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Feng Z, Zhang Z, Yan Z, Gao F, Chen Q. Innovative laparoscopic 'Tunnel' approach in managing hiatal hernia with gastroesophageal reflux disease: a retrospective study. BMC Surg 2025; 25:154. [PMID: 40217214 PMCID: PMC11992776 DOI: 10.1186/s12893-025-02900-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 04/04/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Hiatal hernia (HH) is a major cause of gastroesophageal reflux disease (GERD), and laparoscopic repair combined with anti-reflux surgery is a common treatment. However, postoperative complications such as vagus nerve injury remain a concern. This study introduces a novel Laparoscopic "Tunnel" Approach aiming to minimize damage to the vagus nerve and preserve perigastric vessels. METHODS Clinical data were consecutively collected from patients who underwent laparoscopic "tunnel" approach for the treatment of hiatal hernia combined with gastroesophageal reflux disease at the First Affiliated Hospital of Ningbo University between June 2023 and June 2024. Data collected included age, gender, BMI, DeMeester score, surgical time, and postoperative symptoms. Follow-ups were conducted at 1, 3, and 6 months postoperatively. RESULTS The average age was 54 ± 9 years, BMI was 25.56 ± 4.32 kg/m2, DeMeester score was 118.05 ± 17.71, and GERD-Q score was 13 ± 2. The average surgical time was 115 ± 15 min. Postoperatively, symptoms significantly improved, with an average GERD-Q score of 5 ± 1 at 6 months. At 1 month, dysphagia was observed in 14 patients, belching in 19, abdominal distension in 5, nausea in 16, and diarrhea in 8. By 6 months, only 2 patients exhibited belching, with no other symptoms persisting. No cases of vomiting or gallstones were reported. CONCLUSIONS The Laparoscopic "Tunnel" Approach may effectively minimizes vagus nerve injury and preserves perigastric vessels, resulting in improved postoperative outcomes and quality of life. This method shows potential for wider application in treating HH and GERD. However, since this study was retrospective and lacked a control group, further studies are needed to verify our conclusions.
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Affiliation(s)
- Zhewen Feng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu DistrictZhejiang Province, Ningbo City, China
| | - Zhiping Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu DistrictZhejiang Province, Ningbo City, China
| | - Zhilong Yan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu DistrictZhejiang Province, Ningbo City, China
| | - Feng Gao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu DistrictZhejiang Province, Ningbo City, China
| | - Qingfeng Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu DistrictZhejiang Province, Ningbo City, China.
- Department of General Surgery, Cixi Longshan Hospital, Cixi City, 1200 Lingfeng RoadZhejiang Province, Binhai New TownNingbo, China.
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Zhang S, Kaiya H, Kitazawa T. Physiological roles of ghrelin in the regulation of gastrointestinal motility in vertebrates. Gen Comp Endocrinol 2025; 365:114698. [PMID: 40024446 DOI: 10.1016/j.ygcen.2025.114698] [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: 10/29/2024] [Revised: 02/20/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
Ghrelin is known to be a multifunctional peptide hormone that stimulates not only growth hormone secretion and feeding but also gastrointestinal (GI) functions, including motility, secretion and mucosa proliferation. The aim of this review is to provide a comprehensive overview on the physiological roles of ghrelin in the regulation of GI motility from a comparative perspective. The effects of ghrelin on GI motility differ depending on the species, and ghrelin is a possible regulator of gastric migrating motor complexes (MMCs) in rodents, dogs and house musk shrew (suncus). However, the role of ghrelin has not been clarified in detail in other mammals, including humans and rabbits. Ghrelin is also effective to cause contraction in the GI tract of some non-mammals, but its physiological role is also not clarified at present. Distribution of the growth hormone secretagogue receptor (GHSR, ghrelin receptor) in the GI tract might be connected with the regulatory role of ghrelin in vertebrates. Comparative studies of ghrelin among animals and identification of knowledge gaps must lead us to the functional transition and importance of ghrelin in the GI tract.
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Affiliation(s)
- Shuangyi Zhang
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan; College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Hiroyuki Kaiya
- Grandsoul Research Institute for Immunology, Inc., Uda, Nara 633-2221, Japan; Faculty of Science, University of Toyama, Toyama 930-8555, Japan
| | - Takio Kitazawa
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan.
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3
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Ma Y, Yan Q, Wang P, Guo W, Yu L. Therapeutic potential of ghrelin/GOAT/GHSR system in gastrointestinal disorders. Front Nutr 2024; 11:1422431. [PMID: 39246401 PMCID: PMC11380557 DOI: 10.3389/fnut.2024.1422431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 08/08/2024] [Indexed: 09/10/2024] Open
Abstract
Ghrelin, a peptide primarily secreted in the stomach, acts via the growth hormone secretagogue receptor (GHSR). It regulates several physiological processes, such as feeding behavior, energy homeostasis, glucose and lipid metabolism, cardiovascular function, bone formation, stress response, and learning. GHSR exhibits significant expression within the central nervous system. However, numerous murine studies indicate that ghrelin is limited in its ability to enter the brain from the bloodstream and is primarily confined to specific regions, such as arcuate nucleus (ARC) and median eminence (ME). Nevertheless, the central ghrelin system plays an essential role in regulating feeding behavior. Furthermore, the role of vagal afferent fibers in regulating the functions of ghrelin remains a major topic of discussion among researchers. In recent times, numerous studies have elucidated the substantial therapeutic potential of ghrelin in most gastrointestinal (GI) diseases. This has led to the development of numerous pharmaceutical agents that target the ghrelin system, some of which are currently under examination in clinical trials. Furthermore, ghrelin is speculated to serve as a promising biomarker for GI tumors, which indicates its potential use in tumor grade and stage evaluation. This review presents a summary of recent findings in research conducted on both animals and humans, highlighting the therapeutic properties of ghrelin system in GI disorders.
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Affiliation(s)
- Yunxiao Ma
- Department of Endocrinology and Metabolism of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Qihui Yan
- Department of Endocrinology and Metabolism of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ping Wang
- Department of Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, Jilin University, Changchun, China
| | - Weiying Guo
- Department of Endocrinology and Metabolism of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Lu Yu
- Department of Endocrinology and Metabolism of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
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Knez E, Kadac-Czapska K, Grembecka M. The importance of food quality, gut motility, and microbiome in SIBO development and treatment. Nutrition 2024; 124:112464. [PMID: 38657418 DOI: 10.1016/j.nut.2024.112464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 03/18/2024] [Accepted: 04/04/2024] [Indexed: 04/26/2024]
Abstract
The prevalence of small intestinal bacterial overgrowth (SIBO) is rising worldwide, particularly in nations with high rates of urbanization. Irritable bowel syndrome, inflammatory bowel illnesses, and nonspecific dysmotility are strongly linked to SIBO. Moreover, repeated antibiotic therapy promotes microorganisms' overgrowth through the development of antibiotic resistance. The primary cause of excessive fermentation in the small intestine is a malfunctioning gastrointestinal motor complex, which results in the gut's longer retention of food residues. There are anatomical and physiological factors affecting the functioning of the myoelectric motor complex. Except for them, diet conditions the activity of gastrointestinal transit. Indisputably, the Western type of nutrition is unfavorable. Some food components have greater importance in the functioning of the gastrointestinal motor complex than others. Tryptophan, an essential amino acid and precursor of the serotonin hormone, accelerates intestinal transit, and gastric emptying, similarly to fiber and polyphenols. Additionally, the effect of food on the microbiome is important, and diet should prevent bacterial overgrowth and exhibit antimicrobial effects against pathogens. Therefore, knowledge about proper nutrition is essential to prevent the development and recurrence of SIBO. Since the scientific world was unsure whether there was a long-term or potential solution for SIBO until quite recently, research on a number of the topics included in the article should be performed. The article aimed to summarize current knowledge about proper nutrition after SIBO eradication and the prevention of recurrent bacterial overgrowth. Moreover, a connection was found between diet, gut dysmotility, and SIBO.
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Affiliation(s)
- Eliza Knez
- Department of Bromatology, Medical University of Gdańsk, Gdańsk, Poland
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Ayoub M, Faris C, Tomanguillo J, Anwar N, Chela H, Daglilar E. The Use of Pre-Endoscopic Metoclopramide Does Not Prevent the Need for Repeat Endoscopy: A U.S. Based Retrospective Cohort Study. Life (Basel) 2024; 14:526. [PMID: 38672796 PMCID: PMC11051147 DOI: 10.3390/life14040526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/14/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Peptic ulcer disease (PUD) can cause upper gastrointestinal bleeding (UGIB), often needing esophagogastroduodenoscopy (EGD). Second-look endoscopies verify resolution, but cost concerns prompt research on metoclopramide's efficacy compared to erythromycin. METHODS We analyzed the Diamond Network of TriNetX Research database, dividing UGIB patients with PUD undergoing EGD into three groups: metoclopramide, erythromycin, and no medication. Using 1:1 propensity score matching, we compared repeat EGD, post-EGD transfusion, and mortality within one month in two study arms. RESULTS Out of 97,040 patients, 11.5% received metoclopramide, 3.9% received erythromycin, and 84.6% received no medication. Comparing metoclopramide to no medication showed no significant difference in repeat EGD (10.1% vs. 9.7%, p = 0.34), transfusion (0.78% vs. 0.86%, p = 0.5), or mortality (1.08% vs. 1.08%, p = 0.95). However, metoclopramide had a higher repeat EGD rate compared to erythromycin (9.4% vs. 7.5%, p = 0.003), with no significant difference in transfusion or mortality. CONCLUSIONS The need to repeat EGD was not decreased with pre-EGD use of metoclopramide. If a prokinetic agent is to be used prior to EGD, erythromycin shows superior reduction in the need of repeat EGD as compared to metoclopramide.
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Affiliation(s)
- Mark Ayoub
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
| | - Carol Faris
- Department of General Surgery, Marshall University, Huntington, WV 25755, USA;
| | - Julton Tomanguillo
- Department of Internal Medicine, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
| | - Nadeem Anwar
- Division of Gastroenterology and Hepatology, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
| | - Harleen Chela
- Division of Gastroenterology and Hepatology, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
| | - Ebubekir Daglilar
- Division of Gastroenterology and Hepatology, Charleston Area Medical Center, West Virginia University, Charleston, WV 25304, USA
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Huang J, Suzuki M, Endo A, Watanabe A, Sakata I. The role of free fatty acid receptor-1 in gastric contractions in Suncus murinus. Food Funct 2024; 15:2221-2233. [PMID: 38318756 DOI: 10.1039/d3fo03565d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2024]
Abstract
Motilin is an important hormonal regulator in the migrating motor complex (MMC). Free fatty acid receptor-1 (FFAR1, also known as GPR40) has been reported to stimulate motilin release in human duodenal organoids. However, how FFAR1 regulates gastric motility in vivo is unclear. This study investigated the role of FFAR1 in the regulation of gastric contractions and its possible mechanism of action using Suncus murinus. Firstly, intragastric administration of oleic acid (C18:1, OA), a natural ligand for FFAR1, stimulated phase II-like contractions, followed by phase III-like contractions in the fasted state, and the gastric emptying rate was accelerated. The administration of GW1100, an FFAR1 antagonist, inhibited the effects of OA-induced gastric contractions. Intravenous infusion of a ghrelin receptor antagonist (DLS) or serotonin 4 (5-HT4) receptor antagonist (GR125487) inhibited phase II-like contractions and prolonged the onset of phase III-like contractions induced by OA. MA-2029, a motilin receptor antagonist, delayed the occurrence of phase III-like contractions. In vagotomized suncus, OA did not induce phase II-like contractions. In addition, OA promoted gastric emptying through a vagal pathway during the postprandial period. However, OA did not directly act on the gastric body to induce contractions in vitro. In summary, this study indicates that ghrelin, motilin, 5-HT, and the vagus nerve are involved in the role of FFAR1 regulating MMC. Our findings provide novel evidence for the involvement of nutritional factors in the regulation of gastric motility.
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Affiliation(s)
- Jin Huang
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan.
| | - Miu Suzuki
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan.
| | - Ami Endo
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan.
| | - Ayumi Watanabe
- 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.
- Research Area of Evolutionary Molecular Design, Strategic Research Center, Saitama University, Saitama, Japan
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Zhang S, Kaiya H, Kitazawa T. Does ghrelin regulate intestinal motility in rabbits? An in vitro study using isolated duodenal strips. Gen Comp Endocrinol 2023; 344:114384. [PMID: 37722460 DOI: 10.1016/j.ygcen.2023.114384] [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: 07/10/2023] [Revised: 09/07/2023] [Accepted: 09/15/2023] [Indexed: 09/20/2023]
Abstract
Rabbit duodenum has been used for examining the ability of motilin to cause muscle contraction in vitro. A motilin-related peptide, ghrelin, is known to be involved in the regulation of gastrointestinal (GI) motility in various animals, but its ability to cause rabbit GI contraction have not been well examined. The aim of this study is to clarify the action of rat ghrelin and its interaction with motilin in the rabbit duodenum. The mRNA expression of ghrelin and motilin receptors was also examined using RT-PCR. Rat ghrelin (10-9-10-6 M) did not change the contractile activity of the duodenum measured by the mean muscle tonus and area under the curve of contraction waves. In agreement with this result, the distribution of ghrelin receptor mRNA in the rabbit GI tract varied depending on the GI region from which the samples were taken; the expression level in the duodenum was negligible, but that in the esophagus or stomach was significant. On the other hand, motilin (10-10-10-6 M) caused a concentration-dependent contraction by means of increased mean muscle tonus, and consistently, motilin receptor mRNA was expressed heterogeneously depending on the GI region (esophagus = stomach = colon = rectum < duodenum = jejunum = ileum < cecum). Expression level of motilin receptor was comparable to that of ghrelin receptor in the esophagus and stomach. Pretreatment with ghrelin (10-6 M) prior to motilin did not affect the contractile activity of motilin in the duodenum. In conclusion, ghrelin does not affect muscle contractility or motilin-induced contraction in the rabbit duodenum, which is due to the lack of ghrelin receptors. The present in vitro results suggest that ghrelin might not be a regulator of intestinal motility in rabbits.
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Affiliation(s)
- Shuangyi Zhang
- Laboratory of Veterinary Physiology, College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot 010018, China; School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan
| | - Hiroyuki Kaiya
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 564-8565, Japan; Faculty of Science, University of Toyama, Toyama, Toyama 933-8555, Japan; Grandsoul Research Institute for Immunology, Inc., Uda, Nara 633-2221, Japan
| | - Takio Kitazawa
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan.
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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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Huang YH, Xie C, Chou CY, Jin Y, Li W, Wang M, Lu Y, Liu Z. Subtyping intractable functional constipation in children using clinical and laboratory data in a classification model. Front Pediatr 2023; 11:1148753. [PMID: 37168808 PMCID: PMC10165123 DOI: 10.3389/fped.2023.1148753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 04/03/2023] [Indexed: 05/13/2023] Open
Abstract
Background Children with intractable functional constipation (IFC) who are refractory to traditional pharmacological intervention develop severe symptoms that can persist even in adulthood, resulting in a substantial deterioration in their quality of life. In order to better manage IFC patients, efficient subtyping of IFC into its three subtypes, normal transit constipation (NTC), outlet obstruction constipation (OOC), and slow transit constipation (STC), at early stages is crucial. With advancements in technology, machine learning can classify IFC early through the use of validated questionnaires and the different serum concentrations of gastrointestinal motility-related hormones. Method A hundred and one children with IFC and 50 controls were enrolled in this study. Three supervised machine-learning methods, support vector machine, random forest, and light gradient boosting machine (LGBM), were used to classify children with IFC into the three subtypes based on their symptom severity, self-efficacy, and quality of life which were quantified using certified questionnaires and their serum concentrations of the gastrointestinal hormones evaluated with enzyme-linked immunosorbent assay. The accuracy of machine learning subtyping was evaluated with respect to radiopaque markers. Results Of 101 IFC patients, 37 had NTC, 49 had OOC, and 15 had STC. The variables significant for IFC subtype classification, according to SelectKBest, were stool frequency, the satisfaction domain of the Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL), the emotional self-efficacy for Functional Constipation questionnaire (SEFCQ), motilin serum concentration, and vasoactive intestinal peptide serum concentration. Among the three models, the LGBM model demonstrated an accuracy of 83.8%, a precision of 84.5%, a recall of 83.6%, a f1-score of 83.4%, and an area under the receiver operating characteristic curve (AUROC) of 0.89 in discriminating IFC subtypes. Conclusion Using clinical characteristics measured by certified questionnaires and serum concentrations of the gastrointestinal hormones, machine learning can efficiently classify pediatric IFC into its three subtypes. Of the three models tested, the LGBM model is the most accurate model for the classification of IFC, with an accuracy of 83.8%, demonstrating that machine learning is an efficient tool for the management of IFC in children.
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Affiliation(s)
- Yi-Hsuan Huang
- Department of Gastroenterology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Medical School, Nanjing University, Nanjing, China
| | - Chenjia Xie
- School of Electronic Science and Engineering, Nanjing University, Nanjing, China
| | - Chih-Yi Chou
- College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu Jin
- Department of Gastroenterology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Medical School, Nanjing University, Nanjing, China
| | - Wei Li
- Department of Gastroenterology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Department of Quality Management, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Meng Wang
- Department of Gastroenterology, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Lu
- Department of Gastroenterology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Correspondence: Yan Lu Zhifeng Liu
| | - Zhifeng Liu
- Department of Gastroenterology, Children’s Hospital of Nanjing Medical University, Nanjing, China
- Medical School, Nanjing University, Nanjing, China
- Correspondence: Yan Lu Zhifeng Liu
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Moin K, Funk C, Josephs M, Coombes K, Yeakle M, Gala D, Ahmed-Khan M. Gut-brain axis: Review on the association between Parkinson's disease and plant lectins. Arch Clin Cases 2022; 9:177-183. [PMID: 36628158 PMCID: PMC9769076 DOI: 10.22551/2022.37.0904.10228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal (GI) involvement in the pathogenesis of Parkinson's Disease (PD) has been widely recognized and supported in recent literature. Prospective and retrospective studies found non-motor symptoms within the GI, specifically constipation, precede cardinal signs and cognitive decline by almost 20 years. In 2002, Braak et al. were the first to propose that PD is a six-stage propagating neuropathological process originating from the GI tract (GIT). Aggregated α-synuclein (α-syn) protein from the GIT is pathognomonic for the development of PD. This article reviews the current literature from the past 10 years as well as original research found in PubMed on the combined effects of enteric glial cells and lectins on the development of Parkinson's Disease. Studies have found that these aggregated and phosphorylated proteins gain access to the brain via retrograde transport through fast and slow fibers of intestinal neurons. Plant lectins, commonly found within plant-based diets, have been found to induce Leaky Gut Syndrome and can activate enteric glial cells, causing the release of pro-inflammatory cytokines. Oxidative stress on the enteric neurons, caused by a chronic neuro-inflammatory state, can cause a-syn aggregation and lead to Lewy Body formation, a hallmark finding in PD. Although the current literature provides a connection between the consumption of plant lectins and the pathophysiology of PD, further research is required to evaluate confounding variables such as food antigen mimicry and other harmful substances found in our diets.
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Affiliation(s)
- Kayvon Moin
- American University of the Caribbean, School of Medicine, Cupecoy, Sint Maarten, Netherlands Antilles,Correspondence: Kayvon Moin, American University of the Caribbean, School of Medicine, 1 University Drive at, Jordan Dr, Cupecoy, Sint Maarten, Netherlands Antilles.
| | - Carly Funk
- American University of the Caribbean, School of Medicine, Cupecoy, Sint Maarten, Netherlands Antilles
| | - Meagan Josephs
- American University of the Caribbean, School of Medicine, Cupecoy, Sint Maarten, Netherlands Antilles
| | - Kyle Coombes
- American University of the Caribbean, School of Medicine, Cupecoy, Sint Maarten, Netherlands Antilles
| | - Madeleine Yeakle
- American University of the Caribbean, School of Medicine, Cupecoy, Sint Maarten, Netherlands Antilles
| | - Dhir Gala
- American University of the Caribbean, School of Medicine, Cupecoy, Sint Maarten, Netherlands Antilles
| | - Mohammad Ahmed-Khan
- Danbury Hospital-Yale University, School of Medicine, Danbury, Netherlands Antilles
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Onaga T, Sakai A, Yasui Y. Intravenous administration of xenin-25 accelerates cyclic ruminal contractions in healthy conscious sheep. Neuropeptides 2022; 96:102293. [PMID: 36182703 DOI: 10.1016/j.npep.2022.102293] [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: 08/08/2022] [Revised: 09/07/2022] [Accepted: 09/16/2022] [Indexed: 11/20/2022]
Abstract
The present study aimed to determine the effect and mode of action of the intravenous injection of xenin-25 on cyclic contractions of the rumen in healthy conscious sheep and mode of its action. Clinically healthy male sheep were equipped with a rumen cannula by surgery under anesthesia, and ruminal contractions were recorded with manometry in conscious animals after the recovery period. Intravenous xenin-25 injection induced a cluster of premature ruminal phasic contractions in a dose-dependent manner between 0.03 and 1 nmol/kg, and the change at the highest dose was statistically significant. In contrast, intravenous neurotensin injection inhibited the amplitude of cyclic rumen contractions. The xenin-25 effect was not significantly altered by prior injection of the neurotensin receptor subtype-1 antagonist SR 48692 at 30 and 100 nmol/kg. After euthanasia the ruminal muscles were excised for in vitro experiments. A single xenin-25 application (0.3-10 μM) to the longitudinal and circular muscle strips of the rumen did not induce any change in tension or electric field stimulation-induced phasic contractions of the muscle strips. These results demonstrated that circulating xenin-25 stimulates rumen contractions by acting on sites except the intramural intrinsic nerve plexus or smooth muscles of the rumen, implying that xenin-25 acts on the gastric center and/or cholinergic efferent nerve innervated to the ovine rumen.
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Affiliation(s)
- Takenori Onaga
- Laboratory of Veterinary Physiology, Division of Biosciences, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Japan.
| | - Ami Sakai
- Laboratory of Veterinary Physiology, Division of Biosciences, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Japan
| | - Yumiko Yasui
- Laboratory of Veterinary Physiology, Division of Biosciences, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Japan
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12
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Kobayashi Y, Takemi S, Sakai T, Shibata C, Sakata I. Diurnal changes of colonic motility and regulatory factors for colonic motility in Suncus murinus. Neurogastroenterol Motil 2022; 34:e14302. [PMID: 34846085 DOI: 10.1111/nmo.14302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 11/02/2021] [Accepted: 11/10/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND The aim of this study was to investigate the fundamental mechanisms of colonic motility in the house musk suncus (Suncus murinus) as an established animal model of gut motility. METHODS To measure gut motility in free-moving conscious suncus, strain gauge force transducers were implanted on the serosa of the colon and gastric body. KEY RESULTS We recorded diurnal changes in colonic motility and observed the relationship between feeding and colonic motility. Giant migrating contractions (GMCs) of the colon were invariably detected during defecation and tended to increase during the dark period, thereby indicating that colonic motility has a circadian rhythm. Given that GMCs in the suncus were observed immediately after feeding during the dark period, we assume the occurrence of a gastrocolic reflex in suncus, similar to that observed in humans and dogs. We also examined the factors that regulate suncus GMCs. Intravenous administration of 5-HT (100 µg/kg), substance P (10 and 100 µg/kg), calcitonin gene-related peptide (10 µg/kg), and α2 adrenergic receptor antagonist yohimbine (0.5, 1, and 3 mg/kg) induced GMC-like contractions, as did intragastric and intracolonic administration of the transient receptor potential vanilloid 1 agonist, capsaicin (1 mg/kg). CONCLUSIONS & INFERENCES These results indicate that the fundamental mechanisms of colonic motility in suncus are similar to those in humans and dogs, and we thus propose that suncus could serve as a novel small animal model for studying colonic motility.
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Affiliation(s)
- Yuki Kobayashi
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Shota Takemi
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Takafumi Sakai
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Chikashi Shibata
- Division of Faculty of Medicine, Department of Gastroenterologic Surgery, Tohoku Medical and Pharmacological University, Sendai, Japan
| | - Ichiro Sakata
- Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan.,Division of Strategy Research, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
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13
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Kitazawa T, Kaiya H. Motilin Comparative Study: Structure, Distribution, Receptors, and Gastrointestinal Motility. Front Endocrinol (Lausanne) 2021; 12:700884. [PMID: 34497583 PMCID: PMC8419268 DOI: 10.3389/fendo.2021.700884] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/16/2021] [Indexed: 12/26/2022] Open
Abstract
Motilin, produced in endocrine cells in the mucosa of the upper intestine, is an important regulator of gastrointestinal (GI) motility and mediates the phase III of interdigestive migrating motor complex (MMC) in the stomach of humans, dogs and house musk shrews through the specific motilin receptor (MLN-R). Motilin-induced MMC contributes to the maintenance of normal GI functions and transmits a hunger signal from the stomach to the brain. Motilin has been identified in various mammals, but the physiological roles of motilin in regulating GI motility in these mammals are well not understood due to inconsistencies between studies conducted on different species using a range of experimental conditions. Motilin orthologs have been identified in non-mammalian vertebrates, and the sequence of avian motilin is relatively close to that of mammals, but reptile, amphibian and fish motilins show distinctive different sequences. The MLN-R has also been identified in mammals and non-mammalian vertebrates, and can be divided into two main groups: mammal/bird/reptile/amphibian clade and fish clade. Almost 50 years have passed since discovery of motilin, here we reviewed the structure, distribution, receptor and the GI motility regulatory function of motilin in vertebrates from fish to mammals.
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Affiliation(s)
- Takio Kitazawa
- Comparative Animal Pharmacology, Department of Veterinary Science, Rakuno Gakuen University, Ebetsu, Japan
| | - Hiroyuki Kaiya
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
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14
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Abstract
PURPOSE OF REVIEW Ghrelin was discovered in 1999; extensive research and clinical studies on ghrelin have been published in the last 20 years. Physiological research on ghrelin ranges from its appetite-stimulating effects to its association with energy homeostasis. The physiological effects of ghrelin in the gastrointestinal tract and its relevance in the pathological conditions of the gastrointestinal tract have gradually become clearer. The purpose of the review is to provide current information on ghrelin cell biology and physiology, particularly in the gastrointestinal tract. RECENT FINDINGS Ghrelin-producing cells in the stomach are characterized as X/A-like cells, but immunohistochemical analyses have revealed co-expression of several secreted proteins and hormones in ghrelin-producing cells such as nesfatin-1, somatostatin, and pancreastatin. Furthermore, the local physiological roles and/or mechanisms of ghrelin in gastrointestinal functions such as gastric motility and inflammation are discussed. SUMMARY Ghrelin is a brain-gut hormone with a wide range of physiological actions; hence, it is important to understand its effects on the physiological functions of the gastrointestinal tract to elucidate the biological significance of ghrelin.
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Affiliation(s)
- Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
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15
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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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16
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Yu HZ, Fu MH, Ji XP, E-Ni RG. Progress in research of gastrointestinal motility regulation. Shijie Huaren Xiaohua Zazhi 2020; 28:1183-1191. [DOI: 10.11569/wcjd.v28.i23.1183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal motility is an important part of the physiological function of the digestive tract, and its dysfunction is one of the key factors that cause different gastrointestinal motility disorders. These diseases seriously affect patients' normal life. With the development of scientific research and technology, well-designed research studies have been conducted on the regulatory mechanisms of gastrointestinal motility, which mainly include the regulation of gastrointestinal hormones, intestinal microflora, neurotransmitters, brain-gut peptides, interstitial cells of Cajal, and gastrointestinal electrical activities. In addition, current studies have proved that bitter taste receptors have certain regulatory effects on gastrointestinal motility. This paper primarily discusses the relevant pathways controlling gastrointestinal motility.
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Affiliation(s)
- Hong-Zhen Yu
- School of Mongolian Medicine, Inner Mongolia University for Nationalities, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Ming-Hai Fu
- School of Mongolian Medicine, Inner Mongolia University for Nationalities, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Xiao-Ping Ji
- School of Mongolian Medicine, Inner Mongolia University for Nationalities, Tongliao 028000, Inner Mongolia Autonomous Region, China
| | - Rong-Gui E-Ni
- School of Mongolian Medicine, Inner Mongolia University for Nationalities, Tongliao 028000, Inner Mongolia Autonomous Region, China
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17
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Zhang S, Okuhara Y, Iijima M, Takemi S, Sakata I, Kaiya H, Teraoka H, Kitazawa T. Identification of pheasant ghrelin and motilin and their actions on contractility of the isolated gastrointestinal tract. Gen Comp Endocrinol 2020; 285:113294. [PMID: 31585115 DOI: 10.1016/j.ygcen.2019.113294] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 09/02/2019] [Accepted: 09/29/2019] [Indexed: 12/11/2022]
Abstract
Motilin and ghrelin were identified in the pheasant by molecular cloning, and the actions of both peptides on the contractility of gastrointestinal (GI) strips were examined in vitro. Molecular cloning indicated that the deduced amino acid sequences of the pheasant motilin and ghrelin were a 22-amino acid peptide, FVPFFTQSDIQKMQEKERIKGQ, and a 26-amino acid peptide, GSSFLSPAYKNIQQQKDTRKPTGRLH, respectively. In in vitro studies using pheasant GI strips, chicken motilin caused contraction of the proventriculus and small intestine, whereas the crop and colon were insensitive. Human motilin, but not erythromycin, caused contraction of small intestine. Chicken motilin-induced contractions in the proventriculus and ileum were not inhibited by a mammalian motilin receptor antagonist, GM109. Neither atropine (a cholinergic receptor antagonist) nor tetrodotoxin (a neuron blocker) inhibited the responses of chicken motilin in the ileum but both drugs decreased the responses to motilin in the proventriculus, suggesting that the contractile mechanisms of motilin in the proventriculus was neurogenic, different from that of the small intestine (myogenic). On the other hand, chicken and quail ghrelin did not cause contraction in any regions of pheasant GI tract. Since interaction of ghrelin and motilin has been reported in the house musk shrew, interaction of two peptides was examined. The chicken motilin-induced contractions were not modified by ghrelin, and ghrelin also did not cause any contraction under the presence of motilin, suggesting the absence of interaction in both peptides. In conclusion, both the motilin system and ghrelin system are present in the pheasant. Regulation of GI motility by motilin might be common in avian species. However, absence of ghrelin actions in any GI regions suggests the avian species-related difference in regulation of GI contractility by ghrelin.
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Affiliation(s)
- Shuangyi Zhang
- Department of Veterinary Science, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan; School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan
| | - Yuji Okuhara
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan
| | - Mio Iijima
- 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
| | - Shota Takemi
- 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
| | - 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
| | - Hiroyuki Kaiya
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Hiroki Teraoka
- School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan
| | - Takio Kitazawa
- Department of Veterinary Science, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan.
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18
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Zhou Y, Qin J, Wang Y, Wang Y, Cheng Y. Gastrointestinal and metabolic effects of noodles-based konjac glucomannan in rats. Food Nutr Res 2019; 63:1997. [PMID: 31903092 PMCID: PMC6925537 DOI: 10.29219/fnr.v63.1997] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 08/15/2019] [Accepted: 08/26/2019] [Indexed: 12/25/2022] Open
Abstract
This study was conducted to investigate the hypothesis that the beneficial metabolic effects of dietary fiber, konjac glucomannan (KGM), related with in vivo digestion might be altered if the complicated food matrix was taken into consideration. A diet of precooked noodles (PN), as widely produced and consumed in Asia, was used to simulate an actual food context. Assays were conducted with male Wistar rats (n = 80); the rats were divided into five groups and fed with either PN (control), PN supplemented with medium-dose KGM (MK), precooked low-dose KGM-supplemented noodles (LKD), precooked medium-dose KGM-supplemented noodles (MKD) or precooked high-dose KGM supplemented noodles (HKD). The time-dependent changes in blood glucose and the sensitivity to insulin after intragastric administration were determined to evaluate the postprandial glycemic response. The activity of intestinal Na+-K+-ATPase and the levels of gut hormones including motilin, cholecystokin, GLP-1, and orexin were also determined to provide insights into the function of gastrointestinal motion and after-meal hormonal feedback in each group. The noodles-based KGM showed much more efficacy in sustaining glucose homeostasis compared with KGM supplemented in a diet of noodles, indicating there might be potential long-term health outcomes of satiety and energy balance using noodles-based KGM. The postprandial glycemia was largely moderated by LKD and MKD. Despite the significant reduction in the production of glucose, MKD caused insensitivity to insulin-blood glucose regulation and a rapid gut negative feedback following a severe blood glucose fluctuation. In conclusion, the health-promoting benefits of KGM supplements on glycemic response highly depend on the type of matrix and the dose of KGM.
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Affiliation(s)
- Yun Zhou
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
- College of Food Science, Southwest University, Chongqing, People’s Republic of China
| | - Jiangdan Qin
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yongquan Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yichen Wang
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yongqiang Cheng
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
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19
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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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20
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Goyal RK, Guo Y, Mashimo H. Advances in the physiology of gastric emptying. Neurogastroenterol Motil 2019; 31:e13546. [PMID: 30740834 PMCID: PMC6850045 DOI: 10.1111/nmo.13546] [Citation(s) in RCA: 203] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 11/29/2018] [Accepted: 12/16/2018] [Indexed: 12/16/2022]
Abstract
There have been many recent advances in the understanding of various aspects of the physiology of gastric motility and gastric emptying. Earlier studies had discovered the remarkable ability of the stomach to regulate the timing and rate of emptying of ingested food constituents and the underlying motor activity. Recent studies have shown that two parallel neural circuits, the gastric inhibitory vagal motor circuit (GIVMC) and the gastric excitatory vagal motor circuit (GEVMC), mediate gastric inhibition and excitation and therefore the rate of gastric emptying. The GIVMC includes preganglionic cholinergic neurons in the DMV and the postganglionic inhibitory neurons in the myenteric plexus that act by releasing nitric oxide, ATP, and peptide VIP. The GEVMC includes distinct gastric excitatory preganglionic cholinergic neurons in the DMV and postganglionic excitatory cholinergic neurons in the myenteric plexus. Smooth muscle is the final target of these circuits. The role of the intramuscular interstitial cells of Cajal in neuromuscular transmission remains debatable. The two motor circuits are differentially regulated by different sets of neurons in the NTS and vagal afferents. In the digestive period, many hormones including cholecystokinin and GLP-1 inhibit gastric emptying via the GIVMC, and in the inter-digestive period, hormones ghrelin and motilin hasten gastric emptying by stimulating the GEVMC. The GIVMC and GEVMC are also connected to anorexigenic and orexigenic neural pathways, respectively. Identification of the control circuits of gastric emptying may provide better delineation of the pathophysiology of abnormal gastric emptying and its relationship to satiety signals and food intake.
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Affiliation(s)
- Raj K. Goyal
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
| | - Yanmei Guo
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
| | - Hiroshi Mashimo
- Department of Medicine, VA Boston Healthcare SystemHarvard Medical SchoolBostonMassachusetts
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21
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Kitazawa T, Kaiya H. Regulation of Gastrointestinal Motility by Motilin and Ghrelin in Vertebrates. Front Endocrinol (Lausanne) 2019; 10:278. [PMID: 31156548 PMCID: PMC6533539 DOI: 10.3389/fendo.2019.00278] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 04/16/2019] [Indexed: 12/14/2022] Open
Abstract
The energy balance of vertebrates is regulated by the difference in energy input and energy expenditure. Generally, most vertebrates obtain their energy from nutrients of foods through the gastrointestinal (GI) tract. Therefore, food intake and following food digestion, including motility of the GI tract, secretion and absorption, are crucial physiological events for energy homeostasis. GI motility changes depending on feeding, and GI motility is divided into fasting (interdigestive) and postprandial (digestive) contraction patterns. GI motility is controlled by contractility of smooth muscles of the GI tract, extrinsic and intrinsic neurons (motor and sensory) and some hormones. In mammals, ghrelin (GHRL) and motilin (MLN) stimulate appetite and GI motility and contribute to the regulation of energy homeostasis. GHRL and MLN are produced in the mucosal layer of the stomach and upper small intestine, respectively. GHRL is a multifunctional peptide and is involved in glucose metabolism, endocrine/exocrine functions and cardiovascular and reproductive functions, in addition to feeding and GI motility in mammals. On the other hand, the action of MLN is restricted and species such as rodentia, including mice and rats, lack MLN peptide and its receptor. From a phylogenetic point of view, GHRL and its receptor GHS-R1a have been identified in various vertebrates, and their structural features and various physiological functions have been revealed. On the other hand, MLN or MLN-like peptide (MLN-LP) and its receptors have been found only in some fish, birds and mammals. Here, we review the actions of GHRL and MLN with a focus on contractility of the GI tract of species from fish to mammals.
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Affiliation(s)
- Takio Kitazawa
- Comparative Animal Pharmacology, Department of Veterinary Science, Rakuno Gakuen University, Ebetsu, Japan
- *Correspondence: Takio Kitazawa
| | - Hiroyuki Kaiya
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan
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22
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Rudd JA, Chan SW, Ngan MP, Tu L, Lu Z, Giuliano C, Lovati E, Pietra C. Anti-emetic Action of the Brain-Penetrating New Ghrelin Agonist, HM01, Alone and in Combination With the 5-HT 3 Antagonist, Palonosetron and With the NK 1 Antagonist, Netupitant, Against Cisplatin- and Motion-Induced Emesis in Suncus murinus (House Musk Shrew). Front Pharmacol 2018; 9:869. [PMID: 30127745 PMCID: PMC6087754 DOI: 10.3389/fphar.2018.00869] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 07/18/2018] [Indexed: 11/22/2022] Open
Abstract
Ghrelin has well-known activity to stimulate appetite and weight gain. Evidence suggests that ghrelin may also have effects in reducing chemotherapy-induced emesis via growth hormone secretagogue receptors (GHS-R1A) in the brain. However, it is not known whether the stimulation of GHS-R1A has broad inhibitory anti-emetic effects. In the present studies, we used Suncus murinus to investigate the potential of the new and novel orally bioavailable brain-penetrating GHS-R1A mimetic, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), to reduce emesis induced by a variety of emetic challenges. HM01 (1 to 30 mg/kg, p.o.) antagonized emesis induced by cisplatin (30 mg/kg, i.p.) and by motion (4 cm horizontal displacement, 1 Hz) but was ineffective against emesis induced by nicotine (5 mg/kg, s.c.) and copper sulfate (120 mg/kg by intragastric gavage). In other experiments, HM01 (3 mg/kg, p.o.) enhanced the anti-emetic control of a regimen of palonosetron (0.01 mg/kg, p.o.) alone and palonosetron (0.01 mg/kg p.o.) plus netupitant (1 mg/kg, p.o.). HM01 (10 mg/kg, p.o.) also had positive effects in increasing feeding and drinking in nicotine-treated animals, and it shortened the latency to drink in animals treated with cisplatin. These data indicate that brain-penetrating GHS-R1A agonists may have use alone and/or in combination with standard anti-emetic regimens for the treatment of chemotherapy-induced nausea and vomiting and motion sickness.
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Affiliation(s)
- John A Rudd
- Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.,Brain and Mind Institute, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Sze W Chan
- School of Health Sciences, Caritas Institute of Higher Education, Tseung Kwan O New Town, Hong Kong
| | - Man P Ngan
- Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Longlong Tu
- Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Zengbing Lu
- Emesis Research Group, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Claudio Giuliano
- Helsinn Healthcare SA, Research and Development, Lugano, Switzerland
| | - Emanuela Lovati
- Helsinn Healthcare SA, Research and Development, Lugano, Switzerland
| | - Claudio Pietra
- Helsinn Healthcare SA, Research and Development, Lugano, Switzerland
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23
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Fukui H, Xu X, Miwa H. Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders. J Neurogastroenterol Motil 2018; 24:367-386. [PMID: 29969855 PMCID: PMC6034676 DOI: 10.5056/jnm18071] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 05/21/2018] [Indexed: 12/13/2022] Open
Abstract
Gut microbiota exert a pivotal influence on various functions including gastrointestinal (GI) motility, metabolism, nutrition, immunity, and the neuroendocrine system in the host. These effects are mediated by not only short-chain fatty acids produced by microbiota but also gut hormones and inflammatory signaling by enteroendocrine and immune cells under the influence of the microbiota. GI motility is orchestrated by the enteric nervous system and hormonal networks, and disturbance of GI motility plays an important role in the pathophysiology of functional gastrointestinal disorders (FGIDs). In this context, microbiota-associated mediators are considered to act on specific receptors, thus affecting the enteric nervous system and, subsequently, GI motility. Thus, the pathophysiology of FGIDs is based on alterations of the gut microbiota/gut hormone axis, which have crucial effects on GI motility.
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Affiliation(s)
- Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
| | - Xin Xu
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
- Department of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin,
China
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Mukogawa, Nishinomiya,
Japan
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24
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Deloose E, Corsetti M, Van Oudenhove L, Depoortere I, Tack J. Intragastric infusion of the bitter tastant quinine suppresses hormone release and antral motility during the fasting state in healthy female volunteers. Neurogastroenterol Motil 2018; 30. [PMID: 28776826 DOI: 10.1111/nmo.13171] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 06/29/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intragastric administration of the bitter tastant denatonium benzoate inhibits the increase of motilin plasma levels and antral contractility. While these findings suggest that gastrointestinal bitter taste receptors could be new targets to modulate gastrointestinal motility and hormone release, they need confirmation with other bitter receptor agonists. The primary aim was to evaluate the effect of intragastric administration of the bitter tastant quinine-hydrochloride (QHCl) on motilin and ghrelin plasma levels. Secondly, we studied the effect on interdigestive motility. METHODS Ten healthy female volunteers were recruited (33±4 y; 22±0.5 kg/m²). Placebo or QHCl (10 μmol/kg) was administered intragastrically through a nasogastric feeding tube after an overnight fast in a single-blind randomized fashion. Administration started 20 min after the first phase III of the migrating motor complex. The measurement continued for another 2 h after the administration. Blood samples were collected every 10 min with the baseline sample taken 10 min prior to administration. KEY RESULTS The increase in plasma levels of motilin (administration; P=.04) and total ghrelin (administration; P=.02) was significantly lower after QHCl. The fluctuation of octanoylated ghrelin was reduced after QHCl (time by administration; P=.03). Duodenal motility did not differ. The fluctuation of antral activity differed over time between placebo and QHCl (time by administration; P=.03). CONCLUSIONS AND INFERENCES QHCl suppresses the increase of both motilin and ghrelin plasma levels. Moreover, QHCl reduced the fluctuation of antral motility. These findings confirm the potential of bitter taste receptors as targets for modifying interdigestive motility in man.
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Affiliation(s)
- E Deloose
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - M Corsetti
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium.,National Institute for Health Research, Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | - 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
| | - J Tack
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
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25
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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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26
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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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27
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Jiang Z, Cao LX, Liu B, Chen QC, Shang WF, Zhou L, Li DY, Guo DA, Chen ZQ. Effects of Chinese herbal medicine Xiangbin prescription on gastrointestinal motility. World J Gastroenterol 2017; 23:2987-2994. [PMID: 28522917 PMCID: PMC5413794 DOI: 10.3748/wjg.v23.i16.2987] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Revised: 03/11/2017] [Accepted: 03/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of Xiangbin prescription (XBP), a Chinese herbal concoction, on gastrointestinal motility.
METHODS Forty healthy volunteers were recruited for this randomized controlled trial of XBP. Antroduodenojejunal manometry was used to monitor gastrointestinal motility in these subjects. After the subjects had fasted for at least 12 h, XBP (n = 30) or placebo (n = 10) was orally administrated and gastrointestinal motility was recorded for 4 h. Plasma motilin and ghrelin were measured by enzyme-linked immunosorbent assay.
RESULTS Oral administration of XBP significantly increased the amplitude of duodenal contractions [19.5 (13.0-26.7) vs 16.9 (12.3-23.9), P < 0.05], jejunal contractions [18.3 (15.3-25.0) vs 15.4 (11.7-23.9), P < 0.01], and the motility index of duodenal contractions [522.0 (146.0-139.0) vs 281.0 (76.5-1006.0), P < 0.01] in phase II of the migratory motor complex (MMC), which subsequently initiated the MMC cycle [74.0 (30.0-118.0) vs 116.5 (24.0-219.0), P < 0.05], shortened the duration of phase I of the MMC [42.0 (0.0-90.0) vs 111.5 (42.0-171.0), P < 0.01], and lengthened the duration of phase II of the MMC [120 (21-240) vs 58 (16-170), P < 0.01] compared to the duration before XBP administration. There were significant differences in the amplitude of jejunal contractions [19.8 (14.0-30.0) vs 18.0 (13.0-28.5), P < 0.05], the motility index of duodenal contractions [236.0 (115.0-306.0) vs 195.0 (109.0-310.0), P < 0.05)], and jejunal contractions [214.0 (95.0-403.0) vs 178.0 (55.0-304.0), P < 0.01] in phase III of the MMC. Oral administration of XBP greatly increased plasma motilin (57.69 ± 9.03 vs 49.38 ± 8.63, P < 0.01) and ghrelin (279.20 ± 104.31 vs 238.73 ± 115.59, P < 0.01) concentrations compared to concentrations after oral administration of the placebo.
CONCLUSION XBP can stimulate duodenal and jejunal motility and increase the concentrations of plasma motilin and ghrelin. The clinical applicability of XBP in treating GDIM deserves investigation.
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28
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Colldén G, Tschöp MH, Müller TD. Therapeutic Potential of Targeting the Ghrelin Pathway. Int J Mol Sci 2017; 18:ijms18040798. [PMID: 28398233 PMCID: PMC5412382 DOI: 10.3390/ijms18040798] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 02/07/2023] Open
Abstract
Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome.
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Affiliation(s)
- Gustav Colldén
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
| | - Timo D Müller
- Institute for Diabetes and Obesity & Helmholtz Diabetes Center, Helmholtz Zentrum München German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
- Institute for Diabetes and Obesity (IDO), Business Campus Garching-Hochbrück, Parkring 13, 85748 Garching, Germany.
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29
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Takemi S, Sakata I, Kuroda K, Miyano Y, Mondal A, Sakai T. The important role of ghrelin on gastric contraction in Suncus murinus. Endocr J 2017; 64:S11-S14. [PMID: 28652536 DOI: 10.1507/endocrj.64.s11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Ghrelin, a peptide hormone produced in the stomach, has been known to be involved in the regulation of gastric contraction in humans and rodents. To elucidate the detailed mechanisms of ghrelin on gastric contractions, we used Suncus murinus, a recently established small animal model for gastrointestinal motility. S. murinus produces motilin, a family peptide of ghrelin, and its stomach anatomy and physiological patterns of gastric contractions, in fed and fasted states, are closely similar to humans. Ghrelin administration in phase II, and latter half of phase I, of the migrating motor contractions (MMC) enhanced gastric motility in S. murinus. In addition, we showed that ghrelin and motilin coordinately stimulated strong gastric contractions in vitro and in vivo. We also demonstrated that a pretreatment with a ghrelin antagonist, D-Lys3-GHRP6, inhibited the effects of motilin-induced gastric contractions, and a γ-aminobutyric acid (GABA) antagonist reversed this inhibition. Our results suggest that ghrelin is essential for motilin-induced gastric contractions and that ghrelin-mediated GABAergic neurons are involved in this neural pathway.
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Affiliation(s)
- Shota Takemi
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
| | - Ichiro Sakata
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
| | - Kayuri Kuroda
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
| | - Yuki Miyano
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
| | - Anupon Mondal
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
| | - Takafumi Sakai
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
- Area of Life-Nanobio, Division of Strategy Research, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
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30
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Yong CY, Chen S, Chen H, Chu X, Zhang C, Tan C, Ye L, Li JS. Central neuromechanisms underlying control of intragastric pressure through acupuncture at Zusanli (ST36) in rats: the upper cervical cord is the key link between the ascending and descending pathways. Neural Regen Res 2016; 11:971-6. [PMID: 27482227 PMCID: PMC4962596 DOI: 10.4103/1673-5374.184497] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Sensory inputs stimulated by Zusanli (ST36) acupuncture in the abdomen are known to converge in the upper cervical cord. However, it is unclear whether these inputs are subsequently conveyed to the hypothalamic paraventricular nucleus and what kind of afferent fibers are involved. We focused on the upper cervical cord, where afferent inputs converge, and detected c-fos expression in oxytocinergic neurons. We found that Zusanli acupuncture therapy effectively elevated intragastric pressure, but inhibited expression of c-fos in oxytocinergic neurons of the paraventricular nucleus in upper cervical cord injured rats. These Zusanli acupuncture effects remained even after complete dorsal cord transection. However, after complete transection of the spinal cord or dorsolateral funiculus, the effects were significantly attenuated and even disappeared. These findings suggest that the paraventricular nucleus is responsible for pooling and integrating signals from the Zusanli acupuncture and sensory information from the intragastric pressure variation, thereby contributing to the regulation of intragastric pressure. The upper cervical cord serves as the key link between ascending and descending pathways, which conveys afferent inputs to the paraventricular nucleus through the dorsolateral funiculus.
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Affiliation(s)
- Chun-Yan Yong
- Department of Integrative Medicine, Xiangya Hospital of Central South University, Changsha, Hunan Province, China
| | - Shu Chen
- School of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Heng Chen
- School of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Xiao Chu
- School of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Chao Zhang
- School of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Cheng Tan
- School of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Lan Ye
- School of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha, Hunan Province, China
| | - Jiang-Shan Li
- School of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha, Hunan Province, China
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31
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Apu AS, Mondal A, Kitazawa T, Takemi S, Sakai T, Sakata I. Molecular cloning of motilin and mechanism of motilin-induced gastrointestinal motility in Japanese quail. Gen Comp Endocrinol 2016; 233:53-62. [PMID: 27179882 DOI: 10.1016/j.ygcen.2016.05.017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 05/10/2016] [Accepted: 05/11/2016] [Indexed: 12/16/2022]
Abstract
Motilin, a peptide hormone produced in the upper intestinal mucosa, plays an important role in the regulation of gastrointestinal (GI) motility. In the present study, we first determined the cDNA and amino acid sequences of motilin in the Japanese quail and studied the distribution of motilin-producing cells in the gastrointestinal tract. We also examined the motilin-induced contractile properties of quail GI tracts using an in vitro organ bath, and then elucidated the mechanisms of motilin-induced contraction in the proventriculus and duodenum of the quail. Mature quail motilin was composed of 22 amino acid residues, which showed high homology with chicken (95.4%), human (72.7%), and dog (72.7%) motilin. Immunohistochemical analysis showed that motilin-immunopositive cells were present in the mucosal layer of the duodenum (23.4±4.6cells/mm(2)), jejunum (15.2±0.8cells/mm(2)), and ileum (2.5±0.7cells/mm(2)), but were not observed in the crop, proventriculus, and colon. In the organ bath study, chicken motilin induced dose-dependent contraction in the proventriculus and small intestine. On the other hand, chicken ghrelin had no effect on contraction in the GI tract. Motilin-induced contraction in the duodenum was not inhibited by atropine, hexamethonium, ritanserin, ondansetron, or tetrodotoxin. However, motilin-induced contractions in the proventriculus were significantly inhibited by atropine and tetrodotoxin. These results suggest that motilin is the major stimulant of GI contraction in quail, as it is in mammals and the site of action of motilin is different between small intestine and proventriculus.
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Affiliation(s)
- Auvijit Saha Apu
- 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 Life-NanoBio, Division of Strategy Research, Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Sakura-ku, Saitama 338-8570, Japan
| | - Takio Kitazawa
- Comparative Animal Pharmacology Department of Veterinary Science, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan
| | - Shota Takemi
- 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 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-okubo, Sakura-ku, Saitama 338-8570, Japan.
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32
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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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Effect of Vagus Nerve Integrity on Short and Long-Term Efficacy of Antireflux Surgery. Am J Gastroenterol 2016; 111:508-15. [PMID: 26977759 DOI: 10.1038/ajg.2016.42] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Accepted: 01/24/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Vagus nerve injury is a feared complication of antireflux surgery (ARS) that may negatively affect reflux control. The aim of the present prospective study was to evaluate short-term and long-term impact of vagus nerve injury, evaluated by pancreatic polypeptide response to insulin-induced hypoglycemia (PP-IH), on the outcome of ARS. METHODS In the period from 1990 until 2000, 125 patients with gastroesophageal reflux disease (GERD) underwent ARS at a single center. Before and 6 months after surgery, vagus nerve integrity testing (PP-IH), 24-h pH-monitoring, gastric emptying, and reflux-associated symptoms were evaluated. In 2014, 14-25 years after surgery, 110 patients were contacted again for evaluation of long-term symptomatic outcome using two validated questionnaires (Gastrointestinal Symptom Rating Scale (GSRS) and GERD-Health Related Quality of Life (HRQL)). RESULTS Short-term follow-up: vagus nerve injury (PP peak ≤47 pmol/l) was observed in 23 patients (18%) 6 months after fundoplication. In both groups, a comparable decrease in reflux parameters and symptoms was observed at 6-month follow-up. Postoperative gastric emptying was significantly delayed in the vagus nerve injury group compared with the vagus nerve intact group. Long-term follow-up: patients with vagus nerve injury showed significantly less effective reflux control and a higher re-operation rate. CONCLUSIONS Vagus nerve injury occurs in up to 20% of patients after ARS. Reflux control 6 months after surgery was not affected by vagus nerve injury. However, long-term follow-up showed a negative effect on reflux symptom control and re-operation rate in patients with vagus nerve injury.
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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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Abstract
There remains an unmet need for effective pharmacologic treatments for gastroparesis. Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor and has been shown to regulate energy homeostasis and exert prokinetic effects on gastrointestinal motility. In recent years, several ghrelin receptor agonists have been studied in clinical trials of patients with diabetic gastroparesis. The intravenous macrocyclic peptidomimetic, TZP-101, initially suggested improvement in gastroparesis symptoms with intravenous administration when compared to placebo. However, in subsequent studies of oral preparations, TZP-102 failed to confirm these results. Another ghrelin receptor agonist, RM-131, was recently shown to significantly accelerate gastric emptying (GE) in patients with type 1 and type 2 diabetes and delayed GE. RM-131 reduced total Gastroparesis Cardinal Symptom Index-Daily Diary (GCSI-DD) and composite scores among type 1 diabetics. Continued development of ghrelin agonists should be explored in attempts to expand therapeutic options for the treatment of gastroparesis.
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Goswami C, Tanaka T, Jogahara T, Sakai T, Sakata I. Motilin stimulates pepsinogen secretion in Suncus murinus. Biochem Biophys Res Commun 2015; 462:263-8. [PMID: 25957475 DOI: 10.1016/j.bbrc.2015.04.129] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2015] [Accepted: 04/26/2015] [Indexed: 12/13/2022]
Abstract
Motilin and ghrelin are gastrointestinal hormones that stimulate the migrating motor complex (MMC) of gastrointestinal motility during the fasting state. In this study, we examined the effect of motilin and ghrelin on pepsinogen secretion in anesthetized suncus (house musk shrew, Suncus murinus), a ghrelin- and motilin-producing mammal. By using a gastric lumen-perfusion system, we found that the intravenous administration of carbachol and motilin stimulated pepsinogen secretion, the latter in a dose-dependent manner, whereas ghrelin had no effect. We then investigated the pathways of motilin-induced pepsinogen secretion using acetylcholine receptor antagonists. Treatment with atropine, a muscarinic acetylcholine receptor antagonist, completely inhibited both carbachol and motilin-induced pepsinogen secretion. Motilin-induced pepsinogen secretion was observed in the vagotomized suncus. This is the first report demonstrating that motilin stimulates pepsinogen secretion, and suggest that this effect occurs through a cholinergic pathway in suncus.
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Affiliation(s)
- Chayon Goswami
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama, Japan
| | - Toru Tanaka
- Faculty of Pharmaceutical Sciences, Department of Pharmaceutical and Health Sciences, Josai University, Saitama, Japan
| | - Takamichi Jogahara
- Laboratory of Animal Management and Resources, Department of Zoology, Faculty of Science, Okayama University of Science, Okayama, Japan
| | - Takafumi Sakai
- 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.
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Abstract
PURPOSE OF REVIEW To summarize the recent findings. RECENT FINDINGS Studies of changes in the plasma levels confirm the earlier concepts, but offer little proof of causal effect. It is increasingly realized that peptides produced in the gut have a paracrine role or an indirect effect via the gut-brain axis. Interest in prokinetic peptide agonists remains high despite the failure of two candidate drugs, but relamorelin and camicinal offer new hope. SUMMARY We review the original studies published since January 2013 on peptides produced in the gut and with an effect on gastrointestinal motility.
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Affiliation(s)
- Theo L Peeters
- Gut Peptide Laboratory, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium
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Liu M, Zheng SJ, Xu W, Zhang J, Chen Y, Duan Z. Changing interdigestive migrating motor complex in rats under acute liver injury. BIOMED RESEARCH INTERNATIONAL 2014; 2014:634281. [PMID: 25544942 PMCID: PMC4228720 DOI: 10.1155/2014/634281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 08/30/2014] [Accepted: 08/31/2014] [Indexed: 11/22/2022]
Abstract
Gastrointestinal motility disorder is a major clinical manifestation of acute liver injury, and interdigestive migrating motor complex (MMC) is an important indicator. We investigated the changes and characteristics of MMC in rats with acute liver injury. Acute liver injury was created by d-galactosamine, and we recorded the interdigestive MMC using a multichannel physiological recorder and compared the indexes of interdigestive MMC. Compared with normal controls, antral MMC Phase I duration was significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The duodenal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury. The jejunal MMC cycle and MMC Phases I and IV duration were significantly prolonged and MMC Phase III duration was significantly shortened in the rats with acute liver injury compared with normal controls. Compared with the normal controls, rats with acute liver injury had a significantly prolonged interdigestive MMC cycle, related mainly to longer MMC Phases I and IV, shortened MMC Phase III, and MMC Phase II characterized by increased migrating clustered contractions, which were probably major contributors to the gastrointestinal motility disorders.
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Affiliation(s)
- Mei Liu
- Artificial Liver Center, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
| | - Su-Jun Zheng
- Artificial Liver Center, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China
| | - Weihong Xu
- Department of Rheumatology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jianying Zhang
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
| | - Yu Chen
- Artificial Liver Center, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China
| | - Zhongping Duan
- Artificial Liver Center, Beijing You'an Hospital, Capital Medical University, Beijing 100069, China
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Zhao HX, Yang XH, Li CP, Chen X. Small intestinal smooth muscle cell apoptosis in rats with severe acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2014; 22:4231-4236. [DOI: 10.11569/wcjd.v22.i28.4231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether small intestinal smooth muscle cell apoptosis occurs in rats with severe acute pancreatitis (SAP) and the underlying mechanism.
METHODS: Male SD rats were randomly divided into a sham operation group (SO) and an SAP group. SAP was induced by injecting 3.8% sodium taurocholate solution into the subcapsular region of the pancreas of SD rats. Rats in the SO group were injected with 1 mL/kg normal saline. Forty-eight hours later, pancreatic pathological changes and the transit rate of the small bowel were determined. Cell apoptosis, expression of adenine nucleotide translocator (ANT) mRNA, mitochondrial membrane potential, and cytochrome C (Cyt-C) protein expression in the small intestinal smooth muscle were determined by TUNEL method, RT-PCR, flow cytometry and immunohistochemistry, respectively.
RESULTS: Compared with rats in the SO group, rats in the SAP group developed typical SAP symptoms, with a higher pancreatic pathology score (6.85 ± 1.21 vs 1.13 ± 0.91, P < 0.001). Compared with rats in the SO group, the transit rate of the small intestine was significantly lower (55.91% ± 2.93% vs 68.9% ± 5.69%, P < 0.05), the apoptosis of smooth muscle cells in the small intestine increased significantly (0.056 ± 0.184 vs 0.029 ± 0.038, P < 0.05), the expression of ANT mRNA and Cyt-C protein (0.024 ± 0.001 vs 0.057 ± 0.168, P < 0.001) in the smooth muscle of the small intestine increased significantly, and the mitochondrial membrane potential decreased significantly (5.07 ± 0.92 vs 2.40 ± 0.50, P < 0.05) in the SAP group.
CONCLUSION: The mitochondrial signal transduction pathway contributes to smooth muscle cell apoptosis in the small intestine, which may play a role in small intestinal motility dysfunction in SAP rats.
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Holmes GM, Swartz EM, McLean MS. Fabrication and implantation of miniature dual-element strain gages for measuring in vivo gastrointestinal contractions in rodents. J Vis Exp 2014:51739. [PMID: 25285858 DOI: 10.3791/51739] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Gastrointestinal dysfunction remains a major cause of morbidity and mortality. Indeed, gastrointestinal (GI) motility in health and disease remains an area of productive research with over 1,400 published animal studies in just the last 5 years. Numerous techniques have been developed for quantifying smooth muscle activity of the stomach, small intestine, and colon. In vitro and ex vivo techniques offer powerful tools for mechanistic studies of GI function, but outside the context of the integrated systems inherent to an intact organism. Typically, measuring in vivo smooth muscle contractions of the stomach has involved an anesthetized preparation coupled with the introduction of a surgically placed pressure sensor, a static pressure load such as a mildly inflated balloon or by distending the stomach with fluid under barostatically-controlled feedback. Yet many of these approaches present unique disadvantages regarding both the interpretation of results as well as applicability for in vivo use in conscious experimental animal models. The use of dual element strain gages that have been affixed to the serosal surface of the GI tract has offered numerous experimental advantages, which may continue to outweigh the disadvantages. Since these gages are not commercially available, this video presentation provides a detailed, step-by-step guide to the fabrication of the current design of these gages. The strain gage described in this protocol is a design for recording gastric motility in rats. This design has been modified for recording smooth muscle activity along the entire GI tract and requires only subtle variation in the overall fabrication. Representative data from the entire GI tract are included as well as discussion of analysis methods, data interpretation and presentation.
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Affiliation(s)
- Gregory M Holmes
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine;
| | - Emily M Swartz
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine
| | - Margaret S McLean
- Department of Neural and Behavioral Sciences, Penn State University College of Medicine
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Liu LL, Wang XY. Severe acute pancreatitis complicated with gastrointestinal dysfunction: Pathogenesis, diagnosis and treatment. Shijie Huaren Xiaohua Zazhi 2013; 21:3828-3834. [DOI: 10.11569/wcjd.v21.i34.3828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Severe acute pancreatitis (SAP) is often associated with gastrointestinal dysfunction, leading to gastrointestinal motility disorders and even gastrointestinal failure, which has an important effect on SAP progression and prognosis, directly influences the outcome of treatment, is an important cause of death in patients with SAP, and moreover, has been one of the important prognostic factors for SAP. This review aims to discuss the pathophysiology, pathogenesis, diagnosis and treatment of SAP with gastrointestinal dysfunction.
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Avau B, Carbone F, Tack J, Depoortere I. Ghrelin signaling in the gut, its physiological properties, and therapeutic potential. Neurogastroenterol Motil 2013; 25:720-32. [PMID: 23910374 DOI: 10.1111/nmo.12193] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 06/26/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Ghrelin, an orexigenic hormone secreted from the stomach, was soon after its discovery hypothesized to be a prokinetic agent, due to its homology to motilin. Studies in animals and humans, using ghrelin and ghrelin receptor agonists, confirmed this hypothesis, suggesting a therapeutic potential for the ghrelin receptor in the treatment of gastrointestinal motility disorders. Precilinical studies demonstrated that ghrelin can act directly on ghrelin receptors on the enteric nervous system, but the predominant route of action under physiological circumstances is signaling via the vagus nerve in the upper gastrointestinal tract and the pelvic nerves in the colon. Different pharmaceutical companies have designed stable ghrelin mimetics that revealed promising results in trials for the treatment of diabetic gastroparesis and post-operative ileus. Nevertheless, no drug was able to reach the market so far, facing problems proving superiority over placebo treatment in larger trials. PURPOSE This review aims to summarize the road that led to the current knowledge concerning the prokinetic properties of ghrelin with a focus on the therapeutic potential of ghrelin receptor agonists in the treatment of hypomotility disorders. In addition, we outline some of the problems that could be at the basis of the negative outcome of the trials with ghrelin agonists and question whether the right target groups were selected. It is clear that a new approach is needed to develop marketable drugs with this class of gastroprokinetic agents.
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Affiliation(s)
- B Avau
- Translational Research Center for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
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