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Yokota N, Takemi S, Sakata I. Effect of cholecystokinin on small intestinal motility in suncus murinus. Gen Comp Endocrinol 2023; 342:114352. [PMID: 37517599 DOI: 10.1016/j.ygcen.2023.114352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 05/17/2023] [Accepted: 07/27/2023] [Indexed: 08/01/2023]
Abstract
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.
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Affiliation(s)
- Naho Yokota
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Shota Takemi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; Research Area of Evolutionary Molecular Design, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan.
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2
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Hibberd TJ, Ramsay S, Spencer-Merris P, Dinning PG, Zagorodnyuk VP, Spencer NJ. Circadian rhythms in colonic function. Front Physiol 2023; 14:1239278. [PMID: 37711458 PMCID: PMC10498548 DOI: 10.3389/fphys.2023.1239278] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 08/17/2023] [Indexed: 09/16/2023] Open
Abstract
A rhythmic expression of clock genes occurs within the cells of multiple organs and tissues throughout the body, termed "peripheral clocks." Peripheral clocks are subject to entrainment by a multitude of factors, many of which are directly or indirectly controlled by the light-entrainable clock located in the suprachiasmatic nucleus of the hypothalamus. Peripheral clocks occur in the gastrointestinal tract, notably the epithelia whose functions include regulation of absorption, permeability, and secretion of hormones; and in the myenteric plexus, which is the intrinsic neural network principally responsible for the coordination of muscular activity in the gut. This review focuses on the physiological circadian variation of major colonic functions and their entraining mechanisms, including colonic motility, absorption, hormone secretion, permeability, and pain signalling. Pathophysiological states such as irritable bowel syndrome and ulcerative colitis and their interactions with circadian rhythmicity are also described. Finally, the classic circadian hormone melatonin is discussed, which is expressed in the gut in greater quantities than the pineal gland, and whose exogenous use has been of therapeutic interest in treating colonic pathophysiological states, including those exacerbated by chronic circadian disruption.
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Affiliation(s)
- Timothy J. Hibberd
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Stewart Ramsay
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | | | - Phil G. Dinning
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Colorectal Surgical Unit, Division of Surgery, Flinders Medical Centre, Adelaide, SA, Australia
| | | | - Nick J. Spencer
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
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3
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Seibel J, Neumann A, Müller A, Wonnemann M. Food Interactions Observed in a Pharmacokinetic Investigation Comparing Two Marketed Cold Preparations (BNO1016 and ELOM-080) after Administration to Beagle Dogs - A Pilot Study. PLANTA MEDICA 2023; 89:140-147. [PMID: 35523231 PMCID: PMC9868777 DOI: 10.1055/a-1821-8690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/14/2022] [Indexed: 06/14/2023]
Abstract
Sinupret extract (BNO 1016) and Gelomyrtol forte (ELOM-080) represent the two top-selling cold remedies in Germany nowadays. Whereas BNO 1016 is a typical immediate release coated tablet, ELOM-080 is an enteric-coated soft gelatin capsule. The latter formulation, however, is at risk of pharmacokinetic interactions affecting absorption, especially in cases of concomitant food intake. In the present pilot study, we investigated the risk of a possible food effect in three male beagle dogs. Single doses of BNO 1016 and ELOM-80 were administered under fasting and fed conditions. Blood was sampled up to 30 h post-administration and plasma concentrations of the characteristic ingredients of BNO 1016 as well as ELOM-080 analytes were determined. Pharmacokinetic parameters focusing on the rate and extent of absorption were derived. BNO 1016 analytes demonstrated a similar course in both the fasted and fed states. ELOM-080 analytes also showed a similar picture in the fasted state. However, lag times (time from administration to first quantifiable time point in plasma) of up to 2 h post-administration with corresponding time to reach maximum concentration (obtained directly from the measured concentration) values of 3 to 4 h were observed, reflecting a longer gastric residence time. In the fed state, ELOM-080 showed significant pharmacokinetic characteristics, suggesting a clear food effect. A major observation was a double peak phenomenon that could be observed in two of three dogs. Furthermore, lag times of some analytes, up to 3 - 4 h, and corresponding time to reach maximum concentration values, up to 6 - 8 h, occurred. In contrast to BNO 1016, these findings suggest that, as with other enteric-coated formulations, there may also be a significant risk for food effects with ELOM-080 in humans.
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Affiliation(s)
- Jan Seibel
- Bionorica SE, Dept. Clinical & Scientific Affairs R&D, Neumarkt i. d. O.Pf., Germany
| | - Astrid Neumann
- Bionorica Research GmbH, Dept. Bioanalytics, Innsbruck, Austria
| | - Anne Müller
- Bionorica Research GmbH, Dept. Bioanalytics, Innsbruck, Austria
| | - Meinolf Wonnemann
- Bionorica SE, Dept. Clinical & Scientific Affairs R&D, Neumarkt i. d. O.Pf., Germany
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Mori H, Verbeure W, Tanemoto R, Sosoranga ER, Jan Tack. Physiological functions and potential clinical applications of motilin. Peptides 2023; 160:170905. [PMID: 36436612 DOI: 10.1016/j.peptides.2022.170905] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 11/27/2022]
Abstract
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.
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Affiliation(s)
- Hideki Mori
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Japan
| | - Wout Verbeure
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Rina Tanemoto
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | | | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
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5
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Takemi S, Honda W, Yokota N, Sekiya H, Miura T, Wada R, Sakai T, Sakata I. Molecular cloning of cholecystokinin (CCK) and CCK-A receptor and mechanism of CCK-induced gastrointestinal motility in Suncus murinus. Gen Comp Endocrinol 2022; 327:114074. [PMID: 35700795 DOI: 10.1016/j.ygcen.2022.114074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 06/02/2022] [Accepted: 06/09/2022] [Indexed: 11/25/2022]
Abstract
Cholecystokinin (CCK) is a peptide hormone mainly secreted by small intestinal endocrine I-cells and functions as a regulator of gallbladder contraction, gastric emptying, gastrointestinal (GI) motility, and satiety. The cellular effects of CCK in these peripheral tissues are predominantly mediated via CCK-A receptors which are found in smooth muscles, enteric neurons, and vagal afferent neurons in humans and animal models. Although various functions of CCK have been reported to be neurally mediated, it can also stimulate contraction via the CCK receptor on the smooth muscle. However, the entire underlying neural and cellular mechanisms involved in CCK-induced GI contractions are not clearly understood. Here, we first determined the cDNA and amino acid sequences of CCK and CCK-A receptor along with the distributions of cck mRNA and CCK-producing cells in house musk shrew (Suncus murinus, the laboratory strain named as suncus) and examined the mechanism of CCK-induced contraction in the GI tract. Mature suncus CCK-8 was identical to other mammalian species tested here, and suncus CCK-A receptor presented high nucleotide and amino acid homology with that of human, dog, mouse, and rat, respectively. Suncus CCK mRNA and CCK-producing cells were found mainly in small intestine and colon. In the organ bath study, CCK-8 induced dose-dependent contractions in the suncus stomach, duodenum, and jejunum, and these contractions were inhibited by atropine and CCK-A receptor antagonist. These results suggest that CCK-8-induced contraction is mediated in the myenteric cholinergic neural network and that CCK-A receptor is partly responsible for CCK-8-induced contractions. This study indicates that suncus is a useful animal model to study the functions of CCK involved in GI motility.
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Affiliation(s)
- Shota Takemi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Wataru Honda
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Naho Yokota
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Haruka Sekiya
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Takashi Miura
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Reiko Wada
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Takafumi Sakai
- Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; Area of Life-NanoBio, Division of Strategy Research, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
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6
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Li Y, Kong F. Simulating human gastrointestinal motility in dynamic in vitro models. Compr Rev Food Sci Food Saf 2022; 21:3804-3833. [PMID: 35880687 DOI: 10.1111/1541-4337.13007] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 03/26/2022] [Accepted: 06/22/2022] [Indexed: 01/28/2023]
Abstract
The application of dynamic in vitro gastrointestinal (GI) models has grown in popularity to understand the impact of food structure and composition on human health. Given that GI motility is integral to digestion and absorption, a predictive in vitro model should faithfully replicate the motility patterns and motor functions in vivo. In this review, typical characteristics of gastric and small intestinal motility in humans as well as the biomechanical and hydrodynamic events pertinent to gut motility are summarized. The simulation of GI motility in the presently existing dynamic in vitro models is discussed from an engineering perspective and categorized into hydraulic, piston/probe-driven, roller-driven, pneumatic, and other systems. Each system and its representative models are evaluated in terms of their motility patterns, the key hydrodynamic characteristics concerning gut motility, their performance in simulating the key physiological events, and their ability to establish in vitro-in vivo correlations. Practical Application: The review paper provided useful information in the design of dynamic GI models and the simulation of human gastric and small intestinal motility which are important for understanding food and health.
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Affiliation(s)
- Yiwen Li
- Department of Food Science and Technology, College of Agricultural and Environmental Sciences, University of Georgia, Athens, Georgia, USA
| | - Fanbin Kong
- Department of Food Science and Technology, College of Agricultural and Environmental Sciences, University of Georgia, Athens, Georgia, USA
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Matsumoto M, Takemi S, Sakai T, Sakata I. Identification of motilin in Japanese fire bellied newt. Gen Comp Endocrinol 2022; 323-324:114031. [PMID: 35331740 DOI: 10.1016/j.ygcen.2022.114031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/17/2022] [Accepted: 03/19/2022] [Indexed: 11/30/2022]
Abstract
Motilin, a peptide hormone consisting of 22 amino acid residues, was identified in the duodenum of pigs in the 1970s. It is known to induce gastrointestinal contractions during the interdigestive state in mammals. Although the motilin gene has been identified in various animal species, it has not been studied in amphibians. Here, we identified the motilin gene in the Japanese fire bellied newt (Cynops pyrrhogaster), and conducted an analysis of tissue distribution, morphological observations, and physiological experiments. The deduced mature newt motilin comprises 22 amino acid residues, like in mammals and birds. The C-terminus of the newt motilin showed high homology with motilin from other species compared to the N-terminus region, which is considered the bioactive site. Motilin mRNA expression in newts was abundant in the upper small intestine, with notably high motilin mRNA expression found in the pancreas. Motilin-producing cells were found in the mucosal layer of the upper small intestine and existed as two cell types: open-and closed-type cells. Motilin-producing cells in the pancreas were also found to produce insulin but not glucagon. Newt motilin stimulated gastric contractions but not in other parts of the intestines in vitro, and motilin-induced gastric contraction was significantly inhibited by treatment with atropine, a muscarinic acetylcholine receptor antagonist. These results indicate that motilin is also present in amphibians, and that its gastrointestinal contractile effects are conserved in mammals, birds, and amphibians. Additionally, we demonstrated for the first time the existence of pancreatic motilin, suggesting that newt motilin has an additional unknown physiological role.
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Affiliation(s)
- Mio Matsumoto
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Shota Takemi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Takafumi Sakai
- Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; Area of Life-NanoBio, Division of Strategy Research, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan.
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8
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Ding F, Guo R, Cui ZY, Hu H, Zhao G. Clinical application and research progress of extracellular slow wave recording in the gastrointestinal tract. World J Gastrointest Surg 2022; 14:544-555. [PMID: 35979419 PMCID: PMC9258241 DOI: 10.4240/wjgs.v14.i6.544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/21/2022] [Accepted: 05/17/2022] [Indexed: 02/06/2023] Open
Abstract
The physiological function of the gastrointestinal (GI) tract is based on the slow wave generated and transmitted by the interstitial cells of Cajal. Extracellular myoelectric recording techniques are often used to record the characteristics and propagation of slow wave and analyze the models of slow wave transmission under physiological and pathological conditions to further explore the mechanism of GI dysfunction. This article reviews the application and research progress of electromyography, bioelectromagnetic technology, and high-resolution mapping in animal and clinical experiments, summarizes the clinical application of GI electrical stimulation therapy, and reviews the electrophysiological research in the biliary system.
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Affiliation(s)
- Fan Ding
- Center of Gallbladder Disease, East Hospital of Tongji University, Shanghai 200120, China
- Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200331, China
| | - Run Guo
- Department of Ultrasonography, East Hospital of Tongji University, Shanghai 200120, China
| | - Zheng-Yu Cui
- Department of Internal Medicine of Traditional Chinese Medicine, East Hospital of Tongji University, Shanghai 200120, China
| | - Hai Hu
- Center of Gallbladder Disease, East Hospital of Tongji University, Shanghai 200120, China
- Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200331, China
| | - Gang Zhao
- Center of Gallbladder Disease, East Hospital of Tongji University, Shanghai 200120, China
- Institute of Gallstone Disease, Tongji University School of Medicine, Shanghai 200331, China
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Huizinga JD, Hussain A, Chen JH. Generation of Gut Motor Patterns Through Interactions Between Interstitial Cells of Cajal and the Intrinsic and Extrinsic Autonomic Nervous Systems. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:205-212. [PMID: 36587159 DOI: 10.1007/978-3-031-05843-1_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The musculature of the gastrointestinal tract is a vast network of collaborating excitable cell types. Embedded throughout are the interstitial cells of Cajal (ICC) intertwined with enteric nerves. ICC sense external stimuli such as distention, mediate nerve impulses to smooth muscle cells, and provide rhythmic excitation of the musculature. Neural circuitry involving both the intrinsic and extrinsic autonomic nervous systems, in collaboration with the ICC, orchestrate an array of motor patterns that serve to provide mixing of content to optimize digestion and absorption, microbiome homeostasis, storage, transit, and expulsion. ICC are specialized smooth muscle cells that generate rhythmic depolarization to the musculature and so provide the means for peristaltic and segmenting contractions. Some motor patterns are purely myogenic, but a neural stimulus initiates most, further depolarizing the primary pacemaker cells and the musculature and/or initiating transient pacemaker activity in stimulus-dependent secondary ICC pacemaker cells. From stomach to rectum, ICC networks rhythmically provide tracks along which contractions advance.
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Affiliation(s)
- Jan D Huizinga
- McMaster University, Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Hamilton, ON, Canada.
| | - Amer Hussain
- McMaster University, Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Hamilton, ON, Canada
| | - Ji-Hong Chen
- McMaster University, Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Hamilton, ON, Canada
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Costa M, Wiklendt L, Hibberd T, Dinning P, Spencer NJ, Brookes S. Analysis of Intestinal Movements with Spatiotemporal Maps: Beyond Anatomy and Physiology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:271-294. [PMID: 36587166 DOI: 10.1007/978-3-031-05843-1_26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Over 150 years ago, methods for quantitative analysis of gastrointestinal motor patterns first appeared. Graphic representations of physiological variables were recorded with the kymograph after the mid-1800s. Changes in force or length of intestinal muscles could be quantified, however most recordings were limited to a single point along the digestive tract.In parallel, photography and cinematography with X-Rays visualised changes in intestinal shape, but were hard to quantify. More recently, the ability to record physiological events at many sites along the gut in combination with computer processing allowed construction of spatiotemporal maps. These included diameter maps (DMaps), constructed from video recordings of intestinal movements and pressure maps (PMaps), constructed using data from high-resolution manometry catheters. Combining different kinds of spatiotemporal maps revealed additional details about gut wall status, including compliance, which relates forces to changes in length. Plotting compliance values along the intestine enabled combined DPMaps to be constructed, which can distinguish active contractions and relaxations from passive changes. From combinations of spatiotemporal maps, it is possible to deduce the role of enteric circuits and pacemaker cells in the generation of complex motor patterns. Development and application of spatiotemporal methods to normal and abnormal motor patterns in animals and humans is ongoing, with further technical improvements arising from their combination with impedance manometry, magnetic resonance imaging, electrophysiology, and ultrasonography.
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Affiliation(s)
- Marcello Costa
- College of Medicine and Public Health, Department of Human Physiology, Flinders University, Bedford Park, SA, Australia.
| | - Luke Wiklendt
- Department of Gastroenterology and Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Tim Hibberd
- College of Medicine and Public Health, Department of Human Physiology, Flinders University, Bedford Park, SA, Australia
| | - Phil Dinning
- Department of Gastroenterology and Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Nick J Spencer
- College of Medicine and Public Health, Department of Human Physiology, Flinders University, Bedford Park, SA, Australia
| | - Simon Brookes
- College of Medicine and Public Health, Department of Human Physiology, Flinders University, Bedford Park, SA, Australia
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11
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Stamatopoulos K, O'Farrell C, Simmons M, Batchelor H. In vivo models to evaluate ingestible devices: Present status and current trends. Adv Drug Deliv Rev 2021; 177:113915. [PMID: 34371085 DOI: 10.1016/j.addr.2021.113915] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/27/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022]
Abstract
Evaluation of orally ingestible devices is critical to optimize their performance early in development. Using animals as a pre-clinical tool can provide useful information on functionality, yet it is important to recognize that animal gastrointestinal physiology, pathophysiology and anatomy can differ to that in humans and that the most suitable species needs to be selected to inform the evaluation. There has been a move towards in vitro and in silico models rather than animal models in line with the 3Rs (Replacement, Reduction and Refinement) as well as the better control and reproducibility associated with these systems. However, there are still instances where animal models provide the greatest understanding. This paper provides an overview of key aspects of human gastrointestinal anatomy and physiology and compares parameters to those reported in animal species. The value of each species can be determined based upon the parameter of interest from the ingested device when considering the use of pre-clinical animal testing.
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Affiliation(s)
- Konstantinos Stamatopoulos
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Biopharmaceutics, Pharmaceutical Development, PDS, MST, RD Platform Technology & Science, GSK, David Jack Centre, Park Road, Ware, Hertfordshire SG12 0DP, UK
| | - Connor O'Farrell
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Mark Simmons
- School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - Hannah Batchelor
- Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, Glasgow G4 0RE, UK.
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12
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Wang D, Zhang H, Vu T, Zhan Y, Malhotra A, Wang P, Chitgupi U, Rai A, Zhang S, Wang L, Huizinga JD, Lovell JF, Xia J. Trans-illumination intestine projection imaging of intestinal motility in mice. Nat Commun 2021; 12:1682. [PMID: 33727562 PMCID: PMC7966380 DOI: 10.1038/s41467-021-21930-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 02/18/2021] [Indexed: 02/07/2023] Open
Abstract
Functional intestinal imaging holds importance for the diagnosis and evaluation of treatment of gastrointestinal diseases. Currently, preclinical imaging of intestinal motility in animal models is performed either invasively with excised intestines or noninvasively under anesthesia, and cannot reveal intestinal dynamics in the awake condition. Capitalizing on near-infrared optics and a high-absorbing contrast agent, we report the Trans-illumination Intestine Projection (TIP) imaging system for free-moving mice. After a complete system evaluation, we performed in vivo studies, and obtained peristalsis and segmentation motor patterns of free-moving mice. We show the in vivo typical segmentation motor pattern, that was previously shown in ex vivo studies to be controlled by intestinal pacemaker cells. We also show the effects of anesthesia on motor patterns, highlighting the possibility to study the role of the extrinsic nervous system in controlling motor patterns, which requires unanesthetized live animals. Combining with light-field technologies, we further demonstrated 3D imaging of intestine in vivo (3D-TIP). Importantly, the added depth information allows us to extract intestines located away from the abdominal wall, and to quantify intestinal motor patterns along different directions. The TIP system should open up avenues for functional imaging of the GI tract in conscious animals in natural physiological states.
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Affiliation(s)
- Depeng Wang
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
- Department of Biomedical Engineering, Duke University, Durham, NC, USA
| | - Huijuan Zhang
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Tri Vu
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Ye Zhan
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Akash Malhotra
- Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Pei Wang
- Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Upendra Chitgupi
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Aliza Rai
- Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Sizhe Zhang
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Lidai Wang
- Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Hong Kong, China
| | - Jan D Huizinga
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Ontario, Canada
| | - Jonathan F Lovell
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Jun Xia
- Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY, USA.
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13
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Physical and nutrient stimuli differentially modulate gut motility patterns, gut transit rate, and transcriptome in an agastric fish, the ballan wrasse. PLoS One 2021; 16:e0247076. [PMID: 33571240 PMCID: PMC7877642 DOI: 10.1371/journal.pone.0247076] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 01/31/2021] [Indexed: 12/14/2022] Open
Abstract
The effects of nutrient and mechanical sensing on gut motility and intestinal metabolism in lower vertebrates remains largely unknown. Here we present the transcriptome response to luminal stimulation by nutrients and an inert bolus on nutrient response pathways and also the response on gut motility in a stomachless fish with a short digestive tract; the ballan wrasse (Labrus berggylta). Using an in vitro model, we differentiate how signals initiated by physical stretch (cellulose and plastic beads) and nutrients (lipid and protein) modulate the gut evacuation rate, motility patterns and the transcriptome. Intestinal stretch generated by inert cellulose initiated a faster evacuation of digesta out of the anterior intestine compared to digestible protein and lipid. Stretch on the intestine upregulated genes associated with increased muscle activity, whereas nutrients stimulated increased expression of several neuropeptides and receptors which are directly involved in gut motility regulation. Although administration of protein and lipid resulted in similar bulbous evacuation times, differences in intestinal motility, transit between the segments and gene expression between the two were observed. Lipid induced increased frequency of ripples and standing contraction in the middle section of the intestine compared to the protein group. We suggest that this difference in motility was modulated by factors [prepronociceptin (pnoca), prodynorphin (pdyn) and neuromedin U (nmu), opioid neurotransmitters and peptides] that are known to inhibit gastrointestinal motility and were upregulated by protein and not lipid. Our findings show that physical pressure in the intestine initiate contractions propelling the bolus distally, directly towards the exit, whereas the stimuli from nutrients modulates the motility to prolong the residence time of digesta in the digestive tract for optimal digestion.
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14
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Sekiya H, Yokota N, Takemi S, Nakayama K, Okada H, Sakai T, Sakata I. The inhibitory effect of somatostatin on gastric motility in Suncus murinus. J Smooth Muscle Res 2021; 56:69-81. [PMID: 33473062 PMCID: PMC7817339 DOI: 10.1540/jsmr.56.69] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Gastric contractions show two specific patterns in many species, migrating motor
contractions (MMC) and postprandial contractions (PPCs), that occur in the fasted and fed
states, respectively. In this study, we examined the role of somatostatin (SST) in gastric
motility both in vivo and in vitro using the Asian house
shrew (Suncus murinus). We performed in vivo recordings
of gastric motility and in vitro organ bath experiments using S.
murinus, which was recently established as a small laboratory animal for use in
tests of gastrointestinal motility. SST (1.65 µg kg−1 min−1) was
intravenously administered during phase II of MMC and PPCs. Next, the effect of SST on
motilin-induced gastric contractions at phase I of MMC was measured. Cyclosomatostatin
(CSST), an SST receptor antagonist, was administered at the peak of phase III of MMC. In
addition, the effect of SST (10−11–10−9 M) on motilin-induced
gastric contractions was evaluated using an organ bath experiment in
vitro. In conscious, free-moving S. murinus, the
administration of SST decreased the occurrence of the spontaneous phase II of MMC and
PPCs. Pretreatment with SST and octreotide suppressed the induction of motilin-induced
gastric contractions both in vivo and in vitro.
Administration of CSST before the peak of spontaneous phase III contractions had no effect
on gastric contractions. Endogenous SST is not involved in the regulation of gastric MMC
and PPCs, but exogenous SST suppresses spontaneous gastric contractions. Thus, SST would
be good for treating abnormal gastrointestinal motility disorders.
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Affiliation(s)
- Haruka Sekiya
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Naho Yokota
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Shota Takemi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Keiji Nakayama
- Research Center of Neurology, Discovery and Research, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan
| | - Hiroki Okada
- Discovery Technology Research Laboratories, Discovery and Research, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan
| | - Takafumi Sakai
- Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan.,Area of Life-NanoBio, Division of Strategy Research, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
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15
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Parsons SP, Huizinga JD. Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP. Front Neurosci 2021; 14:592664. [PMID: 33488345 PMCID: PMC7817771 DOI: 10.3389/fnins.2020.592664] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/25/2020] [Indexed: 12/16/2022] Open
Abstract
Nitrergic nerves have been proposed to play a critical role in the orchestration of peristaltic activities throughout the gastrointestinal tract. In the present study, we investigated the role of nitric oxide, using spatiotemporal mapping, in peristaltic activity of the whole ex vivo mouse intestine. We identified a propulsive motor pattern in the form of propagating myogenic contractions, that are clustered by the enteric nervous system into a minute rhythm that is dependent on nitric oxide. The cluster formation was abolished by TTX, lidocaine and nitric oxide synthesis inhibition, whereas the myogenic contractions, occurring at the ICC-MP initiated slow wave frequency, remained undisturbed. Cluster formation, inhibited by block of nitric oxide synthesis, was fully restored in a highly regular rhythmic fashion by a constant level of nitric oxide generated by sodium nitroprusside; but the action of sodium nitroprusside was inhibited by lidocaine indicating that it was relying on neural activity, but not rhythmic nitrergic nerve activity. Hence, distention-induced activity of cholinergic nerves and/or a co-factor within nitrergic nerves such as ATP is also a requirement for the minute rhythm. Cluster formation was dependent on distention but was not evoked by a distention reflex. Block of gap junction conductance by carbenoxolone, dose dependently inhibited, and eventually abolished clusters and contraction waves, likely associated, not with inhibition of nitrergic innervation, but by abolishing ICC network synchronization. An intriguing feature of the clusters was the presence of bands of rhythmic inhibitions at 4-8 cycles/min; these inhibitory patches occurred in the presence of tetrodotoxin or lidocaine and hence were not dependent on nitrergic nerves. We propose that the minute rhythm is generated by nitric oxide-induced rhythmic depolarization of the musculature via ICC-DMP.
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Affiliation(s)
- Sean P. Parsons
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Jan D. Huizinga
- Department of Medicine and School of Biomedical Engineering, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
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16
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Low DY, Pluschke AM, Gerrits WJ, Zhang D, Shelat KJ, Gidley MJ, Williams BA. Cereal dietary fibres influence retention time of digesta solid and liquid phases along the gastrointestinal tract. Food Hydrocoll 2020. [DOI: 10.1016/j.foodhyd.2020.105739] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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17
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Kikuchi K, Noh H, Numayama-Tsuruta K, Ishikawa T. Mechanical roles of anterograde and retrograde intestinal peristalses after feeding in a larval fish ( Danio rerio). Am J Physiol Gastrointest Liver Physiol 2020; 318:G1013-G1021. [PMID: 32281395 DOI: 10.1152/ajpgi.00165.2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Transport in gut is important, not only for digestion, metabolism, and nutrient uptake, but also for microbiotic circumstance in the digestive tract; however, the effects of mixing and pumping in the intestine have not been fully clarified. Therefore, in this study, we quantitatively explored intestinal mixing and pumping, represented using a dispersion coefficient and pressure rise in zebrafish larvae, which is a model organism for vertebrate digestive studies, over time by measuring transport phenomena after feeding. Here we provide the first quantitative evidence of the roles of anterograde and retrograde intestinal peristalses in the larval fish of Danio rerio after feeding in terms of digestive pumping and mixing functions by an in vivo imaging of intestinal propagation waves in the larval intestine. Peristaltic velocities in the anterior and posterior intestines change considerably after feeding for 5 h, while the intervals and amplitudes remain almost constant. The intestinal transport is successively visualized after feeding to elimination. Moreover, the particle tracking velocimetry in the chyme leads our quantitative understanding of outstanding mixing and pumping functions in the anterior and posterior intestines by adopting physical parameters of diffusivity and pressure rise, respectively. From scaling analysis, we found that the anterior intestine maintains mixing for 5 h from feeding, whereas the posterior intestine activates gradually pumping up. These results suggest that time change of pumping and mixing functions of intestinal peristalsis could considerably influence the nutrient uptake and microbiotic circumstance in the larval fish intestine.NEW & NOTEWORTHY Transport in gut is important, not only for digestion, metabolism, and nutrient uptake, but also for microbiotic circumstance; however, hydrodynamic effects in the intestine have not been fully clarified. We provide the first quantitative evidence of the mechanical roles of anterograde and retrograde intestinal peristalses in the larval fish of Danio rerio by adopting physical parameters of diffusivity and pressure rise. The intestine transitionally regulates mixing and pumping functions by peristaltic propagations after feeding.
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Affiliation(s)
- Kenji Kikuchi
- Department of Finemechanics, Graduate School of Engineering, Tohoku University, Sendai, Japan.,Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | - Hyeongtak Noh
- Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
| | | | - Takuji Ishikawa
- Department of Finemechanics, Graduate School of Engineering, Tohoku University, Sendai, Japan.,Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan
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18
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Liu C, Saw KS, Dinning PG, O'Grady G, Bissett I. Manometry of the Human Ileum and Ileocaecal Junction in Health, Disease and Surgery: A Systematic Review. Front Surg 2020; 7:18. [PMID: 32351970 PMCID: PMC7174608 DOI: 10.3389/fsurg.2020.00018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 03/20/2020] [Indexed: 01/14/2023] Open
Abstract
Background: The terminal ileum and ileocaecal junction form a transition zone in a relatively inaccessible portion of the gastrointestinal tract. Little is known about the motility of this region with few detailed studies, indicating the need for a robust synthesis of current knowledge. This review aimed to evaluate the quantitative and qualitative data on the manometry findings of the terminal ileum and ileocaecal junction during the fasting and post-prandial periods in healthy individuals and patients with motility disorders or patients after bowel surgery. Methods: A systematic search of five databases (Medline, Pubmed, Embase, Scopus, and Cochrane Library) was performed. Studies that presented manometry data from the human ileum or ileocaecal junction were included. Results: Forty-two studies met the inclusion criteria. The main motility patterns reported in the terminal ileum during fasting were the migrating motor complex, discrete clustered contractions, prolonged propagated contractions and phasic contractions. Post-prandial motility featured irregular, intense contractions. Some studies found a region of sustained increased pressure at the ileocaecal junction while others did not. Patients with motility disorders showed differences in manometry including retrograde propagation of phase III. Patients post-bowel surgery showed differences including higher incidence of phase III. Conclusion: Motility patterns of the terminal ileum differ between fasting and fed states. Large variability existed in manometry recordings of the terminal ileum. Technical challenges and lack of standardized definitions may reduce accuracy of manometry assessment. Further research is needed to understand how this key portion of the gut physiologically functions.
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Affiliation(s)
- Chen Liu
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Kai Sheng Saw
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Phil G Dinning
- Departments of Gastroenterology and Surgery, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia
| | - Gregory O'Grady
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Ian Bissett
- Department of Surgery, University of Auckland, Auckland, New Zealand
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19
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Costa M, Hibberd TJ, Keightley LJ, Wiklendt L, Arkwright JW, Dinning PG, Brookes SJH, Spencer NJ. Neural motor complexes propagate continuously along the full length of mouse small intestine and colon. Am J Physiol Gastrointest Liver Physiol 2020; 318:G99-G108. [PMID: 31709829 DOI: 10.1152/ajpgi.00185.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cyclical propagating waves of muscle contraction have been recorded in isolated small intestine or colon, referred to here as motor complexes (MCs). Small intestinal and colonic MCs are neurogenic, occur at similar frequencies, and propagate orally or aborally. Whether they can be coordinated between the different gut regions is unclear. Motor behavior of whole length mouse intestines, from duodenum to terminal rectum, was recorded by intraluminal multisensor catheter. Small intestinal MCs were recorded in 27/30 preparations, and colonic MCs were recorded in all preparations (n = 30) with similar frequencies (0.54 ± 0.03 and 0.58 ± 0.02 counts/min, respectively). MCs propagated across the ileo-colonic junction in 10/30 preparations, forming "full intestine" MCs. The cholinesterase inhibitor physostigmine increased the probability of a full intestine MC but had no significant effect on frequency, speed, or direction. Nitric oxide synthesis blockade by Nω-nitro-l-arginine, after physostigmine, increased MC frequency in small intestine only. Hyoscine-resistant MCs were recorded in the colon but not small intestine (n = 5). All MCs were abolished by hexamethonium (n = 18) or tetrodotoxin (n = 2). The enteric neural mechanism required for motor complexes is present along the full length of both the small and large intestine. In some cases, colonic MCs can be initiated in the distal colon and propagate through the ileo-colonic junction, all the way to duodenum. In conclusion, the ileo-colonic junction provides functional neural continuity for propagating motor activity that originates in the small or large intestine.NEW & NOTEWORTHY Intraluminal manometric recordings revealed motor complexes can propagate antegradely or retrogradely across the ileo-colonic junction, spanning the entire small and large intestines. The fundamental enteric neural mechanism(s) underlying cyclic motor complexes exists throughout the length of the small and large intestine.
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Affiliation(s)
- Marcello Costa
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia
| | - Timothy James Hibberd
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia
| | - Lauren J Keightley
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia
| | - Lukasz Wiklendt
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia
| | - John W Arkwright
- Computer Science, Engineering and Mathematics, Flinders University, Adelaide, South Australia, Australia
| | - Philip G Dinning
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia.,Department of Gastroenterology and Surgery, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia
| | - Simon J H Brookes
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia
| | - Nick J Spencer
- College of Medicine and Public Health and Centre for Neuroscience, Flinders University, Adelaide, South Australia, Australia
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20
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Grover M, Farrugia G, Stanghellini V. Gastroparesis: a turning point in understanding and treatment. Gut 2019; 68:2238-2250. [PMID: 31563877 PMCID: PMC6874806 DOI: 10.1136/gutjnl-2019-318712] [Citation(s) in RCA: 157] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 07/29/2019] [Accepted: 08/22/2019] [Indexed: 12/21/2022]
Abstract
Gastroparesis is defined by delayed gastric emptying (GE) and symptoms of nausea, vomiting, bloating, postprandial fullness, early satiety and abdominal pain. Most common aetiologies include diabetes, postsurgical and postinfectious, but in many cases it is idiopathic. Clinical presentation and natural history vary by the aetiology. There is significant morbidity and healthcare utilisation associated with gastroparesis. Mechanistic studies from diabetic animal models of delayed GE as well as human full-thickness biopsies have significantly advanced our understanding of this disorder. An innate immune dysregulation and injury to the interstitial cells of Cajal and other components of the enteric nervous system through paracrine and oxidative stress mediators is likely central to the pathogenesis of gastroparesis. Scintigraphy and 13C breath testing provide the most validated assessment of GE. The stagnant gastroparesis therapeutic landscape is likely to soon see significant changes. Relatively newer treatment strategies include antiemetics (aprepitant), prokinetics (prucalopride, relamorelin) and fundic relaxants (acotiamide, buspirone). Endoscopic pyloromyotomy appears promising over the short term, especially for symptoms of nausea and vomiting. Further controlled trials and identification of the appropriate subgroup with pyloric dysfunction and assessment of long-term outcomes are essential. This review highlights the clinical presentation, diagnosis, mechanisms and treatment advancements for gastroparesis.
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Affiliation(s)
- Madhusudan Grover
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gianrico Farrugia
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vincenzo Stanghellini
- Department of Digestive Diseases and Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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21
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Horita T, Koyama K, Takemi S, Tanaka T, Sakai T, Sakata I. GABAergic and glutamatergic neurons in the brain regulate phase II of migrating motor contractions in the Suncus murinus. J Smooth Muscle Res 2019; 54:91-99. [PMID: 30787212 PMCID: PMC6380905 DOI: 10.1540/jsmr.54.91] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
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.
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Affiliation(s)
- Taichi Horita
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Kouhei Koyama
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Shota Takemi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
| | - Toru Tanaka
- Faculty of Pharmaceutical Sciences, Department of Pharmaceutical and Health Sciences, Josai University, 1-1 Keiyaki dai, Sakado, Saitama 350-0295, Japan
| | - Takafumi Sakai
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan.,Area of Life-NanoBio, Division of Strategy Research, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan
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22
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Utility of animal gastrointestinal motility and transit models in functional gastrointestinal disorders. Best Pract Res Clin Gastroenterol 2019; 40-41:101633. [PMID: 31594654 DOI: 10.1016/j.bpg.2019.101633] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 07/17/2019] [Indexed: 01/31/2023]
Abstract
Alteration in the gastrointestinal (GI) motility and transit comprises an important component of the functional gastrointestinal disorders (FGID). Available animal GI motility and transit models are to study symptoms (delayed gastric emptying, constipation, diarrhea) rather than biological markers to develop an effective treatment that targets the underlying mechanism of altered GI motility in patients. Animal data generated from commonly used methods in human like scintigraphy, breath test and wireless motility capsule may directly translate to the clinic. However, species differences in the control mechanism or pharmacological responses of GI motility may compromise the predictive and translational value of the preclinical data to human. In this review we aim to provide a summary on animal models used to mimic GI motility alteration in FGID, and the impact of the species differences in the physiological and pharmacological responses on the translation of animal GI motility and transit data to human.
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23
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Deloose E, Verbeure W, Depoortere I, Tack J. Motilin: from gastric motility stimulation to hunger signalling. Nat Rev Endocrinol 2019; 15:238-250. [PMID: 30675023 DOI: 10.1038/s41574-019-0155-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
After the discovery of motilin in 1972, motilin and the motilin receptor were studied intensely for their role in the control of gastrointestinal motility and as targets for treating hypomotility disorders. The genetic revolution - with the use of knockout models - sparked novel insights into the role of multiple peptides but contributed to a decline in interest in motilin, as this peptide and its receptor exist only as pseudogenes in rodents. The past 5 years have seen a major surge in interest in motilin, as a series of studies have shown its relevance in the control of hunger and regulation of food intake in humans in both health and disease. Luminal stimuli, such as bitter tastants, have been identified as modulators of motilin release, with effects on hunger and food intake. The current state of knowledge and potential implications for therapy are summarized in this Review.
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Affiliation(s)
- Eveline Deloose
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Wout Verbeure
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Inge Depoortere
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research in Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.
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24
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Baker JR, Dickens JR, Koenigsknecht M, Frances A, Lee AA, Shedden KA, Brasseur JG, Amidon GL, Sun D, Hasler WL. Propagation Characteristics of Fasting Duodeno-Jejunal Contractions in Healthy Controls Measured by Clustered Closely-spaced Manometric Sensors. J Neurogastroenterol Motil 2019; 25:100-112. [PMID: 30646481 PMCID: PMC6326202 DOI: 10.5056/jnm18112] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 10/22/2018] [Accepted: 11/05/2018] [Indexed: 12/20/2022] Open
Abstract
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.
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Affiliation(s)
- Jason R Baker
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA
| | | | | | - Ann Frances
- School of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Allen A Lee
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Kerby A Shedden
- School of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - James G Brasseur
- Department of Aerospace Engineering Sciences, University of Colorado Boulder, Boulder, CO, USA
| | - Gordon L Amidon
- School of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Duxin Sun
- School of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - William L Hasler
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA
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25
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Ang D, Pannemans J, Vanuytsel T, Tack J. A single-center audit of the indications and clinical impact of prolonged ambulatory small intestinal manometry. Neurogastroenterol Motil 2018; 30:e13357. [PMID: 29717525 DOI: 10.1111/nmo.13357] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 03/23/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Small bowel manometry is a diagnostic test available only in a few specialized referral centers. Its exact place in the management of refractory symptoms is controversial. METHODS The records of all patients who underwent 24-hour ambulatory duodenojejunal manometry over a 6-year period were retrospectively reviewed. We studied the clinical indications for small bowel manometry, and reviewed the impact of manometric findings on the clinical outcome. One hundred and forty-six studies were performed in 137 patients (46M, 91F) with a mean age of 44.9 ± 15.7 years. Mean follow-up duration was 15.1 ± 22.6 months. Appropriate endoscopic, radiological and gastric scintigraphy studies were performed in all patients prior to small bowel manometry. Criteria for abnormal motor activity were based on Bharucha's classification. KEY RESULTS The indications for small bowel manometry were chronic abdominal pain (n = 43), slow-transit constipation (n = 17), refractory gastroparesis (n = 16), chronic diarrhea (n = 7), recurrent episodes of subocclusion (n = 16), postsurgical evaluation (n = 36), suspicion of gut involvement in systemic disease (n = 9), and unexplained nausea (n = 2). The most common finding was a normal 24-hour ambulatory small bowel manometry (n = 113). Thirty-three studies yielded abnormal findings which included extrinsic neuropathy (n = 6), intrinsic neuropathy (n = 18), intestinal myopathy (n = 2), and subocclusion (n = 7). Ambulatory small bowel manometry excluded a generalized motility disorder in 77% and had a significant impact on the subsequent clinical course in 23%. CONCLUSIONS & INFERENCES Ambulatory small bowel manometry is a useful and safe diagnostic tool to complement traditional investigative modalities in patients with severe unexplained abdominal symptoms.
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Affiliation(s)
- D Ang
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Aging, KU Leuven, Leuven, Belgium.,Division of Gastroenterology, University Hospitals, Leuven, Belgium
| | - J Pannemans
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Aging, KU Leuven, Leuven, Belgium.,Division of Gastroenterology, University Hospitals, Leuven, Belgium
| | - T Vanuytsel
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Aging, KU Leuven, Leuven, Belgium.,Division of Gastroenterology, University Hospitals, Leuven, Belgium
| | - J Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Aging, KU Leuven, Leuven, Belgium.,Division of Gastroenterology, University Hospitals, Leuven, Belgium
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26
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Mikami T, Ito K, Diaz-Tartera HO, Hellström PM, Mochiki E, Takemi S, Tanaka T, Tsuda S, Jogahara T, Sakata I, Sakai T. Study of termination of postprandial gastric contractions in humans, dogs and Suncus murinus: role of motilin- and ghrelin-induced strong contraction. Acta Physiol (Oxf) 2018; 222. [PMID: 28786555 DOI: 10.1111/apha.12933] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/07/2017] [Accepted: 08/01/2017] [Indexed: 12/16/2022]
Abstract
AIM Stomach contractions show two types of specific patterns in many species, that is migrating motor contraction (MMC) and postprandial contractions (PPCs), in the fasting and fed states respectively. We found gastric PPCs terminated with migrating strong contractions in humans, dogs and suncus. In this study, we reveal the detailed characteristics and physiological implications of these strong contractions of PPC. METHODS Human, suncus and canine gastric contractions were recorded with a motility-monitoring ingestible capsule and a strain-gauge force transducer. The response of motilin and ghrelin and its receptor antagonist on the contractions were studied by using free-moving suncus. RESULTS Strong gastric contractions were observed at the end of a PPC in human, dog and suncus models, and we tentatively designated this contraction to be a postprandial giant contraction (PPGC). In the suncus, the PPGC showed the same property as those of a phase III contraction of MMC (PIII-MMC) in the duration, motility index and response to motilin or ghrelin antagonist administration. Ghrelin antagonist administration in the latter half of the PPC (LH-PPC) attenuated gastric contraction prolonged the duration of occurrence of PPGC, as found in PII-MMC. CONCLUSION It is thought that the first half of the PPC changed to PII-MMC and then terminated with PIII-MMC, suggesting that PPC consists of a digestive phase (the first half of the PPC) and a discharge phase (LH-PPC) and that LH-PPC is coincident with MMC. In this study, we propose a new approach for the understanding of postprandial contractions.
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Affiliation(s)
- T. Mikami
- Area of Regulatory Biology; Division of Life Science; Graduate School of Science and Engineering; Saitama University; Saitama Japan
| | - K. Ito
- Area of Regulatory Biology; Division of Life Science; Graduate School of Science and Engineering; Saitama University; Saitama Japan
| | | | - P. M. Hellström
- Department of Medical Sciences; Uppsala University; Uppsala Sweden
| | - E. Mochiki
- Department of Digestive Tract and General Surgery; Saitama Medical Center; Saitama Medical University; Kawagoe Japan
| | - S. Takemi
- Area of Regulatory Biology; Division of Life Science; Graduate School of Science and Engineering; Saitama University; Saitama Japan
| | - T. Tanaka
- Department of Pharmaceutical and Health Sciences; Faculty of Pharmaceutical Sciences; Josai University; Saitama Japan
| | - S. Tsuda
- Area of Regulatory Biology; Division of Life Science; Graduate School of Science and Engineering; Saitama University; Saitama Japan
| | - T. Jogahara
- Laboratory of Animal Management and Resources; Department of Zoology; Faculty of Science; Okayama University of Science; Okayama Japan
| | - I. Sakata
- Area of Regulatory Biology; Division of Life Science; Graduate School of Science and Engineering; Saitama University; Saitama Japan
| | - T. Sakai
- Area of Life-NanoBio; Division of Strategy Research, Graduate School of Science and Engineering; Saitama University; Saitama Japan
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27
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Deloose E, Depoortere I, de Hoon J, Van Hecken A, Dewit OE, Vasist Johnson LS, Barton ME, Dukes GE, Tack J. Manometric evaluation of the motilin receptor agonist camicinal (GSK962040) in humans. Neurogastroenterol Motil 2018; 30. [PMID: 28782145 DOI: 10.1111/nmo.13173] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 06/30/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. METHODS In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial. KEY RESULTS The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH. CONCLUSIONS AND INFERENCES Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848.
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Affiliation(s)
- E Deloose
- KU Leuven (University of Leuven), TARGID, Leuven, Belgium
| | - I Depoortere
- KU Leuven (University of Leuven), TARGID, Leuven, Belgium
| | - J de Hoon
- KU Leuven (University of Leuven), Center for Clinical Pharmacology, Leuven, Belgium
| | - A Van Hecken
- KU Leuven (University of Leuven), Center for Clinical Pharmacology, Leuven, Belgium
| | - O E Dewit
- GSK Research and Development, GSK, Cambridge, UK
| | | | - M E Barton
- GSK Research and Development, GSK, Research Triangle Park, NC, USA
| | - G E Dukes
- GSK Research and Development, GSK, Research Triangle Park, NC, USA
| | - J Tack
- KU Leuven (University of Leuven), TARGID, Leuven, Belgium
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28
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Abstract
Humans swallow a great variety and often large amounts of chemicals as nutrients, incidental food additives and contaminants, drugs, and inhaled particles and chemicals, thus exposing the gastrointestinal tract to many potentially toxic substances. It serves as a barrier in many cases to protect other components of the body from such substances and infections. Fortunately, the gastrointestinal tract is remarkably robust and generally is able to withstand multiple daily assaults by the chemicals to which it is exposed. Some chemicals, however, can affect one or more aspects of the gastrointestinal tract to produce abnormal events that reflect toxicity. It is the purpose of this chapter to evaluate the mechanisms by which toxic chemicals produce their deleterious effects and to determine the consequences of the toxicity on integrity of gastrointestinal structure and function. Probably because of the intrinsic ability of the gastrointestinal tract to resist toxic chemicals, there is a paucity of data regarding gastrointestinal toxicology. It is therefore necessary in many cases to extrapolate toxic mechanisms from infectious processes, inflammatory conditions, ischemia, and other insults in addition to more conventional chemical sources of toxicity.
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29
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Mondal A, Koyama K, Mikami T, Horita T, Takemi S, Tsuda S, Sakata I, Sakai T. Underlying mechanism of the cyclic migrating motor complex in Suncus murinus: a change in gastrointestinal pH is the key regulator. Physiol Rep 2017; 5:5/1/e13105. [PMID: 28082431 PMCID: PMC5256163 DOI: 10.14814/phy2.13105] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 12/04/2016] [Accepted: 12/08/2016] [Indexed: 02/07/2023] Open
Abstract
In the fasted gastrointestinal (GI) tract, a characteristic cyclical rhythmic migrating motor complex (MMC) occurs in an ultradian rhythm, at 90–120 min time intervals, in many species. However, the underlying mechanism directing this ultradian rhythmic MMC pattern is yet to be completely elucidated. Therefore, this study aimed to identify the possible causes or factors that involve in the occurrence of the fasting gastric contractions by using Suncus murinus a small model animal featuring almost the same rhythmic MMC as that found in humans and dogs. We observed that either intraduodenal infusion of saline at pH 8 evoked the strong gastric contraction or continuously lowering duodenal pH to 3‐evoked gastric phase II‐like and phase III‐like contractions, and both strong contractions were essentially abolished by the intravenous administration of MA 2029 (motilin receptor antagonist) and D‐Lys3‐GHRP6 (ghrelin receptor antagonist) in a vagus‐independent manner. Moreover, we observed that the prostaglandin E2‐alpha (PGE2‐α) and serotonin type 4 (5HT4) receptors play important roles as intermediate molecules in changes in GI pH and motilin release. These results suggest a clear insight mechanism that change in the duodenal pH to alkaline condition is an essential factor for stimulating the endogenous release of motilin and governs the fasting MMC in a vagus‐independent manner. Finally, we believe that the changes in duodenal pH triggered by flowing gastric acid and the release of duodenal bicarbonate through the involvement of PGE2‐α and 5HT4 receptor are the key events in the occurrence of the MMC.
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Affiliation(s)
- Anupom Mondal
- Department of Life Nano-Bio, Strategic Research Division, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Kouhei Koyama
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Takashi Mikami
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Taichi Horita
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Shota Takemi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Sachiko Tsuda
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Takafumi Sakai
- Department of Life Nano-Bio, Strategic Research Division, Graduate School of Science and Engineering, Saitama University, Saitama, Japan .,Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
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30
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Sanderson JJ, Boysen SR, McMurray JM, Lee A, Stillion JR. The effect of fasting on gastrointestinal motility in healthy dogs as assessed by sonography. J Vet Emerg Crit Care (San Antonio) 2017; 27:645-650. [DOI: 10.1111/vec.12673] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/14/2016] [Accepted: 04/12/2016] [Indexed: 11/28/2022]
Affiliation(s)
- Jillian J. Sanderson
- Department of Veterinary Clinical and Diagnostic Sciences, Faculty of Veterinary Medicine; University of Calgary; Calgary Alberta Canada
| | - Søren R. Boysen
- Department of Veterinary Clinical and Diagnostic Sciences, Faculty of Veterinary Medicine; University of Calgary; Calgary Alberta Canada
- Western Veterinary Specialist and Emergency Centre; Calgary Alberta Canada
| | - Jantina M. McMurray
- Department of Veterinary Clinical and Diagnostic Sciences, Faculty of Veterinary Medicine; University of Calgary; Calgary Alberta Canada
| | - Albert Lee
- Department of Veterinary Clinical and Diagnostic Sciences, Faculty of Veterinary Medicine; University of Calgary; Calgary Alberta Canada
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31
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Romański KW. Importance of the enteric nervous system in the control of the migrating motility complex. Physiol Int 2017; 104:97-129. [PMID: 28665193 DOI: 10.1556/2060.104.2017.2.4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The migrating motility complex (MMC), a cyclical phenomenon, represents rudimentary motility pattern in the gastrointestinal tract. The MMC is observed mostly in the stomach and gut of man and numerous animal species. It contains three or four phases, while its phase III is the most characteristic. The mechanisms controlling the pattern are unclear in part, although the neural control of the MMC seems crucial. The main goal of this article was to discuss the importance of intrinsic innervation of the gastrointestinal tract in MMC initiation, migration, and cessation to emphasize that various MMC-controlling mechanisms act through the enteric nervous system. Two main neural regions, central and peripheral, are able to initiate the MMC. However, central regulation of the MMC may require cooperation with the enteric nervous system. When central mechanisms are not active, the MMC can be initiated peripherally in any region of the small bowel. The enteric nervous system affects the MMC in response to the luminal stimuli which can contribute to the initiation and cessation of the cycle, and it may evoke irregular phasic contractions within the pattern. The hormonal regulators released from the endocrine cells may exert a modulatory effect upon the MMC mostly through the enteric nervous system. Their central action could also be considered. It can be concluded that the enteric nervous system is involved in the great majority of the MMC-controlling mechanisms.
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Affiliation(s)
- K W Romański
- 1 Department of Animal Physiology, Faculty of Veterinary Medicine, Wrocław University of Environmental and Life Sciences , Wrocław, Poland
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32
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Deloose E, Janssen P, Corsetti M, Biesiekierski J, Masuy I, Rotondo A, Van Oudenhove L, Depoortere I, Tack J. Intragastric infusion of denatonium benzoate attenuates interdigestive gastric motility and hunger scores in healthy female volunteers. Am J Clin Nutr 2017; 105:580-588. [PMID: 28148502 DOI: 10.3945/ajcn.116.138297] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 12/19/2016] [Indexed: 11/14/2022] Open
Abstract
Background: Denatonium benzoate (DB) has been shown to influence ongoing ingestive behavior and gut peptide secretion.Objective: We studied how the intragastric administration of DB affects interdigestive motility, motilin and ghrelin plasma concentrations, hunger and satiety ratings, and food intake in healthy volunteers.Design: Lingual bitter taste sensitivity was tested with the use of 6 concentrations of DB in 65 subjects. A placebo or 1 μmol DB/kg was given intragastrically to assess its effect on fasting gastrointestinal motility and hunger ratings, motilin and ghrelin plasma concentrations, satiety, and caloric intake.Results: Women (n = 39) were more sensitive toward a lingual bitter stimulus (P = 0.005) than men (n = 26). In women (n = 10), intragastric DB switched the origin of phase III contractions from the stomach to the duodenum (P = 0.001) and decreased hunger ratings (P = 0.04). These effects were not observed in men (n = 10). In women (n = 12), motilin (P = 0.04) plasma concentrations decreased after intragastric DB administration, whereas total and octanoylated ghrelin were not affected. The intragastric administration of DB decreased hunger (P = 0.008) and increased satiety ratings (P = 0.01) after a meal (500 kcal) in 13 women without affecting gastric emptying in 6 women. Caloric intake tended to decrease after DB administration compared with the placebo (mean ± SEM: 720 ± 58 compared with 796 ± 45 kcal; P = 0.08) in 20 women.Conclusions: Intragastric DB administration decreases both antral motility and hunger ratings during the fasting state, possibly because of a decrease in motilin release. Moreover, DB decreases hunger and increases satiety ratings after a meal and shows potential for decreasing caloric intake. This trial was registered at clinicaltrials.gov as NCT02759926.
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Affiliation(s)
- Eveline Deloose
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Pieter Janssen
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Maura Corsetti
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and.,National Institute for Health Research, Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals National Health Service Trust, University of Nottingham, Nottingham, United Kingdom
| | - Jessica Biesiekierski
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Imke Masuy
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Alessandra Rotondo
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Lukas Van Oudenhove
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Inge Depoortere
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium; and
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Problems with extracellular recording of electrical activity in gastrointestinal muscle. Nat Rev Gastroenterol Hepatol 2016; 13:731-741. [PMID: 27756919 PMCID: PMC8325940 DOI: 10.1038/nrgastro.2016.161] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Motility patterns of the gastrointestinal tract are important for efficient processing of nutrients and waste. Peristalsis and segmentation are based on rhythmic electrical slow waves that generate the phasic contractions fundamental to gastrointestinal motility. Slow waves are generated and propagated actively by interstitial cells of Cajal (ICC), and these events conduct to smooth muscle cells to elicit excitation-contraction coupling. Extracellular electrical recording has been utilized to characterize slow-wave generation and propagation and abnormalities that might be responsible for gastrointestinal motility disorders. Electrode array recording and digital processing are being used to generate data for models of electrical propagation in normal and pathophysiological conditions. Here, we discuss techniques of extracellular recording as applied to gastrointestinal organs and how mechanical artefacts might contaminate these recordings and confound their interpretation. Without rigorous controls for movement, current interpretations of extracellular recordings might ascribe inaccurate behaviours and electrical anomalies to ICC networks and gastrointestinal muscles, bringing into question the findings and validity of models of gastrointestinal electrophysiology developed from these recordings.
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34
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Brijs J, Hennig GW, Kellermann AM, Axelsson M, Olsson C. The presence and role of interstitial cells of Cajal in the proximal intestine of shorthorn sculpin (Myoxocephalus scorpius). ACTA ACUST UNITED AC 2016; 220:347-357. [PMID: 27875260 DOI: 10.1242/jeb.141523] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 11/03/2016] [Indexed: 12/27/2022]
Abstract
Rhythmic contractions of the mammalian gastrointestinal tract can occur in the absence of neuronal or hormonal stimulation owing to the generation of spontaneous electrical activity by interstitial cells of Cajal (ICC) that are electrically coupled to smooth muscle cells. The myogenically driven component of gastrointestinal motility patterns in fish probably also involves ICC; however, little is known of their presence, distribution and function in any fish species. In the present study, we combined immunohistochemistry and in vivo recordings of intestinal motility to investigate the involvement of ICC in the motility of the proximal intestine in adult shorthorn sculpin (Myoxocephalus scorpius). Antibodies against anoctamin 1 (Ano1, a Ca2+-activated Cl- channel), revealed a dense network of multipolar, repeatedly branching cells in the myenteric region of the proximal intestine, similar in many regards to the mammalian ICC-MY network. The addition of benzbromarone, a potent blocker of Ano1, altered the motility patterns seen in vivo after neural blockade with TTX. The results indicate that ICC are integral for the generation and propagation of the majority of rhythmic contractile patterns in fish, although their frequency and amplitude can be modulated via neural activity.
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Affiliation(s)
- Jeroen Brijs
- Department of Biological and Environmental Sciences, University of Gothenburg, SE-405 30 Göteborg, Sweden
| | - Grant W Hennig
- Department of Physiology and Cell Biology, University of Reno, Nevada, NV 89557, USA
| | - Anna-Maria Kellermann
- Department of Nature and Engineering, Bremen University of Applied Sciences, Bremen 28199, Germany
| | - Michael Axelsson
- Department of Biological and Environmental Sciences, University of Gothenburg, SE-405 30 Göteborg, Sweden
| | - Catharina Olsson
- Department of Biological and Environmental Sciences, University of Gothenburg, SE-405 30 Göteborg, Sweden
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35
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Abstract
AbstractThe stomach and small intestine manifest a myoelectric activity pattern called the migrating myoelectric complex (MMC), which is controlled by both environmental and intrinsic factors. The daily MMC pattern has been little investigated, therefore the purpose of the present study was to study it, in weaned pigs given food twice a day. A wireless telemetric recording system was used for 24-h electromyography of the antrum and duodenum. The activity of the antrum showed little change if any, whereas the myoelectric activity of the duodenum significantly changed with respect to the time of day and feeding in conscious pigs. Namely, there were more frequent and regular MMC cycles occurring in the duodenum at night as compared with that during daytime. This change was due to the shortening of phase II of the MMC cycles that were registered at night. Phase I of the MMC showed transient variability in relation to feeding with no impact on the day/night differences. Phase III of the duodenal MMC cycle as well as the ‘feeding pattern’ did not change along with the time of day and feeding regime. In conclusion, daily variation in the duodenum may provide different conditions for digestive processes in the day and night.
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36
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Modification of drug delivery to improve antibiotic targeting to the stomach. Ther Deliv 2016; 6:741-62. [PMID: 26149788 DOI: 10.4155/tde.15.35] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The obstacles to the successful eradication of Helicobacter pylori infections include the presence of antibiotic-resistant bacteria and therapy requiring multiple drugs with complicated dosing schedules. Other obstacles include bacterial residence in an environment where high antibiotic concentrations are difficult to achieve. Biofilm production by the bacteria is an additional challenge to the effective treatment of this infection. Conventional oral formulations used in the treatment of this infection have a short gastric residence time, thus limiting the duration of exposure of drug to the bacteria. This review summarizes the current research in the development of gastroretentive formulations and the prospective future applications of this approach in the targeted delivery of drugs such as antibiotics to the stomach.
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37
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Affiliation(s)
- Jackie D Wood
- Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, 304 Hamilton Hall, 1645 Neil Avenue, Columbus, OH, 43210, USA.
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38
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Yoshimura M, Mikami T, Kuroda K, Nishida M, Ito K, Mondal A, Koyama K, Jogahara T, Sakata I, Sakai T. Involvement of Transient Receptor Potential Vanilloid Receptor 1, (TRPV1)-Expressing Vagal Nerve in the Inhibitory Effect of Gastric Acidification on Exogenous Motilin-Induced Gastric Phase III Contractions in Suncus murinus. Dig Dis Sci 2016; 61:1501-11. [PMID: 26860510 DOI: 10.1007/s10620-015-4023-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 12/20/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND Gastric acidification inhibits motilin-induced gastric phase III contractions. However, the underlying mechanism has not been thoroughly investigated. Here, we studied the inhibitory mechanism by gastric acidification on motilin-induced contraction in Suncus murinus (S. murinus). METHODS We measured interdigestive gastric phase III contractions in conscious, freely moving S. murinus, and examined the inhibitory effect of gastric acidification on motilin action and the involvement of the vagus nerve and transient receptor potential vanilloid receptor 1 (TRPV1) in the inhibitory mechanism. RESULTS A bolus injection of motilin evoked phase III-like contractions during intravenous infusion of saline. Intragastric acidification (pH 1.5-2.5) inhibited motilin-induced phase III contractions in a pH-dependent manner and significantly decreased the motility index at a pH below 2.0. In contrast, intraduodenal acidification (pH 2.0) failed to inhibit motilin-induced contractions. Vagotomy significantly alleviated the suppression of motilin-induced gastric contractions under acidic conditions (pH 2.0), suggesting vagus nerve involvement. Moreover, intragastric acidification (pH 2.0) significantly increased the number of c-Fos-positive cells in the nucleus tractus solitarii. In vagotomized S. murinus, the number of c-Fos-positive cells did not change, even under gastric acidification conditions. TRPV1 mRNA was highly expressed in the muscle and mucosal regions of the antrum and the nodose ganglion, whereas was not detected in the upper small intestine. Capsazepin, a TRPV1 antagonist, completely rescued the inhibitory effect of gastric acidification. CONCLUSIONS Gastric acidification in S. murinus inhibits motilin-induced contractions, a finding similar to results observed in humans, while TRPV1-expressing vagus nerves play a role in the inhibitory mechanism.
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Affiliation(s)
- Makoto Yoshimura
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Takashi Mikami
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Kayuri Kuroda
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Maki Nishida
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Kazuma Ito
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Anupom Mondal
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Kouhei Koyama
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Takamichi Jogahara
- Laboratory of Animal Management and Resources, Department of Zoology, Faculty of Science, Okayama University of Science, Okayama, 700-8525, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Takafumi Sakai
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan.
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Dudani A, Aizawa S, Zhi G, Tanaka T, Jogahara T, Sakata I, Sakai T. The proximal gastric corpus is the most responsive site of motilin-induced contractions in the stomach of the Asian house shrew. J Comp Physiol B 2016; 186:665-75. [PMID: 27062028 DOI: 10.1007/s00360-016-0985-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 03/24/2016] [Accepted: 03/29/2016] [Indexed: 11/27/2022]
Abstract
The migrating motor complex (MMC) is responsible for emptying the stomach during the interdigestive period, in preparation for the next meal. It is known that gastric phase III of MMC starts from the proximal stomach and propagates the contraction downwards. We hypothesized that a certain region of the stomach must be more responsive to motilin than others, and that motilin-induced strong gastric contractions propagate from that site. Stomachs of the Suncus or Asian house shrew, a small insectivorous mammal, were dissected and the fundus, proximal corpus, distal corpus, and antrum were examined to study the effect of motilin using an organ bath experiment. Motilin-induced contractions differed in different parts of the stomach. Only the proximal corpus induced gastric contraction even at motilin 10(-10) M, and strong contraction was induced by motilin 10(-9) M in all parts of the stomach. The GPR38 mRNA expression was also higher in the proximal corpus than in the other sections, and the lowest expression was observed in the antrum. GPR38 mRNA expression varied with low expression in the mucosal layer and high expression in the muscle layer. Additionally, motilin-induced contractions in each dissected part of the stomach were inhibited by tetrodotoxin and atropine pretreatment. These results suggest that motilin reactivity is not consistent throughout the stomach, and an area of the proximal corpus including the cardia is the most sensitive to motilin.
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Affiliation(s)
- Amrita Dudani
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Sayaka Aizawa
- Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Kita-ku, Okayama, 700-8530, Japan
| | - Gong Zhi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Toru Tanaka
- Department of Pharmaceutical and Health Sciences, Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keiyaki dai, Sakado, Saitama, 350-0295, Japan
| | - Takamichi Jogahara
- Laboratory of Animal Management and Resources, Department of Zoology, Faculty of Science, Okayama University of Science, 1-1 Ridaicho, Kita-ku, Okayama, 700-0005, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan
| | - Takafumi Sakai
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama, 338-8570, Japan.
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Deloose E, Vos R, Janssen P, Van den Bergh O, Van Oudenhove L, Depoortere I, Tack J. The motilin receptor agonist erythromycin stimulates hunger and food intake through a cholinergic pathway. Am J Clin Nutr 2016; 103:730-7. [PMID: 26817505 DOI: 10.3945/ajcn.115.113456] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 12/16/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Motilin-induced phase III contractions have been identified as a hunger signal. These phase III contractions occur as part of the migrating motor complex (MMC), a contractility pattern of the gastrointestinal tract during fasting. The mechanism involved in this association between subjective hunger feelings and gastrointestinal motility during the MMC is largely unknown, however, as is its ability to stimulate food intake. OBJECTIVES We sought to 1) investigate the occurrence of hunger peaks and their relation to phase III contractions, 2) evaluate whether this relation was cholinergically driven, and 3) assess the ability of the motilin receptor agonist erythromycin to induce food intake. DESIGN An algorithm was developed to detect hunger peaks. The association with phase III contractions was studied in 14 healthy volunteers [50% men; mean ± SEM age: 25 ± 2 y; mean ± SEM body mass index (BMI; in kg/m(2)): 23 ± 1]. The impact of pharmacologically induced phase III contractions on the occurrence of hunger peaks and the involvement of a cholinergic pathway were assessed in 14 healthy volunteers (43% men; age: 29 ± 3 y; BMI: 23 ± 1). Last, the effect of erythromycin administration on food intake was examined in 15 healthy volunteers (40% men; age: 28 ± 3 y; BMI: 22 ± 1). RESULTS The occurrence of hunger peaks and their significant association with phase III contractions was confirmed (P < 0.0001). Pharmacologically induced phase III contractions were also significantly associated with hunger peaks (P < 0.05), and this association involved a cholinergic pathway. Administering erythromycin significantly stimulated food intake compared with placebo (53% ± 13% compared with 10% ± 5%; P < 0.05). CONCLUSIONS Motilin-induced phase III contractions induced hunger feelings through a cholinergic pathway. Moreover, erythromycin stimulated food intake, suggesting a physiologic role of motilin as an orexigenic signal from the gastrointestinal tract. This trial was registered at www.clinicaltrials.gov as NCT02633579.
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Affiliation(s)
- Eveline Deloose
- Translational Research Centre for Gastrointestinal Disorders (TARGID) and
| | - Rita Vos
- Translational Research Centre for Gastrointestinal Disorders (TARGID) and
| | - Pieter Janssen
- Translational Research Centre for Gastrointestinal Disorders (TARGID) and
| | - Omer Van den Bergh
- Research Group on Health Psychology, Department of Psychology, Catholic University of Leuven, Leuven, Belgium
| | | | - Inge Depoortere
- Translational Research Centre for Gastrointestinal Disorders (TARGID) and
| | - Jan Tack
- Translational Research Centre for Gastrointestinal Disorders (TARGID) and
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Deloose E, Tack J. Redefining the functional roles of the gastrointestinal migrating motor complex and motilin in small bacterial overgrowth and hunger signaling. Am J Physiol Gastrointest Liver Physiol 2016; 310:G228-33. [PMID: 26660537 DOI: 10.1152/ajpgi.00212.2015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 12/07/2015] [Indexed: 01/31/2023]
Abstract
During the fasting state the upper gastrointestinal tract exhibits a specific periodic migrating contraction pattern that is known as the migrating motor complex (MMC). Three different phases can be distinguished during the MMC. Phase III of the MMC is the most active of the three and can start either in the stomach or small intestine. Historically this pattern was designated to be the housekeeper of the gut since disturbances in the pattern were associated with small intestinal bacterial overgrowth; however, its role in the involvement of hunger sensations was already hinted in the beginning of the 20th century by both Cannon (Cannon W, Washburn A. Am J Physiol 29: 441-454, 1912) and Carlson (Carlson A. The Control of Hunger in Health and Disease. Chicago, IL: Univ. of Chicago Press, 1916). The discovery of motilin in 1973 shed more light on the control mechanisms of the MMC. Motilin plasma levels fluctuate together with the phases of the MMC and induce phase III contractions with a gastric onset. Recent research suggests that these motilin-induced phase III contractions signal hunger in healthy subjects and that this system is disturbed in morbidly obese patients. This minireview describes the functions of the MMC in the gut and its regulatory role in controlling hunger sensations.
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Affiliation(s)
- Eveline Deloose
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
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Tack J, Deloose E, Ang D, Scarpellini E, Vanuytsel T, Van Oudenhove L, Depoortere I. Motilin-induced gastric contractions signal hunger in man. Gut 2016; 65:214-24. [PMID: 25539673 DOI: 10.1136/gutjnl-2014-308472] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 11/24/2014] [Indexed: 12/12/2022]
Abstract
RATIONALE Hunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin. OBJECTIVES To study the relationship between hunger and MMC phases (I-III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite. FINDINGS In fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (β=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower. CONCLUSIONS Motilin-induced gastric phase III is a hunger signal from GIT in man.
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Affiliation(s)
- J Tack
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - E Deloose
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - D Ang
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - E Scarpellini
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - T Vanuytsel
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - L Van Oudenhove
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - I Depoortere
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
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Kuroda K, Hequing H, Mondal A, Yoshimura M, Ito K, Mikami T, Takemi S, Jogahara T, Sakata I, Sakai T. Ghrelin Is an Essential Factor for Motilin-Induced Gastric Contraction in Suncus murinus. Endocrinology 2015; 156:4437-47. [PMID: 26441238 DOI: 10.1210/en.2015-1561] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Motilin was discovered in the 1970s as the most important hormone for stimulating strong gastric contractions; however, the mechanisms by which motilin causes gastric contraction are not clearly understood. Here, we determined the coordinated action of motilin and ghrelin on gastric motility during fasted and postprandial contractions by using house musk shrew (Suncus murinus; order: Insectivora, suncus named as the laboratory strain). Motilin-induced gastric contractions at phases I and II of the migrating motor complex were inhibited by pretreatment with (D-Lys(3))-GHRP-6 (6 mg/kg/h), a ghrelin receptor antagonist. Administration of the motilin receptor antagonist MA-2029 (0.1 mg/kg) and/or (D-Lys(3))-GHRP-6 (0.6 mg/kg) at the peak of phase III abolished the spontaneous gastric phase III contractions in vivo. Motilin did not stimulate gastric contractions in the postprandial state. However, in the presence of a low dose of ghrelin, motilin evoked phase III-like gastric contractions even in the postprandial state, and postprandial gastric emptying was accelerated. In addition, pretreatment with (D-Lys(3))-GHRP-6 blocked the motilin-induced gastric contraction in vitro and in vivo, and a γ-aminobutyric acid (GABA) antagonist reversed this block in gastric contraction. These results indicate that blockade of the GABAergic pathway by ghrelin is essential for motilin-induced gastric contraction.
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Affiliation(s)
- Kayuri Kuroda
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Huang Hequing
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Anupom Mondal
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Makoto Yoshimura
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Kazuma Ito
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Takashi Mikami
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Shota Takemi
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Takamichi Jogahara
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
| | - Takafumi Sakai
- Area of Regulatory Biology (K.K., H.H., A.M., M.Y., K.I., T.M., S.T., I.S., T.S.), Division of Life Science, Graduate School of Science and Engineering, Saitama University, Shimo-ohkubo, Sakuraku, Saitama 338-8570, Japan; and Laboratory of Animal Management and Resources (T.J.), Department of Zoology, Okayama University of Science, Okayama 700-0005, Japan
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Al-Saffar A, Nogueira da Costa A, Delaunois A, Leishman DJ, Marks L, Rosseels ML, Valentin JP. Gastrointestinal Safety Pharmacology in Drug Discovery and Development. Handb Exp Pharmacol 2015; 229:291-321. [PMID: 26091645 DOI: 10.1007/978-3-662-46943-9_12] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and biochemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug-related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a-chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries.
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Affiliation(s)
- Ahmad Al-Saffar
- Faculty of Medicine, Department of Medical Sciences, Uppsala University, 751 85, Uppsala, Sweden
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Lammers WJEP. Normal and abnormal electrical propagation in the small intestine. Acta Physiol (Oxf) 2015; 213:349-59. [PMID: 25156937 DOI: 10.1111/apha.12371] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 06/03/2014] [Accepted: 08/19/2014] [Indexed: 12/15/2022]
Abstract
As in other muscular organs, small intestinal motility is determined to a large degree by the electrical activities that occur in the smooth muscle layers of the small intestine. In recent decades, the interstitial cells of Cajal, located in the myenteric plexus, have been shown to be responsible for the generation and propagation of the electrical impulse: the slow wave. It was also known that the slow waves as such do not cause contraction, but that the action potentials ('spikes') that are generated by the slow waves are responsible for the contractions. Recording from large number of extracellular electrodes simultaneously is one method to determine origin and pattern of propagation of these electrical signals. This review reports the characteristics of slow wave propagation through the intestinal tube, the occurrence of propagation blocks along its length, which explains the well-known decrease in frequency, and the specific propagation pattern of the spikes that follow the slow waves. But the value of high-resolution mapping is highest in discovering and analysing mechanisms of arrhythmias in the gut. Most recently, circus movements (also called 're-entries') have been described in the small intestine in several species. Moreover, several types of re-entries have now been described, some similar to what may occur in the heart, such as functional re-entries, but others more unique to the small intestine, such as circumferential re-entry. These findings seem to suggest the possibilities of hitherto unknown pathologies that may be present in the small intestine.
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Affiliation(s)
- W. J. E. P. Lammers
- Departments of Physiology; College of Medicine and Health Sciences; UAE University; Al Ain United Arab Emirates
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46
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Mazet B. Gastrointestinal motility and its enteric actors in mechanosensitivity: past and present. Pflugers Arch 2014; 467:191-200. [PMID: 25366494 DOI: 10.1007/s00424-014-1635-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Revised: 10/14/2014] [Accepted: 10/19/2014] [Indexed: 12/14/2022]
Abstract
Coordinated contractions of the smooth muscle layers of the gastrointestinal (GI) tract are required to produce motor patterns that ensure normal GI motility. The crucial role of the enteric nervous system (ENS), the intrinsic ganglionated network located within the GI wall, has long been recognized in the generation of the main motor patterns. However, devising an appropriate motility requires the integration of informations emanating from the lumen of the GI tract. As already found more than half a century ago, the ability of the GI tract to respond to mechanical forces such as stretch is not restricted to neuronal mechanisms. Instead, mechanosensitivity is now recognized as a property of several non-neuronal cell types, the excitability of which is probably involved in shaping the motor patterns. This brief review gives an overview on how mechanosensitivity of different cell types in the GI tract has been established and, whenever available, on what ionic conductances are involved in mechanotransduction and their potential impact on normal GI motility.
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Affiliation(s)
- Bruno Mazet
- Aix Marseille Université, CNRS, CRN2M UMR 7286, CS80011 Bd Pierre Dramard, 13344, Marseille Cedex 15, France,
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Brijs J, Hennig GW, Axelsson M, Olsson C. Effects of feeding on in vivo motility patterns in the proximal intestine of shorthorn sculpin (Myoxocephalus scorpius). J Exp Biol 2014; 217:3015-27. [PMID: 24948631 PMCID: PMC4148186 DOI: 10.1242/jeb.101741] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 06/10/2014] [Indexed: 01/16/2023]
Abstract
This is the first study to catalogue the diverse array of in vivo motility patterns in a teleost fish and how they are affected by feeding. Video recordings of exteriorised proximal intestine from fasted and fed shorthorn sculpin (Myoxocephalus scorpius) were used to generate spatio-temporal maps to portray and quantify motility patterns. Propagating and non-propagating contractions were observed to occur at different frequencies and durations. The most apparent difference between the feeding states was that bands of relatively high amplitude contractions propagating slowly in the anal direction were observed in all fasted fish (N=10) but in only 35% of fed fish (N=11). Additionally, fed fish displayed a reduced frequency (0.21±0.03 versus 0.32±0.06 contractions min(-1)) and rhythmicity of these contractions compared with fasted fish. Although the underlying mechanisms of these slow anally propagating contractions differ from those of mammalian migrating motor complexes, we believe that they may play a similar role in shorthorn sculpin during the interdigestive period, to potentially remove food remnants and prevent the establishment of pathogens. 'Ripples' were the most prevalent contraction type in shorthorn sculpin and may be important during mixing and absorption. The persistence of shallow ripples and pendular movements of longitudinal muscle after tetrodotoxin (1 μmol l(-1)) treatment suggests these contractions were myogenic in origin. The present study highlights both similarities and differences in motility patterns between shorthorn sculpin and other vertebrates, as well as providing a platform to examine other aspects of gastrointestinal functions in fish, including the impact of environmental changes.
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Affiliation(s)
- Jeroen Brijs
- Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, Sweden
| | - Grant W Hennig
- Department of Physiology and Cell Biology, University of Reno, NV, USA
| | - Michael Axelsson
- Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, Sweden
| | - Catharina Olsson
- Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, Sweden
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Sjögren E, Abrahamsson B, Augustijns P, Becker D, Bolger MB, Brewster M, Brouwers J, Flanagan T, Harwood M, Heinen C, Holm R, Juretschke HP, Kubbinga M, Lindahl A, Lukacova V, Münster U, Neuhoff S, Nguyen MA, Peer AV, Reppas C, Hodjegan AR, Tannergren C, Weitschies W, Wilson C, Zane P, Lennernäs H, Langguth P. In vivo methods for drug absorption – Comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects. Eur J Pharm Sci 2014; 57:99-151. [PMID: 24637348 DOI: 10.1016/j.ejps.2014.02.010] [Citation(s) in RCA: 201] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 02/15/2014] [Accepted: 02/17/2014] [Indexed: 01/11/2023]
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Tittel A, Schippers E, Anurov M, Titkova S, Ottinger A, Schumpelick V. Shorter postoperative atony after laparoscopic-assisted colonic resection? Surg Endosc 2014; 15:508-12. [PMID: 11353971 DOI: 10.1007/s004640000270] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2000] [Accepted: 03/24/2000] [Indexed: 11/24/2022]
Abstract
BACKGROUND The duration of the postoperative ileus after laparoscopic surgery remains a controversial topic. The aim of our study was to compare the restoration of intestinal motility after laparoscopically assisted and conventional resection of the distal colon in a canine model. METHODS Two weeks after the implantation of three electrodes on the jejunum, the distal colon was resected in a laparoscopic-assisted or conventional procedure in two groups of four dogs each. Gastrointestinal motility was monitored by registration of the electromyograhic activity of the small intestine and by intermittent fluoroscopies of radiopaque markers. RESULTS Electrical activity in the early postoperative period was characterized by the basic electrical rhythm and the absence of spike activity. The first postoperative activity front of the migrating motility complex (MMC), indicating the restoration of motility, occurred significantly earlier after laparoscopic-assisted resection (4.5 +/- 1 hr) than after conventional resection (31 +/- 10 h). Radiological observations showed a significantly delayed gastric emptying and a prolonged transit of radiopaque markers to the rectum after open surgery. CONCLUSION These results support the hypothesis that laparoscopic-assisted resection of the colon leads to a shortened postoperative atony in comparison to open surgery.
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Affiliation(s)
- A Tittel
- Department of Surgery, Medical Faculty of the RWTH Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany.
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Davis SS, Stockwell AF, Taylor MJ, Hardy JG, Whalley DR, Wilson CG, Bechgaard H, Christensen FN. The effect of density on the gastric emptying of single- and multiple-unit dosage forms. Pharm Res 2013; 3:208-13. [PMID: 24271583 DOI: 10.1023/a:1016334629169] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gastric emptying of pellets and single units of different densities has been followed in healthy subjects using the technique of gamma scintigraphy. The gastric emptying of the light pellets was affected by their buoyancy in the upper part of the stomach. However, the mean gastric emptying rates of pellets and single units were not significantly affected by density. Floating or buoyant delivery systems may have little advantage over conventional systems. The presence of food in the stomach was found to be the major factor in determining the gastric emptying of single units.
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Affiliation(s)
- S S Davis
- Department of Pharmacy, University of Nottingham, Nottingham, UK
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