The role of free fatty acid receptor-1 in gastric contractions in Suncus murinus.

Motilin is an important hormonal regulator in the migrating motor complex (MMC). Free fatty acid receptor-1 (FFAR1, also known as GPR40) has been reported to stimulate motilin release in human duodenal organoids. However, how FFAR1 regulates gastric motility in vivo is unclear. This study investigated the role of FFAR1 in the regulation of gastric contractions and its possible mechanism of action using Suncus murinus. Firstly, intragastric administration of oleic acid (C18:1, OA), a natural ligand for FFAR1, stimulated phase II-like contractions, followed by phase III-like contractions in the fasted state, and the gastric emptying rate was accelerated. The administration of GW1100, an FFAR1 antagonist, inhibited the effects of OA-induced gastric contractions. Intravenous infusion of a ghrelin receptor antagonist (DLS) or serotonin 4 (5-HT4) receptor antagonist (GR125487) inhibited phase II-like contractions and prolonged the onset of phase III-like contractions induced by OA. MA-2029, a motilin receptor antagonist, delayed the occurrence of phase III-like contractions. In vagotomized suncus, OA did not induce phase II-like contractions. In addition, OA promoted gastric emptying through a vagal pathway during the postprandial period. However, OA did not directly act on the gastric body to induce contractions in vitro. In summary, this study indicates that ghrelin, motilin, 5-HT, and the vagus nerve are involved in the role of FFAR1 regulating MMC. Our findings provide novel evidence for the involvement of nutritional factors in the regulation of gastric motility.

Effect of cholecystokinin on small intestinal motility in suncus murinus.

In a fasting gastrointestinal tract, a characteristic cyclical rhythmic migrating motor complex (MMC) occur that comprises of three phases: I, II, and III. Among these, phase III contractions propagate from the stomach to the lower intestine in mammals, including humans, dogs, and Suncus murinus (suncus). Apart from the phase III of MMC propagating from the stomach, during the gastric phase II, small intestine-originated strong contractions propagate to the lower small intestine; however, the mechanism of contractions originating in the small intestine has not been clarified. In this study, we aimed to elucidate the role of cholecystokinin (CCK) in small intestinal motility. Administration of sulfated CCK-8 in phase I induced phase II-like contractions in the small intestine, which lasted for approximately 10-20 min and then returned to the baseline, while no change was observed in the stomach. Contractions of small intestine induced by CCK-8 were abolished by lorglumide, a CCK1 receptor antagonist. Gastrin, a ligand for the CCK2 receptor, evoked strong contractions in the stomach, but did not induce contractions in the small intestine. To examine the effect of endogenous CCK on contractions of small intestinal origin, lorglumide was administered during phase II. However, there was no change in the duodenal motility pattern, and strong contractions of small intestinal origin were not abolished by treatment with lorglumide. These results suggest that exogenous CCK stimulates contractions of small intestine via CCK1 receptors, whereas endogenous CCK is not involved in the strong contractions of small intestinal origin.

Clinical Utility of Ileal Motility in Children With Defecation Disorders and Children With Chronic Intestinal Pseudo-Obstruction.

BACKGROUND: Little is known about ileal motility patterns and their utility in children. Here, we present our experience with children undergoing ileal manometry (IM). METHODS: A retrospective review of children with ileostomy comparing IM between 2 groups: A [chronic intestinal pseudo-obstruction (CIPO)] and B (feasibility of ileostomy closure in children with defecation disorders). We also compared the IM findings with those from antroduodenal manometry (ADM), and evaluated the joint effect of age, sex, and study indication group on IM results. RESULTS: A total of 27 children (median age 5.8 years old, range 0.5-16.74 years, 16 were female) were included (12 in group A and 15 in group B). There was no association between IM interpretation and sex; however younger age was associated with abnormal IM ( P = 0.021). We found a significantly higher proportion of patients with presence of phase III of the migrating motor complex (MMC) during fasting and normal postprandial response in group B than in group A ( P < 0.001). Logistic regression analysis revealed that only Group B was associated with normal IM ( P < 0.001). We found a moderate agreement for the presence of phase III MMC and postprandial response between IM and ADM (kappa = 0.698, P = 0.008 and kappa = 0.683, P = 0.009, respectively). CONCLUSION: IM is abnormal in patients with CIPO and normal in patients with defecation disorders, suggesting that IM may be not needed for ostomy closure in those with defecation disorders. IM has a moderate agreement with ADM and could be used as a surrogate for small bowel motility.

Physiological functions and potential clinical applications of motilin.

Motilin is a gastrointestinal hormone secreted by the duodenum. This peptide regulates a characteristic gastrointestinal contraction pattern, called the migrating motor complex, during the fasting state. Motilin also affects the pressure of the lower esophageal sphincter, gastric motility and gastric accommodation in the gastrointestinal tract. Furthermore, motilin induces bile discharge into the duodenum by promoting gallbladder contraction, pepsin secretion in the stomach, pancreatic juice and insulin secretion from the pancreas. In recent years, it has been shown that motilin is associated with appetite, and clinical applications are expected for diseases affected by food intake, e.g. obesity, by regulating motilin levels. Gastric acid and bile are the two major physiological regulators for motilin release. Caloric foods have varying effects on motilin levels, depending on their composition. Among non-caloric foods, bitter substances reduce motilin levels and are therefore expected to have an appetite-suppressing effect. Various motilin receptor agonists and antagonists have been developed but have yet to reach clinical use.

Antroduodenal motility recording identifies characteristic patterns in gastroparesis related to underlying etiology.

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 < 0.01 and 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.

Propagation patterns of jejunal motor activity measured by high-resolution water-perfused manometry.

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.

Alteration of sphingosine-1-phosphate with aging induces contractile dysfunction of colonic smooth muscle cells via Ca2+ -activated K+ channel (BKCa ) upregulation.

BACKGROUND: Age-associated changes alter calcium-activated potassium channel (BKCa ) expression of colon. Sphingolipids (SLs) are important cell membrane structural components; altered composition of SLs may affect BKCa expression. This study investigated the mechanism by which sphingosine-1-phosphate (S1P) contributes to age-associated contractile dysfunction. METHODS: Fifty male Sprague Dawley rats of different ages were randomly assigned to five age-groups, namely 3, 6, 12, 18, and 24 months. BKCa expression, S1P levels, and phosphorylated myosin light chain (p-MLC) levels were tested in colonic tissues. In the absence and presence of S1P treatment, BKCa expression, p-MLC levels, and intracellular calcium mobilization were tested in vitro. BKCa small interfering RNA (siRNA) was used to investigate whether p-MLC expression and calcium mobilization were affected by BKCa in colonic smooth muscle cells (SMCs). The expressions of phosphorylated protein kinase B, c-Jun N-terminal kinases (JNKs), extracellular-regulated protein kinases, nuclear factor kappa-B (NF-κB), and protein kinase Cζ (PKCζ ) were examined to investigate the correlation between S1P and BKCa . KEY RESULTS: Sphingosine-1-phosphate levels and sphingosine-1-phosphate receptor 2 (S1PR2) and BKCa expressions were upregulated and p-MLC expression was downregulated in the colonic tissues, age dependently. In the cultured SMCs, S1P treatment increased BKCa expression and reduced calcium concentration and p-MLC was observed. BKCa siRNA increased calcium concentration, and p-MLC levels significantly compared with control. We also showed that S1P upregulated BKCa through PKCζ , JNK, and NF-κB pathways. CONCLUSIONS AND INFERENCES: In conclusion, S1P and S1PR2 participate in age-associated contractile dysfunction via BKCa upregulation through PKCζ , JNK, and NF-κB pathways.

Advances in colonic motor complexes in mice.

The primary functions of the gastrointestinal (GI) tract are to absorb nutrients, water, and electrolytes that are essential for life. This is accompanied by the capability of the GI tract to mix ingested content to maximize absorption and effectively excrete waste material. There have been major advances in understanding intrinsic neural mechanisms involved in GI motility. This review highlights major advances over the past few decades in our understanding of colonic motor complexes (CMCs), the major intrinsic neural patterns that control GI motility. CMCs are generated by rhythmic coordinated firing of large populations of myenteric neurons. Initially, it was thought that serotonin release from the mucosa was required for CMC generation. However, careful experiments have now shown that neither the mucosa nor endogenous serotonin are required, although, evidence suggests enteroendocrine (EC) cells modulate CMCs. The frequency and extent of propagation of CMCs are highly dependent on mechanical stimuli (circumferential stretch). In summary, the isolated mouse colon emerges as a good model to investigate intrinsic mechanisms underlying colonic motility and provides an excellent preparation to explore potential therapeutic agents on colonic motility, in a highly controlled in vitro environment. In addition, during CMCs, the mouse colon facilitates investigations into the emergence of dynamic assemblies of extensive neural networks, applicable to the nervous system of different organisms.

Is the 'reverse onion skin' phenomenon more prevalent than we thought during intramuscular myoelectric recordings from low to maximal force outputs?

There are isolated instances in the literature that suggest the 'onion skin' phenomenon is not always present. That is, newly recruited high threshold motor units (MU) have higher discharge rates than previously recruited low threshold MUs. Therefore, the purpose of this paper was to investigate the presence of the 'onion skin' phenomenon in a large sample of intramuscular myoelectric recordings from low to maximal force outputs. Forty-eight participants performed rapid isometric dorsiflexion contractions at 20, 40, 60, 80 and 100 % MVC while intramuscular electrical activity was recorded. A bivariate frequency-distribution of the motor unit discharge rate and motor unit action potential peak-to-peak (P-P) amplitude was assessed. There was a significant difference in bivariate frequency-distribution across force levels (D's = 0.1083-0.3094, p's < 0.001). Newly recruited high threshold MUs did have lower discharge rates, but there was an increase in the presence of high threshold, large P-P amplitude MUs with higher discharge rates than lower threshold MUs (reverse onion skin) during the stable portion of the force output. The recruitment of high threshold MUs with higher discharge rates decreased the level of common drive from the cross-correlation (Rxy) = 0.79 at 20 % MVC to Rxy = 0.68 at 100 % MVC (p < 0.01), but it remained high. As the interference pattern becomes more complex with the recruitment of more motor units at higher force outputs, intramuscular electrodes may be more discriminating while recording motor unit activity leading to the identification of both the 'reverse onion skin' and 'onion skin' phenomenon being present.

Characterization of alternating neurogenic motor patterns in mouse colon.

BACKGROUND: Colonic motor complexes (CMCs) have been widely recorded in the large intestine of vertebrates. We have investigated whether in the smooth muscle, a single unified pattern of electrical activity, or different patterns of electrical activity give rise to the different neurogenic patterns of motility underlying CMCs in vitro. METHODS: To study differences of the CMCs between proximal and distal colon, we used a novel combination of techniques to simultaneously record muscle diameter and force at multiple sites along the whole mouse colon ex vivo. In addition, electrical activity of smooth muscle was recorded by suction electrodes. KEY RESULTS: Two distinct types of CMCs were distinguished; CMCs that propagated along the entire colon (complete CMC) and CMCs which were restricted to the proximal colon (incomplete CMC). The two types of CMC often occurred in the same preparations. Incomplete CMCs had longer bursts of smooth muscle action potentials than complete CMCs and propagated more slowly. Interestingly, both types of CMC were associated with similar frequency bursts of smooth muscle action potentials at ~2.4 Hz. In the most proximal colon, an additional firing frequency was detected close to ~7 Hz generating multiple peaks within each CMC. CONCLUSIONS & INFERENCES: We report distinct characteristics underlying complete and incomplete CMCs in isolated mouse colon. Recognizing these distinct patterns of motility will be important for future interpretation of analysis of murine colonic motility recordings. The identification of alternating patterns of motor activity in proximal colon, but not distal colon may reflect specific neural mechanisms for fecal pellet formation.

Toxoplasma gondii infection impairs the colonic motility of rats due to loss of myenteric neurons.

BACKGROUND: Toxoplasma gondii infection causes intestinal inflammation and diarrhea indicating possible intestinal motor dysfunction. Anatomical studies have shown alterations in the colonic myenteric plexus, but it is unknown whether this impacts motility and therefore whether motility is a target for treatment. We determined whether colonic coordinated movements are compromised by toxoplasmic infection and how it is associated with anatomical changes. METHODS: Male Wistar rats were evaluated at 6, 12, 24, 48, and 72 hours and 30 days postinfection (dpi) and controls. Infected rats received orally 5 × 103 sporulated oocysts of strain ME-49 (genotype II) of T gondii. The colon was collected for anatomical analysis (including the myenteric plexus immunolabeled with HuC/D, nNOS, and ChAT) and motility analysis in vitro (conventional manometry). Fecal output was measured daily. KEY RESULTS: At 12 hours postinfection, T gondii caused hypertrophy of the muscularis externa layer of the distal colon. There was loss of total, nitrergic, and cholinergic myenteric neurons in the proximal colon at 30 day postinfection (dpi); however, only loss of cholinergic neurons was found in the distal colon. Contractile complexes in the middle and distal colon were longer in duration in infected animals, which was associated with slower migration of the colonic motor complex. However, gastrointestinal transit time and fecal pellet output remained unchanged during the T gondii infection. CONCLUSIONS AND INFERENCES: Toxoplasma gondii caused myenteric neuronal loss in the proximal and distal colon and altered the motility pattern in the middle and distal colon to a more propulsive phenotype.

Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility.

The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.

Motilin: a panoply of communications between the gut, brain, and pancreas.

Introduction: Motilin was first alluded to nearly a century ago. But it remains a rather abstruse peptide, in the shadow of its younger but more lucid 'cousin' ghrelin.Areas covered: The review aimed to bring to the fore multifarious aspects of motilin research with a view to aiding prioritization of future studies on this gastrointestinal peptide.Expert opinion: Growing evidence indicates that rodents (mice, rats, guinea pigs) do not have functional motilin system and, hence, studies in these species are likely to have a minimal translational impact. Both the active peptide and motilin receptor were initially localized to the upper gastrointestinal tract only but more recently - also to the brain (in both humans and other mammals with functional motilin system). Motilin is now indisputably implicated in interdigestive contractile activity of the gastrointestinal tract (in particular, gastric phase III of the migrating motor complex). Beyond this role, evidence is building that there is a cross-talk between motilin system and the brain-pancreas axis, suggesting that motilin exerts not only contractile but also orexigenic and insulin secretagogue actions.

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.

Identification of multiple distinct neurogenic motor patterns that can occur simultaneously in the guinea pig distal colon.

In the guinea pig distal colon, nonpropulsive neurally mediated motor patterns have been observed in different experimental conditions. Isolated segments of guinea pig distal colon were used to investigate these neural mechanisms by simultaneously recording wall motion, intraluminal pressure, and smooth muscle electrical activity in different conditions of constant distension and in response to pharmacological agents. Three distinct neurally dependent motor patterns were identified: transient neural events (TNEs), cyclic motor complexes (CMC), and distal colon migrating motor complexes (DCMMC). These could occur simultaneously and were distinguished by their electrophysiological, mechanical, and pharmacological features. TNEs occurred at irregular intervals of ~3s, with bursts of action potentials at 9 Hz. They propagated orally at 12 cm/s via assemblies of ascending cholinergic interneurons that activated final excitatory and inhibitory motor neurons, apparently without involvement of stretch-sensitive intrinsic primary afferent neurons. CMCs occurred during maintained distension and consisted of clusters of closely spaced TNEs, which fused to cause high-frequency action potential firing at 7 Hz lasting ~10 s. They generated periodic pressure peaks mediated by stretch-sensitive intrinsic primary afferent neurons and by cholinergic interneurons. DCMMCs were generated by ongoing activity in excitatory motor neurons without apparent involvement of stretch-sensitive neurons, cholinergic interneurons, or inhibitory motor neurons. In conclusion, we have identified three distinct motor patterns that can occur concurrently in the isolated guinea pig distal colon. The mechanisms underlying the generation of these neural patterns likely involve recruitment of different populations of enteric neurons with distinct temporal activation properties.

Osteopathic Manipulative Treatment Alters Gastric Myoelectric Activity in Healthy Subjects.

Objectives: It is unclear whether osteopathic manipulative treatment (OMT) affects gastric myoelectric activity (GMA), an index of gastric motility. We hypothesized that OMT significantly alters power spectral density (PSD) analyses of electrogastrography (EGG) recordings, an index of GMA, compared with time control OMT. Design: GMA data were obtained from nine subjects before and after OMT and time control on separate days in a cross-over design. Fifteen-minute EGG recordings were obtained before and after each intervention and after a water challenge (WC). Percent power in the normogastric range (PPN) was estimated from PSD analyses. Absolute percent change of PPN and dominant frequency (DF) from baseline to postintervention and baseline to post-WC was computed and compared using two-way repeated-measures ANOVA. Results: OMT altered PPN versus time control (time control: 5.3% ± 1.2%; OMT: 24.5% ± 4.5%; p = 0.015). WC altered PPN compared with time control (post-time control ΔPPN: 5.3% ± 1.2%; post-drink ΔPPN: 30.3% ± 7.2%; p < 0.01). However, WC did not alter PPN with prior OMT treatment (post-OMT ΔPPN: 24.5% ± 4.5%; post-WC ΔPPN: 19.4% ± 5.6%; p = 0.47). Nevertheless, OMT reduced the rate of change for DF compared with time control (WC post-time control: 37.9% ± 7.4%; WC post-OMT: 20.0% ± 5.9%; p = 0.02). Conclusions: We conclude that (1) OMT significantly alters GMA compared with time control and that (2) OMT reduces the rate of change in the frequency response to WC within the normal frequency range of 2-4 cycles per minute, indicating a physiological effect.

Cyclic Change of Sphincter of Oddi Motility and Its Relationship with Small Bowel Migrating Motor Complex in Humans.

BACKGROUND: Several animal and human studies have reported that sphincter of Oddi (SO) motility shows cyclical changes during the fasting state. However, to date, the relationship between the SO motility and the migrating motor complex (MMC) of the small bowel (SB) remains unclear in humans. AIMS: We observed SO motility over a long study period and evaluated its relationship with the MMC of the SB in humans using percutaneous long-term manometry. METHODS: Our study included patients with hepatolithiasis who required percutaneous transhepatic catheter placement and subsequently underwent choledochoscopy and stone removal. Long-term percutaneous transhepatic SO manometry was performed after complete stone removal. SO and SB motility were simultaneously recorded. RESULTS: SO motility showed cyclical phasic changes with periodic high-frequency contractions similar to the MMC contractions of the SB. All high-frequency contractions of the SO coincided with phase III contractions of the MMC of the SB. The proportions of phase III contractions of SO and SB were similar, but the proportions of phase I (P = 0.001) and phase II (P = 0.002) contractions were significantly different. The mean basal SO pressure was observed to significantly increase in phase III compared to phase I (P = 0.001) and phase II (P = 0.001) contractions. CONCLUSIONS: SO motility in humans showed cyclical phasic changes closely coordinated with the MMC of the SB in a fasting state; however, the proportion of phases differed between the SO and the SB. The basal pressure significantly increased during physiological high-frequency phase III contractions of the SO.

Identification of a Rhythmic Firing Pattern in the Enteric Nervous System That Generates Rhythmic Electrical Activity in Smooth Muscle.

The enteric nervous system (ENS) contains millions of neurons essential for organization of motor behavior of the intestine. It is well established that the large intestine requires ENS activity to drive propulsive motor behaviors. However, the firing pattern of the ENS underlying propagating neurogenic contractions of the large intestine remains unknown. To identify this, we used high-resolution neuronal imaging with electrophysiology from neighboring smooth muscle. Myoelectric activity underlying propagating neurogenic contractions along murine large intestine [also referred to as colonic migrating motor complexes, (CMMCs)] consisted of prolonged bursts of rhythmic depolarizations at a frequency of ∼2 Hz. Temporal coordination of this activity in the smooth muscle over large spatial fields (∼7 mm, longitudinally) was dependent on the ENS. During quiescent periods between neurogenic contractions, recordings from large populations of enteric neurons, in mice of either sex, revealed ongoing activity. The onset of neurogenic contractions was characterized by the emergence of temporally synchronized activity across large populations of excitatory and inhibitory neurons. This neuronal firing pattern was rhythmic and temporally synchronized across large numbers of ganglia at ∼2 Hz. ENS activation preceded smooth muscle depolarization, indicating rhythmic depolarizations in smooth muscle were controlled by firing of enteric neurons. The cyclical emergence of temporally coordinated firing of large populations of enteric neurons represents a unique neural motor pattern outside the CNS. This is the first direct observation of rhythmic firing in the ENS underlying rhythmic electrical depolarizations in smooth muscle. The pattern of neuronal activity we identified underlies the generation of CMMCs.SIGNIFICANCE STATEMENT How the enteric nervous system (ENS) generates neurogenic contractions of smooth muscle in the gastrointestinal (GI) tract has been a long-standing mystery in vertebrates. It is well known that myogenic pacemaker cells exist in the GI tract [called interstitial cells of Cajal (ICCs)] that generate rhythmic myogenic contractions. However, the mechanisms underlying the generation of rhythmic neurogenic contractions of smooth muscle in the GI tract remains unknown. We developed a high-resolution neuronal imaging method with electrophysiology to address this issue. This technique revealed a novel pattern of rhythmic coordinated neuronal firing in the ENS that has never been identified. Rhythmic neuronal firing in the ENS was found to generate rhythmic neurogenic depolarizations in smooth muscle that underlie contraction of the GI tract.

The effect of arabinoxylooligosaccharides on upper gastroduodenal motility and hunger ratings in humans.

BACKGROUND AND AIMS: Prebiotics such as Arabinoxylooligosaccharides (AXOS) are non-digestible, fermentable food ingredients stimulating growth/activity of colonic bacteria with enhanced carbohydrates fermentation (CF) in humans. The migrating motor complex (MMC) of the gastrointestinal tract has been recently identified as an important hunger signal, but no data are available yet on the role of acute CF on MMC activity and related hunger ratings. Thus, we aimed to study the effect of acute AXOS CF on MMC and hunger in humans. METHODS: A total of 13 healthy volunteers were randomized in a single-blind crossover placebo-controlled study where 9.4 g of AXOS or 10 g of maltodextrin and 1 g of unlabelled lactose ureide (LU) were given 12 hours prior to the study and, in the next morning, together with a pancake containing 500 mg of 13 C-LU. In 10 hours after the meal, 13 CO2 and hydrogen excretion were determined every 15 minutes while hunger/appetite ratings every 2 minutes through a VAS questionnaire. Five hours after the meal, antroduodenal motility was measured using HRM. KEY RESULTS: AXOS significantly increased CF (158 ± 81 vs 840 ± 464 H2 ppm*minute, placebo vs AXOS, P < .05) without affecting the orocecal transit time (OCTT). AXOS had no significant effect on the occurrence, origin, and duration of phase III and on the total number, origin, and duration of phases I and II. Hunger and appetite scores prior and after phase III were not affected by AXOS. CONCLUSIONS: AXOS acutely increases colonic fermentation, but this neither affects OCTT, activity of the MMC, nor interdigestive hunger scores in man.

GABAergic and glutamatergic neurons in the brain regulate phase II of migrating motor contractions in the Suncus murinus.

Gastric contractions exhibit characteristic motor patterns in the fasted state, known as migrating motor contractions (MMC). MMC consist of three periodically repeated phases (phase I, II and III) and are known to be regulated by hormones and the autonomic and enteric nervous systems. However, the central regulation of gastric contractions in the fasted state is not completely understood. Here, we have examined the central effects of motilin, ghrelin, γ-aminobutyric acid (GABA) and L-glutamate signaling on gastric MMC by using suncus (Suncus murinus) as an animal model, because of their similar gastric motor patterns to those observed in humans and dogs. Intracerebroventricular (i.c.v.) administration of motilin and ghrelin had no effect on phase I and II contractions, respectively. Conversely, i.c.v. administration of GABAA receptor antagonist, during phase I of the MMC, evoked phase II-like contractions and significantly increased the motility index (MI). This was compared with the i.c.v. administration of GABA which inhibited spontaneous phase II contractions with a significantly decreased MI. In addition, i.c.v. administration of L-glutamate during phase I also induced phase II-like irregular contractions with a significant increase in the MI. Taken together with previous findings, these results suggest that central GABAergic and glutamatergic signaling, with the coordination of both peripheral motilin and ghrelin, regulate phase II contractions of MMC in the fasted state.