF: 11.1 ± 1.8 mmHg vs ON: 7.2 ± 1.8 mmHg; p < 0.05) in ON. The LES resting pressure remained unchanged during the two periods. This resulted in a decrease in the intrabolus pressure ( p = 0.03). No difference was observed for the upper esophageal sphincter, nor the pharyngeal contraction amplitude and velocity. Conclusions & Inferences In conclusion, STN stimulation in PD patients increased esophageal body contractions and enhanced the LES opening. This suggests that the nigrostriatal-striatonigral loop is involved in the control of esophageal motility. [ABSTRACT FROM AUTHOR]

Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5-HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex-GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs Tph1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic Tph1 protein (P < 0.05) and 5-HT concentrations (GF, 17 ± 3 ng/mg; HM, 25 ± 2 ng/mg; and CR, 35 ± 3 ng/mg; P < 0.05). Enterochromaffin (EC) cell numbers (cells producing 5-HT) were unchanged. Short-chain fatty acids (SCFAs) promoted TPH1 transcription in BON cells (human EC cell model). Thus, gut microbiota acting through SCFAs are important determinants of enteric 5-HT production and homeostasis. [ABSTRACT FROM AUTHOR]

Background & Aims Brain-derived neurotrophic factor ( BDNF) may play a critical role in gut motility. We aimed to investigate BDNF's physiologic effects on gut motility in slow-transit constipation ( STC) and to explore the underlying molecular mechanisms. Methods BDNF expression and alterations of colonic nerve fibre density in STC patients were first investigated. BDNF's effects on gastrointestinal motility of both BDNF+/− mice and loperamide-induced constipation mice were then examined in vivo and in vitro. Smooth muscle α-actin ( α- SMA) expression, and nerve fibre, neuromuscular junction ( NMJ) and smooth muscle cell ( SMC) alterations were investigated. Finally, the effects of BDNF-induced TrkB-phospholipase C/inositol trisphosphate (TrkB- PLC/ IP3) pathway activation on gut motility were investigated. Results In STC patients, BDNF expression and nerve fibre density were decreased, and mucosal nerve fibre ultrastructural degenerations were demonstrated. Gut motility was decreased in vivo and in vitro in BDNF+/− and constipation mice, with BDNF dose-dependently increasing gut motility. In BDNF+/− mice, α- SMA expression and nerve fibre density were decreased, and nerve fibre, NMJ and SMC ultrastructural degenerations were observed. Finally, TrkB- PLC/ IP3 pathway antagonists dramatically attenuated BDNF's excitatory effect on gut motility, and exogenous BDNF induced an obvious increase in IP3 expression. Conclusions BDNF plays an important regulatory role in gut motility in STC. It was mediated by altering the intestinal innervation structure, as well as smooth muscle secondary degeneration through a mechanism involving TrkB- PLC/ IP3 pathway activation. [ABSTRACT FROM AUTHOR]

Obesity and type II diabetes mellitus have reached epidemic proportions. From this perspective, knowledge about the regulation of satiety and food intake is more important than ever. The gut releases several peptides upon feeding, which affect hypothalamic pathways involved in the regulation of satiety and metabolism. Within the hypothalamus, there are complex interactions between many nuclei of which the arcuate nucleus is considered as one of the most important hypothalamic centres that regulates food intake. The neuropeptides, which are present in the hypothalamus and are involved in regulating food intake, also play a key role in regulating glucose metabolism and energy expenditure. In synchrony with the effects of those neuropeptides, gastrointestinal hormones also affect glucose metabolism and energy expenditure. In this review, the effects of the gastrointestinal hormones ghrelin, cholecystokinin, peptide YY, glucagon-like peptide, oxyntomodulin and gastric inhibitory polypeptide on glucose and energy metabolism are reviewed. These gut hormones affect glucose metabolism at different levels: by altering food intake and body weight, and thereby insulin sensitivity; by affecting gastric delay and gut motility, and thereby meal-related fluctuations in glucose levels; by affecting insulin secretion, and thereby plasma glucose levels, and by affecting tissue specific insulin sensitivity of glucose metabolism. These observations point to the notion of a major role of the gut–brain axis in the integrative physiology of whole body fuel metabolism. [ABSTRACT FROM AUTHOR]

The digestion, absorption and post absorptive metabolism of a radiolabelled triacylglycerol (TAG; triolein) and a free fatty acid (FFA; oleic acid), delivered by tube feeding, was studied in herring Clupea harengus larvae, using metabolic chambers and video analysis. In general, a large amount of the delivered lipid was evacuated. Most of the evacuation occurred between 2 and 6 h after tube feeding although a group of larvae responded by rapidly evacuating the lipid (>50% before 2 h). The volume of the tube-fed lipid affected its utilization. A small volume of triolein (9·2 nl, representing c. 6% of gut filling capacity) resulted in a lower proportion of fast evacuating larvae and improved utilization (lower evacuation and higher absorption: body incorporation and catabolism) compared with 50·6 nl ( c. 17% of gut filling capacity). Increases in the volume of tube fed triolein enhanced only marginally label absorption and led to a steep rise in evacuation. At a comparable high volume (50·6 nl), oleic acid, which does not require digestion, was better absorbed and less evacuated than triolein. The video observation of the lipid digestive process revealed a considerable gut contractile activity that appeared effective in processing the tube fed lipid. Also, the gut wall seemed very sensitive to physical pressure. Signs of chemical degradation during lipid digestion were also noted. The metabolic studies, together with video image analysis, suggested that the limiting step for the utilization of high dietary lipid levels may have been the lipid absorption into the enterocytes and transport into the body, rather than lipid digestion. The results support the notion that the rate of lipid digestion and absorption in fishes is slower than that of mammals. [ABSTRACT FROM AUTHOR]

Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid-induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple-dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral-cecal transit time from a pretreatment baseline value of 101.3±29.4 min (mean±SD) to 82.5±20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538±237 and 675±180 ng/mL after doses 1 and 2, respectively. Based on 6-hour sampling periods, the plasma half-life, 2.5±0.5 and 2.9±0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid-naive volunteers suggests that endogenous opioids modulate human gut motility. [ABSTRACT FROM PUBLISHER]

1. A traditional approach to the nutritional ecology of herbivores is that larger animals can tolerate a diet of lesser quality due to a higher digestive efficiency bestowed on them by comparatively long ingesta retention times and lower relative energy requirements.2. There are important physiological disadvantages that larger animals must compensate for, namely a lower gut surface : gut volume ratio, larger ingesta particle size and greater losses of faecal bacterial material due to more fermentation. Compensating adaptations could include an increased surface enlargement in larger animals, increased absorption rates per unit of gut surface, and increased gut motility to enhance mixing of ingesta.3. A lower surface : volume ratio, particularly in sacciform forestomach structures, could be a reason for the fact that methane production is of significant scope mainly in large herbivores and not in small herbivores with comparably long retention times; in the latter, the substrate for methanogenesis– the volatile fatty acids– could be absorbed faster due to a more favourable gut surface : volume ratio.4. Existing data suggest that in herbivores, an increase in fibre digestibility is not necessarily accompanied by an increase in overall apparent dry matter digestibility. This indicates a comparative decrease of theapparentdigestibility of non-fibre material, either due to a lesser utilization of non-fibre substrate or an increased loss of endogenous/bacterial substance. Quantitative research on these mechanisms is warranted in order to evaluate whether an increase in body size represents a net increase of digestive efficiency or just a shift of digestive focus. [ABSTRACT FROM AUTHOR]

Abstract Background : All gut movements are claimed to be activated essentially by the concentric contraction of the circular muscle, moving the chyme aborally. The role of the longitudinal smooth muscle of the small intestine in gut motility is poorly understood; this point was investigated in the current study. Methods : The abdomens of 14 crossbreed dogs (eight dogs, six bitches) were opened. A segment of the small intestine was distended by a balloon in increments of 2 mL of saline, and the pressure and electrical activity were recorded proximally and distally to the balloon. The gut wall around the balloon was anesthetized and the test was repeated. The longitudinal muscle coat of the small intestine segment was then excised, and the pressure response and electrical activity were recorded on ileal distension. Results : Two milliliter ileal distension produced pressure decrease (P < 0.05) proximally and distally to the balloon and caused balloon movement. Four, 6 and 8 mL distension effected similar pressure response, while 10 mL showed no response. Electrical waves were recorded from the three electrodes applied to the ileal segment. Upon ileal distension, electrical activity increased over the distended area, with no activity proximally and distally to it. Balloon distension of the anesthetized ileal segment produced no pressure response or electrical activity. After longitudinal myectomy, no electrical activity was recorded at rest or upon ileal distension, and the balloon did not move. Conclusion : Ileal distension initiated circular muscle contraction only in the presence of the overlying longitudinal muscle, which appears to transmit the electrical activity to the circular muscle upon ileal distension. Ileal contraction is suggested to initiate ileal hypotonia in the proximal and distal ileal segments mediated through an ‘ileo–ileal inhibitory reflex’ that leads to aboral progress of the proximally and distally located chyme.... [ABSTRACT FROM AUTHOR]

AbstractBackground: The clinical usefulness of the radiopaque marker method for detecting diabetic gastrointestinal motility disturbances, was evaluated by examining 21 type II diabetes subjects who did not have any neuropathic symptoms. Methods: After administration of a Sitzmark capsule®, markers were located using plain abdominal radiographs, and the transit time of the markers through seven areas of digestive tract was calculated by Arhan’s methods. The plasma concentration of acetaminophen at 45 min after oral administration was measured to evaluate gastric emptying time. The coefficient of variation of R-R intervals on the electrocardiograms (CVR-R) was measured to evaluate parasympathetic autonomic function. Results: In the diabetics, the average (± SD) transit time through upper digestive tracts was slightly but not significantly elongated compared with control subjects (14.4 ± 8.3 vs 9.9 ± 6.1 h). Significant elongation was observed in transit time through the lower digestive tracts or the whole gut (44.6 ± 20.9 and 57.9 ± 22.3 h, respectively) compared with control subjects (23.3 ± 8.5 and 33.2 ± 11.0 h). The transit time of the markers from stomach to small intestine was highly correlated (r = 0.693) with plasma concentration of acetaminophen. The transit time through either the whole colon (r = 0.564) or the whole gut (r = 0.630) was highly correlated with CVR-R. Conclusions: These findings suggest that the radiopaque marker method is a useful tool for detecting the sections of the digestive tract responsible for gut motility disturbances. In type II diabetics with no neuropathic symptoms, the lower digestive tracts may deteriorate prior to the impairment of upper digestive tracts. [ABSTRACT FROM AUTHOR]

Background: In recent years, high‐resolution manometry has been used in an attempt to gain a greater insight into the physiology/pathophysiology of colonic contractile activity in healthy adults and patients with colonic motility disorders. New colonic motor patterns have been identified and characterized, however, the clinical significance of these findings remains undetermined. Purpose: This review will assess the current literature on colonic high‐resolution manometry and determine if this procedure has advanced our understanding of colonic motility. The limitations, future directions, and the potential of this technique to assess the effects of treatment upon colonic motor patterns will also be discussed. This review assesses the current literature on colonic high‐resolution manometry to determine if this procedure has advanced our understanding of colonic motility in healthy adults and patients with colonic disorders. [ABSTRACT FROM AUTHOR]

CHARGE syndrome is an autosomal dominant genetic condition that is primarily diagnosed based on clinical features, with genetic testing available for confirmation. The CHARGE mnemonic stands for some of the common characteristics: coloboma, heart defects, atresia/stenosis of the choanae, retardation of growth/development, genitourinary anomalies, and ear abnormalities (CHARGE). However, many of the common clinical features are not captured by this mnemonic, including cranial nerve dysfunction, considered by some to be one of the major diagnostic criteria. Over 90% of individuals experience feeding and gastrointestinal dysfunction, which carries great morbidity and mortality. The aim of this review is to examine the nature of gastrointestinal (GI) symptoms and feeding difficulties in CHARGE syndrome, focusing on their underlying pathology, associated investigations, and available treatment options. We also provide information on available tools (for parents, clinicians, and researchers) that are important additions to the lifelong healthcare management of every individual with CHARGE syndrome. We review how cranial nerve dysfunction is one of the most important characteristics underlying the pervasive GI and feeding dysfunction, and discuss the need for future research on gut innervation and motility in this genetic disorder., (© 2017 Wiley Periodicals, Inc.)

Current evidence suggests that an association exists between non-inflammatory hereditary disorders of connective tissue such as the Ehlers-Danlos syndromes (EDS) and gastrointestinal (GI) symptoms. Patients with EDS can present with both structural problems such as hiatus hernias, visceroptosis, rectoceles, and rectal prolapse as well as functional problems such as disordered gut motility. It has recently been demonstrated that patients with hypermobile EDS (hEDS) present with GI symptoms related to the fore and hind-gut and these patients frequently meet the criteria for functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome. Presence of GI symptoms in EDS patients influences their quality of life. Specific evidence based management guidelines for the management of GI symptoms in EDS patients do not exist and these patients are often treated symptomatically. There is, however, recognition that certain precautions need to be taken for those patients undergoing surgical treatment. Future studies are required to identify the mechanisms that lead to GI symptoms in patients with EDS and more specific treatment guidelines are required. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)