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S farmakopejskimi napravami za preskušanje sproščanja ne moremo ustvarjati dinamičnega okolja, ki ga v gastrointestinalnem traktu in vivo izkusijo trdne peroralne farmacevtske oblike. Najbolj težavna je simulacija mehanskih tlačnih in erozijskih obremenitev, ki so jim mehansko občutljive farmacevtske oblike izpostavljene zaradi želodčne motilitete. V sklopu magistrske naloge smo v biorelevantni aparaturi za preskušanje sproščanja - napravi za posnemanje gibanja želodca - ki lahko na različne načine posnema dinamično okolje v gastrointestinalnem traktu, določili ustrezne eksperimentalne pogoje za simulacijo želodčne motilitete v stanju na tešče. Motilitetni vzorec v stanju na tešče, imenovan tudi migracijski motorični kompleks, zaznamujejo štiri faze z značilnimi frekvencami in amplitudami kontrakcij, ki jih in vivo lahko merimo na različne načine, tudi s tlačnim senzorjem brezžične motilitetne kapsule SmartPill®. Eksperimentalno delo smo začeli s potrditvijo linearnega razmerja med nastavitvami parametrov in generiranimi tlaki v lumnu naprave za posnemanje gibanja želodca, ki smo jih prav tako merili s SmartPill®. S pomočjo meritev tlakov med migracijskim motoričnim kompleksom in vivo smo pripravili zaporedje programov, ki je v napravi za posnemanje gibanja želodca simuliralo značilne kontrakcije štirih faz migracijskega motoričnega kompleksa. Med simulacijo je naprava proizvajala maksimalne tlake do 220 mbar, ki so približno skladni meritvam in vivo. Za konec smo pripravljeno simulacijo ovrednotili s preskusi sproščanja učinkovine iz dveh hidrofilnih ogrodnih tablet z različno vsebnostjo hidroksipropilmetilceluloze. Dobljene profile sproščanj smo primerjali z rezultati preskušanja sproščanja v aparaturi USP2. Ko smo sproščanje izvajali v napravi za simulacijo želodčnega gibanja, smo dobili večje razlike med profiloma sproščanja testnih formulacij, kot ko smo sproščanje izvajali v USP2. Značilno razliko med profiloma sproščanja, ki je skladna z obnašanjem testnih formulacij in vivo, smo dobili, ko smo v napravi za posnemanje želodčnega gibanja sproščanje izvajali v biorelevantnem mediju, ki posnema želodčne pogoje na tešče (FaSSGF). Compendial dissolution methods cannot simulate the dynamic environment in the gastrointestinal tract experienced by solid oral dosage forms in vivo. The biggest challenge lays in the simulation of mechanical and erosion stresses and pressures exerted on mechanically sensitive dosage forms as a result of stomach motility. The main goal of the research was the establishment of appropriate experimental conditions that simulate fasted stomach motility on a novel dissolution apparatus advanced gastric simulator - which can simulate the dynamic environment in the gastrointestinal tract in different ways. Fasted stomach motility can be described by a pattern of contractions called the migrating motor complex, comprised of four phases with characteristic contraction frequencies and amplitudes. Such parameters can be measured in vivo via different methods, including the pressure sensor of a Wireless motility capsule, SmartPill®. Experiments were started with the confirmation of a linear relationship between advanced gastric simulator settings and pressures generated in its lumen, measured with the SmartPill®. With the help of data on luminal pressures in vivo, we prepared a programme sequence, simulating the contractions during the four phases of the migrating motor complex. Pressures of up to 220 mbar were measured during the simulation and resembled the in vivo data. We finished the experiments with validation of the prepared programme sequence via dissolution testing of two hydrophilic matrix tablets with varying amounts of hypromellose. Drug release profiles were compared to the results of dissolution testing in the USP2 apparatus. When dissolution was performed in the advanced gastric simulator, larger differences between drug release profiles of both formulations were observed, compared to dissolution testing in USP2. Significant difference, compliant with in vivo behaviour of tested formulations, was acquired when dissolution media “Fasted State Simulated Gastric Fluid (FaSSGF)“ was used in the advanced gastric simulator.

Key points In herbivores, including guinea pigs, clearly defined faecal pellets are formed at a distinct location along the large intestine (colonic flexure). The mechanism underlying formation of these faecal pellets at this region has remained, until now, a major unresolved issue. We reveal a progressive and gradual reduction in water content of faecal content along the bowel. Hence, the distinct transition from amorphous to pellet shaped faecal content could not be explained by a dramatic increase in water reabsorption from a specific site. We discovered novel patterns of anterograde neurogenic and retrograde myogenic motor activity that facilitate the formation of faecal pellets. The formation of "pellet-like" boluses at the colonic flexure involves the interaction of an antegrade migrating motor complex in the proximal colon and retrograde myogenic slow phasic contractions at the colonic flexure. The findings uncover major new intrinsic mechanisms responsible for the formation of discrete faecal scybala in the large intestine of a vertebrate. Abstract Soft faecal material is transformed into discrete, pellet-shaped faeces at the colonic flexure. Here, analysis of water content in natural faecal material revealed a decline from cecum to rectum without significant changes at the flexure. Thus, pellet formation is not explained by changes in viscosity alone. We then used video imaging of colonic wall movements with electromyography in isolated preparations containing guinea-pig proximal colon, colonic flexure and distal colon. To study the pellet formation process, the colonic segments were infused with artificial contents (Krebs solution and 4-6% methylcellulose) to simulate physiological faecal content flow. Remarkably, pellet formation took place in vitro, without extrinsic neural inputs. Infusion evoked slowly propagating neurogenic contractions, the proximal colonic migrating motor complexes (∼0.6cpm), which initiated pellet formation at the flexure. Lesion of the flexure, but not the proximal colon, disrupted formation of normal individual pellets. In addition, a distinct myogenic mechanism was identified, whereby slow phasic contractions (∼1.9cpm) initiated at the flexure and propagated short distances retrogradely into the proximal colon and antegradely into the distal colon. There were no detectable changes in the density or distribution of pacemaker-type Interstitial Cells of Cajal across the flexure. The findings provide new insights into how solid faecal content is generated, suggesting the major mechanisms underlying faecal pellet formation involve the unique interaction at the colonic flexure between antegrade PCMMCs, organized by enteric neurons, and retrograde myogenic SPCs. Additional, as yet unidentified extrinsic and/or humoral influences appear to contribute to processing of faecal content, in vivo. This article is protected by copyright. All rights reserved.

Intestinal catheters have been used for decades in human nutrition, physiology. pharmacokinetics, and gut microbiome research, facilitating the delivery of compounds directly into the intestinal lumen or the aspiration of intestinal fluids in human subjects. Such research provides insights about (local) dynamic metabolic and other intestinal luminal processes. but working with catheters might pose challenges to biomedical researchers and clinicians. Here, we provide an overview of practical and technical aspects of applying naso- and oro-intestinal catheters for delivery of compounds and sampling luminal fluids from the jejunum, ileum, and colon in vivo. The recent literature was extensively reviewed, and combined with experiences and insights we gained through our own clinical trials. We included 60 studies that involved a total of 720 healthy subjects and 42 patients. Most of the studies investigated multiple intestinal regions (24 studies), followed by studies investigating only the jejunum (21 studies), ileum (13 studies), or colon (2 studies). The ileum and colon used to be relatively inaccessible regions in vivo. Custom-made state-of-theart catheters are available with numerous options for the design, such as multiple lumina, side holes. and inflatable balloons for catheter progression or isolation of intestinal segments. These allow for multiple controlled sampling and compound delivery options in different intestinal regions. Intestinal catheters were often used for delivery (23 studies), sampling (10 studies), or both (27 studies). Sampling speed decreased with increasing distance from the sampling syringe to the specific intestinal segment (i.e., speed highest in duodenum, lowest in ileum/colon). No serious adverse events were reported in the literature, and a dropout rate of around 10% was found for these types of studies. This review is highly relevant for researchers who are active in various research areas and want to expand their research with the use of intestinal catheters in humans in vivo.

Intestinal catheters have been used for decades in human nutrition, physiology, pharmacokinetics, and gut microbiome research, facilitating the delivery of compounds directly into the intestinal lumen or the aspiration of intestinal fluids in human subjects. Such research provides insights about (local) dynamic metabolic and other intestinal luminal processes, but working with catheters might pose challenges to biomedical researchers and clinicians. Here, we provide an overview of practical and technical aspects of applying naso- and oro-intestinal catheters for delivery of compounds and sampling luminal fluids from the jejunum, ileum, and colon in vivo. The recent literature was extensively reviewed, and combined with experiences and insights we gained through our own clinical trials. We included 60 studies that involved a total of 720 healthy subjects and 42 patients. Most of the studies investigated multiple intestinal regions (24 studies), followed by studies investigating only the jejunum (21 studies), ileum (13 studies), or colon (2 studies). The ileum and colon used to be relatively inaccessible regions in vivo. Custom-made state-of-the-art catheters are available with numerous options for the design, such as multiple lumina, side holes, and inflatable balloons for catheter progression or isolation of intestinal segments. These allow for multiple controlled sampling and compound delivery options in different intestinal regions. Intestinal catheters were often used for delivery (23 studies), sampling (10 studies), or both (27 studies). Sampling speed decreased with increasing distance from the sampling syringe to the specific intestinal segment (i.e., speed highest in duodenum, lowest in ileum/colon). No serious adverse events were reported in the literature, and a dropout rate of around 10% was found for these types of studies. This review is highly relevant for researchers who are active in various research areas and want to expand their research with the use of intestinal catheters in humans in vivo.

Background Gastroparesis (GP) is a gastrointestinal disorder associated with significant morbidity and healthcare costs. GP patients form a heterogeneous population with diverse etiology, and treatment is often challenging due to a poorly understood underlying pathophysiology. The aim of the present study was to assess antroduodenal motility patterns among the different GP etiologies. Methods We reviewed antroduodenal manometry (ADM) recordings of patients with confirmed GP between 2009 and 2019. ADM measurements were evaluated for fed period duration, number of phase III contractions and migrating motor complexes (MMCs), motility index (MI), and presence of neuropathic patterns. Key results A total of 167 GP patients (142 women, median age 45 [31-57]) were included. The following etiologies were identified: idiopathic n = 101; post-surgery n = 36; and diabetes n = 30. Fed period duration was significantly longer in idiopathic (p < 0.01) and diabetic GP patients (p < 0.05) compared with post-surgery GP patients. Furthermore, the number and duration of phase III contractions and the number of MMCs were significantly lower in idiopathic and diabetic patients compared with post-surgery GP patients (p < 0.01). Likewise, absence of MMCs during 6-h recording was more often observed in idiopathic and diabetes GP patients compared with post-surgery GP patients (resp. p p < 0.05). Conclusions and Inferences Antroduodenal motility patterns are different among GP etiologies. A dysmotility spectrum was identified with different patterns ranging from post-surgery GP to idiopathic and diabetic GP.

Propofol and dexmedetomidine are popular used for sedation in ICU, however, inadequate attention has been paid to their effect on gastrointestinal tract (GIT) motility. Present study aimed to compare the effect of propofol and dexmedetomidine on GIT motility at parallel level of sedation and explore the possible mechanism. Male C57BL/6 mice (8–10 weeks) were randomly divided into control, propofol and dexmedetomidine group. After intraperitoneal injection of propofol or dexmedetomidine, comparable sedative level was confirmed by sedative score, physiological parameters and electroencephalogram (EEG). Different segments of GIT motility in vivo (gastric emptying, small intestine transit, distal colon bead expulsion, stool weight and number of fecal pellets, gastrointestinal transit and whole gut transit time) and colonic migrating motor complexes (CMMCs) pattern in vitro were evaluated. The Ca2+ response of primary enteric glia was examined under the treatment of propofol or dexmedetomidine. There is little difference in physiological parameters and composite permutation entropy index (CPEI) between administration of 50 mg/kg propofol and 40 μg/kg dexmedetomidine, indicated that parallel level of sedation was reached. Data showed that propofol and dexmedetomidine had significantly inhibitory effect on GIT motility while dexmedetomidine was stronger. Also, the amplitude (ΔF/F0) of Ca2+ response in primary enteric glia was attenuated after treated with the sedatives while the effect of dexmedetomidine was greater than propofol. These findings demonstrated that dexmedetomidine caused stronger inhibitory effects on GIT motility in sedative mice, which may involve impaired Ca2+ response in enteric glia. Hence, dexmedetomidine should be carefully applied especially for potential GIT dysmotility patient.

Among all the side effects, opioid-induced constipation (OIC) has the highest incidence rate in people who take chronic opioid therapy. Increasing evidence shows that enteric glial cells (EGCs) play a pivotal role in the modulation of gastrointestinal motility. We aim to investigate whether EGCs are involved in OIC and possible mechanisms. Eight-week male C57BL/6 mice were randomized into four groups: the control group, the morphine group, the gliotoxin fluorocitrate (FC) group, and the FC plus morphine group. OIC was induced by injection of morphine subcutaneously. Colonic motility was evaluated by in vivo motility assays and colonic migrating motor complex (CMMC) in vitro. Both the Ca2+ responses and the release of inflammatory cytokine by EGCs were detected in vitro. Proteins were detected by immunofluorescence staining and Western blot. The morphine group showed prolonged gastrointestinal motility compared with the control group. Once EGCs were disrupted by FC, such inhibitory effect was abolished. There was a remarkable enhancement of the GFAP expression on colonic EGCs. Immunofluorescence exhibited that μ-opioid receptor (MOR) collocated with GFAP, indicating the existence of MOR in EGCs. Moreover, morphine activated the EGCs significantly through enhancing GFAP expression and Ca2+ amplitude. Both effects can be reversed by MOR-siRNA. Morphine treatment elevated the enteric glial release of proinflammatory cytokines notably and this effect was abolished when EGCs were silenced by MOR-siRNA. The activation of EGCs via MOR and the increased proinflammatory cytokine from EGCs may be involved in morphine-induced constipation. These results provided a potential therapeutic target for OIC.

BACKGROUND Interdigestive migrating motor complexes (MMC) produce periodic contractions in the gastrointestinal tract, but the exact mechanism of action still remains unclear. Intramuscular interstitial cells of Cajal (ICC-IM) participate in gastrointestinal hormone and neuromodulation, but the correlation between ICC-IM and MMC is also unclear. We found that xiangbinfang granules (XBF) mediated the phase III contraction of MMC. Here, the effects of XBF on gastric antrum motility in W/Wv mice and the effects of ICC-IM on gastric antrum MMC are reported. AIM To observe the effects of ICC-IM on gastric antrum motility and to establish the mechanism of XBF in promoting gastric antrum motility. METHODS The density of c-kit-positive ICC myenteric plexus (ICC-MP) and ICC-IM in the antral muscularis of W/Wv and wild-type (WT) mice was examined by confocal microscopy. The effects of XBF on gastric antrum slow waves in W/Wv and WT mice were recorded by intracellular amplification recording. Micro-strain-gauge force transducers were implanted into the gastric antrum to monitor the MMC and the effect of XBF on gastric antrum motility in conscious W/Wv and WT mice. RESULTS In the gastric antrum of W/Wv mice, c-kit immunoreactivity was significantly reduced, and no ICC-IM network was observed. Spontaneous rhythmic slow waves also appeared in the antrum of W/Wv mice, but the amplitude of the antrum slow wave decreased significantly in W/Wv mice (22.62 ± 2.23 mV vs 2.92 ± 0.52 mV, P < 0.0001). MMCs were found in 7 of the 8 WT mice but no complete MMC cycle was found in W/Wv mice. The contractile frequency and amplitude index of the gastric antrum were significantly increased in conscious WT compared to W/Wv mice (frequency, 3.53 ± 0.18 cpm vs 1.28 ± 0.12 cpm; amplitude index, 23014.26 ± 1798.65 mV·20 min vs 3782.16 ± 407.13 mV·20 min; P < 0.0001). XBF depolarized smooth muscle cells of the gastric antrum in WT and W/Wv mice in a dose-dependent manner. Similarly, the gastric antrum motility in WT mice was significantly increased after treatment with XBF 5 mg (P < 0.05). Atropine (0.1 mg/kg) blocked the enhancement of XBF in WT and W/Wv mice completely, while tetrodotoxin (0.05 mg/kg) partially inhibited the enhancement by XBF. CONCLUSION ICC-IM participates in the regulation of gastric antrum MMC in mice. XBF induces MMC III-like contractions that enhance gastric antrum motility via ICC-IM in mice.

Purpose Hirschsprung disease (HSCR) is characterized by distal intestinal aganglionosis. While surgery is lifesaving, gastrointestinal (GI) motility disorders persist in many patients. Our objective was to determine whether enteric nervous system (ENS) abnormalities exist in the ganglionated portions of the GI tract far proximal to the aganglionic region and whether these are associated with GI dysmotility. Methods Using Ednrb-null mice, a model of HSCR, immunohistochemical analysis was performed to evaluate quantitatively ENS structure in proximal colon, small intestine, and stomach. Gastric emptying and intestinal transit were measured in vivo and small and large bowel contractility was assessed by spatiotemporal mapping ex vivo. Results Proximal colon of HSCR mice had smaller ganglia and decreased neuronal fiber density, along with a marked reduction in migrating motor complexes. The distal small intestine exhibited significantly fewer ganglia and decreased neuronal fiber density, and this was associated with delayed small intestinal transit time. Finally, in the stomach of HSCR mice, enteric neuronal packing density was increased and gastric emptying was faster. Conclusions ENS abnormalities and motility defects are present throughout the ganglionated portions of the GI tract in Ednrb-deficient mice. This may explain the GI morbidity that often occurs following pull-through surgery for HSCR.

Gastrointestinal (GI) dysfunction is a common comorbidity of chronic obstructive pulmonary disease (COPD) for which a major cause is cigarette smoking (CS). The underlying mechanisms and precise effects of CS on gut contractility, however, are not fully characterised. Therefore, the aim of the present study was to investigate whether CS impacts GI function and structure in a mouse model of CS-induced COPD. We also aimed to investigate GI function in the presence of ebselen, an antioxidant that has shown beneficial effects on lung inflammation resulting from CS exposure. Mice were exposed to CS for 2 or 6 months. GI structure was analysed by histology and immunofluorescence. After 2 months of CS exposure, ex vivo gut motility was analysed using video-imaging techniques to examine changes in colonic migrating motor complexes (CMMCs). CS decreased colon length in mice. Mice exposed to CS for 2 months had a higher frequency of CMMCs and a reduced resting colonic diameter but no change in enteric neuron numbers. Ten days cessation after 2 months CS reversed CMMC frequency changes but not the reduced colonic diameter phenotype. Ebselen treatment reversed the CS-induced reduction in colonic diameter. After 6 months CS, the number of myenteric nitric-oxide producing neurons was significantly reduced. This is the first evidence of colonic dysmotility in a mouse model of CS-induced COPD. Dysmotility after 2 months CS is not due to altered neuron numbers; however, prolonged CS-exposure significantly reduced enteric neuron numbers in mice. Further research is needed to assess potential therapeutic applications of ebselen in GI dysfunction in COPD.

Background/Aims: Patients with Duchenne muscular dystrophy exhibit significant, ongoing impairments in gastrointestinal (GI) function likely resulting from dysregulated nitric oxide production. Compounds increasing neuronal nitric oxide synthase expression and/or activity could improve GI dysfunction and enhance quality of life for dystrophic patients. We used video imaging and spatiotemporal mapping to identify GI dysfunction in mdx dystrophic mice and determine whether dietary intervention to enhance nitric oxide could alleviate aberrant colonic activity in muscular dystrophy. Methods: Four-week-old male C57BL/10 and mdx mice received a specialized diet either with no supplementation (control) or supplemented (1 g/kg/day) with L-alanine, L-arginine, or L-citrulline for 8 weeks. At the conclusion of treatment, mice were sacrificed by cervical dislocation and colon motility examined by spatiotemporal (ST) mapping ex vivo. Results: ST mapping identified increased contraction number in the mid and distal colon of mdx mice on control and L-alanine supplemented diets relative to C57BL/10 mice (P < 0.05). Administration of either L-arginine or L-citrulline attenuated contraction number in distal colons of mdx mice relative to C57BL/10 mice. Conclusions: GI dysfunction in Duchenne muscular dystrophy has been sadly neglected as an issue affecting quality of life. ST mapping identified regional GI dysfunction in the mdx dystrophic mouse. Dietary interventions to increase nitric oxide signaling in the GI tract reduced the number of colonic contractions and alleviated colonic constriction at rest. These findings in mdx mice reveal that L-arginine can improve colonic motility and has potential therapeutic relevance for alleviating GI discomfort, improving clinical care, and enhancing quality of life in Duchenne muscular dystrophy.

Purpose Limited means exist to assess gastrointestinal activity in pediatric patients postoperatively. Recently, myoelectric gastrointestinal activity recorded by cutaneous patches has been shown in adult patients to be predictive of clinical return of gastrointestinal function postoperatively. The aim of this case series is to demonstrate the feasibility of this system in pediatric patients and to correlate myoelectric signals with return of bowel function clinically. Methods Pediatric patients undergoing abdominal surgery were recruited to have wireless patches placed on the abdomen within two hours postoperatively. Myoelectric data were transmitted wirelessly to a mobile device with a user-interface and forwarded to a cloud server where processing algorithms identified episodes of motor activity, quantified their parameters and nominally assigned them to specific gastrointestinal organs based on their frequencies. Results Three patients (ages 5 months, 4 year, 16 year) were recruited for this study. Multiple patches were placed on the older subjects, while the youngest had a single patch due to space limitations. Rhythmic signals of the stomach, small intestine, and colon could be identified in all three subjects. Patients showed gradual increase in myoelectric intestinal and colonic activity leading up to the first recorded bowel movement. Conclusion Measuring myoelectric intestinal activity continuously using a wireless patch system is feasible in a wide age range of pediatric patients. The increase in activity over time correlated well with the patients' return of bowel function. More studies are planned to determine if this technology can predict return of bowel function or differentiate between physiologic ileus and pathologic conditions.

Background/Aims Interstitial 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. Methods Western 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. Results PCO 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. Conclusions Colonic 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.

Key points 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. Abstract 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.

Objectives Antroduodenal manometry (ADM) is used to evaluate antral and small intestinal motility, with the presence of phase III migrating motor complexes (MMC) indicating an intact enteric neuromuscular system. The lack of evidence-based or consensus-driven established norms for MMC in fasting phase and after provocative testing marks a major limitation in the interpretation of ADM studies. We aimed to determine the characteristics of MMC in fasting and post-provocative phase in children. Methods Data from subjects aged ≤ 20 years with ADM results evaluated at Neuro-gastroenterology and Motility Disorders Center, Cincinnati Children's Hospital Medical Center from January 2018 to March 2019 were analyzed. Results Forty-eight ADM tracings that did not demonstrate abnormal patterns were included; the mean age was 10.00 ± 5.72 years and 50% were male. Indications for ADM included: vomiting (27.1%), feeding intolerance (27.1%), abdominal pain (16.6%), nausea (14.6%), and abdominal distension (14.6%). Thirty-seven percent of subjects had enteral access for feeds. During fasting, one-third of all MMC originated in the antrum. Azithromycin-induced MMC occurred in 28% of subjects and two-thirds of these originated in the antrum with antral contractions of significantly higher frequency and amplitude compared to fasting. Octreotide significantly increased frequency, amplitude, and duration of MMC compared to fasting, with 76% originating in the antrum. Both azithromycin and octreotide induced more than one MMC in a third of subjects. Conclusions We describe the characteristics of antral and small intestinal motility during fasting and after provocative testing in children. These values will help standardize our interpretation of pediatric ADM studies.

Introduction Some patients with Parkinson's disease (PD) undergoing levodopa‒carbidopa intestinal gel (LCIG) treatment experience motor fluctuations in the afternoon. The migrating motor complex, a specific periodic migrating contraction pattern occurring in the stomach and small intestine during the fasting state, can affect drug absorption. We aimed to compare the pharmacokinetic parameters between two conditions (with and without lunch) and assessed the influence of the fasting state on the levodopa pharmacokinetics in LCIG treatment. Methods We evaluated the levodopa pharmacokinetics from 12:00 p.m. to 6:00 p.m. in 10 LCIG-treated PD patients in the presence and absence of lunch. Results The maintenance dose of LCIG correlated strongly with the mean plasma concentration of levodopa in the absence (r = 0.94, coefficient of determination (R2) = 0.89, p Conclusions Plasma concentrations of levodopa fluctuated more in patients undergoing LCIG treatment without than with lunch. Our results indicate that a small amount of food intake may be a better corrective approach for worsening of symptoms in the fasting state rather than additional levodopa.

Altres ajuts: acords transformatius de la UAB Background: The manometric diagnosis of severe intestinal dysmotility is performed at most institutions using catheters with 2-8 sensors 5-10 cm apart. The recent application of high-resolution manometry catheters with closely spaced sensors to other gut segments has been highly successful. The objective of the present study was to determine the feasibility of a jejunal high-resolution manometry method and to carry out a descriptive analysis of normal jejunal motor function. Methods: A 36-channel high-resolution water-perfused manometry catheter (MMS-Laborie, Enschede, The Netherlands) was orally placed in the jejunum of 18 healthy subjects (10 men, eight women; 21-38 age range). Intestinal motility was recorded during 5 h, 3 during fasting, and 2 after a 450 kcal solid-liquid meal. Analysis of motility patterns was supported by computerized tools. Key Results: All healthy subjects except one showed at least one complete migrating motor complex during the 3 h fasting period. Phase III activity lasted 5 ± 1 min and migrated aborally at a velocity of 7 ± 3 cm/min. High-resolution spatial analysis showed that during phase III each individual contraction propagated rapidly (75 ± 37 cm/min) over a 32 ± 10 cm segment of the jejunum. During phase II, most contractile activity corresponded to propagated contractile events which increased in frequency from early to late phase II (0.5 ± 0.9 vs 2.5 ± 1.3 events/10 min, respectively; p < 0.001). After meal ingestion, non-propagated activity increased, whereas propagated events were less frequent than during late phase II. Conclusions & Inferences: Jejunal motility analysis with high-resolution manometry identifies propagated contractile patterns which are not apparent with conventional manometric catheters.

Background Recent 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). Methods We 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. Results The number of MMC phase IIIs in FD was significantly lower than that in HC (2.6 ± 1.4 vs 4.8 ± 1.7, p

Background/aims High-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. Methods Ten 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. Results Twenty-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). Conclusions Intestinal 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.

ObjectiveThe effectiveness of µ-opioid receptor (MOPr) agonists for treatment of visceral pain is compromised by constipation, respiratory depression, sedation and addiction. We investigated whether a fentanyl analogue, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), which preferentially activates MOPr in acidified diseased tissues, would inhibit pain in a preclinical model of inflammatory bowel disease (IBD) without side effects in healthy tissues.DesignAntinociceptive actions of NFEPP and fentanyl were compared in control mice and mice with dextran sodium sulfate colitis by measuring visceromotor responses to colorectal distension. Patch clamp and extracellular recordings were used to assess nociceptor activation. Defecation, respiration and locomotion were assessed. Colonic migrating motor complexes were assessed by spatiotemporal mapping of isolated tissue. NFEPP-induced MOPr signalling and trafficking were studied in human embryonic kidney 293 cells.ResultsNFEPP inhibited visceromotor responses to colorectal distension in mice with colitis but not in control mice, consistent with acidification of the inflamed colon. Fentanyl inhibited responses in both groups. NFEPP inhibited the excitability of dorsal root ganglion neurons and suppressed mechanical sensitivity of colonic afferent fibres in acidified but not physiological conditions. Whereas fentanyl decreased defecation and caused respiratory depression and hyperactivity in mice with colitis, NFEPP was devoid of these effects. NFEPP did not affect colonic migrating motor complexes at physiological pH. NFEPP preferentially activated MOPr in acidified extracellular conditions to inhibit cAMP formation, recruit β-arrestins and evoke MOPr endocytosis.ConclusionIn a preclinical IBD model, NFEPP preferentially activates MOPr in acidified microenvironments of inflamed tissues to induce antinociception without causing respiratory depression, constipation and hyperactivity.

BACKGROUND: Different peripheral pathways are implicated in the regulation of the food ingestion-digestion cycle. METHODS: Narrative review on gastrointestinal mechanisms involved in satiety and hunger signalling. RESULTS: Combined mechano- and chemoreceptors, peripherally released peptide hormones and neural pathways provide feedback to the brain to determine sensations of hunger (increase energy intake) or satiation (cessation of energy intake) and regulate the human metabolism. The gastric accommodation reflex, which consists of a transient relaxation of the proximal stomach during food intake, has been identified as a major determinant of meal volume, through activation of tension-sensitive gastric mechanoreceptors. Motilin, whose release is the trigger of gastric Phase 3, has been identified as the major determinant of return of hunger after a meal. In addition, the release of several peptide hormones such as glucagon-like peptide 1 (GLP-1), cholecystokinin as well as motilin and ghrelin contributes to gut-brain signalling with relevance to control of hunger and satiety. A number of nutrients, such as bitter tastants, as well as pharmacological agents, such as endocannabinoid receptor antagonists and GLP-1 analogues act on these pathways to influence hunger, satiation and food intake. CONCLUSION: Gastrointestinal mechanisms such as gastric accommodation and motilin release are key determinants of satiety and hunger. ispartof: UNITED EUROPEAN GASTROENTEROLOGY JOURNAL vol:9 issue:6 pages:727-734 ispartof: location:England status: published

The enteric nervous system (ENS) is an extensive network comprising millions of neurons and glial cells contained within the wall of the gastrointestinal tract. The major functions of the ENS that have been most studied include the regulation of local gut motility, secretion, and blood flow. Other areas that have been gaining increased attention include its interaction with the immune system, with the gut microbiota and its involvement in the gut-brain axis, and neuro-epithelial interactions. Thus, the enteric circuitry plays a central role in intestinal homeostasis, and this becomes particularly evident when there are faults in its wiring such as in neurodevelopmental or neurodegenerative disorders. In this review, we first focus on the current knowledge on the cellular composition of enteric circuits. We then further discuss how enteric circuits detect and process external information, how these signals may be modulated by physiological and pathophysiological factors, and finally, how outputs are generated for integrated gut function. ispartof: CELLULAR AND MOLECULAR LIFE SCIENCES vol:77 issue:22 pages:4505-4522 ispartof: location:Switzerland status: published