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Mostafa MEA, Alrasheed T. Improvement of irritable bowel syndrome with glucagon like peptide-1 receptor agonists: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2025; 16:1548346. [PMID: 40134805 PMCID: PMC11932899 DOI: 10.3389/fendo.2025.1548346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 02/10/2025] [Indexed: 03/27/2025] Open
Abstract
Introduction Irritable bowel syndrome (IBS) is a severe gastrointestinal condition with symptoms like pain, bloating, diarrhea, and constipation. Glucagon-like peptide-1 (GLP-1) receptors, expressed in the central nervous system and peripheral tissues, have been found to affect gut motility. GLP-1 and its analog ROSE-010 have been shown to inhibit the migrating motor complex and decrease gastrointestinal motility in IBS patients. Aim This systematic review and meta-analysis aim to assess the efficacy and safety of GLP-1 receptor agonists in providing pain and symptom relief for individuals with IBS. Methods The study conducted extensive searches across various databases, including Cochrane Library, Web of Science, PubMed, Google Scholar, and Science Direct, to identify studies on IBS and related drugs. A search strategy using keywords and medical subject heading terms (MeSH) was developed to ensure inclusivity. Exclusion criteria included non-English language studies, books, conference papers, case reports, in vitro studies, animal studies, and non-original articles. Results The study found that ROSE-010 (100 µg) significantly lowered pain intensity in IBS patients compared to a placebo, with an overall odds ratio of 2.30, 95% CI: 1.53-3.46. ROSE-010 (300 µg) is more effective than a placebo for all irritable bowel syndrome subtypes, with consistent effects across trials. ROSE-010 is linked to a greater incidence of nausea, vomiting, and headache than placebo. Conclusion ROSE-010, a glucagon-like peptide-1 receptor agonist, has been shown to reduce pain in individuals with IBS. However, its higher frequency of nausea, vomiting, and headache suggests the need for close monitoring and individualized treatment plans. Further investigation is needed to understand its impact on different IBS subtypes and long-term effects. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024613545.
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Affiliation(s)
- Mohamed E. A. Mostafa
- Department of Anatomy, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
| | - Tariq Alrasheed
- Department of Internal Medicine, Faculty of Medicine, University of Tabuk, Tabuk, Saudi Arabia
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He Y, Xu B, Zhang M, Chen D, Wu S, Gao J, Liu Y, Zhang Z, Kuang J, Fang Q. Advances in GLP-1 receptor agonists for pain treatment and their future potential. J Headache Pain 2025; 26:46. [PMID: 40016636 PMCID: PMC11869436 DOI: 10.1186/s10194-025-01979-4] [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: 01/16/2025] [Accepted: 02/13/2025] [Indexed: 03/01/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show substantial efficacy in regulating blood glucose levels and lipid metabolism, initially as an effective treatment for diabetes mellitus. In recent years, GLP-1RAs have become a focal point in the medical community due to their innovative treatment mechanisms, robust therapeutic efficacy, and expansive development prospects. Notably, GLP-1RAs benefit pain management through their neuroprotective and metabolic regulatory properties, such as inhibiting inflammation responses and oxidative stress, promoting β-endorphin release and modulating several other crucial biological pathways. Hence GLP-1RAs hold promise for repurposing as treatments for pain disorders. In this narrative review, we thoroughly trace the current preclinical and clinical evidence of seven pain modalities, including inflammatory pain, osteoarthritis, visceral pain, neuropathic pain, diabetic neuropathy, cancer pain and headache, to support the efficacy and underlying biological mechanisms of GLP-1RAs as therapeutic agents for pain suffering. Despite these promising findings, further research is necessary to establish their long-term efficacy, optimal dosing strategies, and potential synergistic interactions of GLP-1RAs with existing pain management therapies. Future clinical trials should aim to distinguish the direct analgesic effects of GLP-1RAs from their metabolic benefits and explore their broader applications in pain conditions. The ongoing exploration of new indications for GLP-1RAs further highlights their transformative potential in advancing medical treatments across diverse clinical fields.
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Affiliation(s)
- Yongtao He
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Biao Xu
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Mengna Zhang
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Dan Chen
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Shuyuan Wu
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Jie Gao
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Yongpeng Liu
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Zixin Zhang
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Junzhe Kuang
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China
| | - Quan Fang
- Institute of Physiology, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, PR China.
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Gul U, Aung T, Martin M, Farrukh DN, Shah PC, Lovely ZS, Marroquín León E, Alansaari M, Maini S, Fariduddin MM, Ullah A, Nazir Z. A Comprehensive Review of the Role of GLP-1 Agonists in Weight Management and Their Effect on Metabolic Parameters Such as Blood Glucose, Cholesterol, and Blood Pressure. Cureus 2024; 16:e76519. [PMID: 39872560 PMCID: PMC11771532 DOI: 10.7759/cureus.76519] [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] [Accepted: 12/27/2024] [Indexed: 01/30/2025] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been developed to manage type 2 diabetes mellitus. Although, in the last 10 years, the use of GLP-1 RAs, especially semaglutide and liraglutide, has increased, its clinical implications and how it affects metabolic parameters have yet to be fully consolidated. This narrative review explores the metabolic effects of GLP-1 RAs in weight management, blood glucose, cardiovascular health, lipid profiles, and blood pressure. Data were collected by comparing GLP-1 RAs, such as semaglutide, liraglutide, tripeptide, and exenatide, as well as comparing them to a baseline treatment group. GLP-1 RAs have shown consistent results in managing blood glucose levels by lowering HbA1c with minimal hypoglycemic risk and increasing insulin production and synthesis. GLP-1 RAs have been found to improve overall cardiovascular health and reduce major adverse cardiovascular events (MACE) by improving the endothelial function of the vasculature and lowering ANP (atrial natriuretic peptide) production, leading to reduced blood pressure. In addition to the cardiovascular benefits, GLP-1 RAs have a varying effect on lipid profiles, finding statistically significant results for low-density lipoprotein cholesterol levels. In conjunction with all the effects, GLP-1 RAs have been found to lower weight and aid in weight management.
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Affiliation(s)
- Ushna Gul
- Internal Medicine, Khyber Medical College, Peshawar, PAK
| | - Thandar Aung
- Accident and Emergency, St. Ann's Bay Hospital, St. Ann's Bay, JAM
| | - Mehwish Martin
- Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
| | | | - Pari C Shah
- Family Medicine, Northeast Ohio Medical University, Xenia, USA
| | - Zeenia S Lovely
- Emergency, Kerala University of Health and Sciences, Cochin, IND
| | | | - Mohamed Alansaari
- Internal Medicine, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin, IRL
| | - Shriya Maini
- Internal Medicine, Dayanand Medical College and Hospital, Punjab, IND
| | | | | | - Zahra Nazir
- Internal Medicine, Combined Military Hospital, Quetta, PAK
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Sendzischew Shane MA, Ruddy J, Cline M, Rosenbaum DP, Edelstein S, Moshiree B. Review of the Patient Burden and Therapeutic Landscape of Irritable Bowel Syndrome with Constipation in the United States. Clin Exp Gastroenterol 2024; 17:227-253. [PMID: 39114809 PMCID: PMC11303673 DOI: 10.2147/ceg.s464375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/25/2024] [Indexed: 08/10/2024] Open
Abstract
Irritable bowel syndrome (IBS) is a common disorder of the gut-brain axis. IBS with constipation (IBS-C) accounts for approximately one-third of IBS cases and is associated with substantial burden of illness and decreased quality of life. This narrative review provides an overview of the current and upcoming treatment options and disease management for IBS-C from a US perspective and discusses the importance of the relationship between patient and health care provider in diagnosis and treatment. A positive diagnostic strategy for IBS-C is recommended, based on clinical history, physical examination, and minimal laboratory tests. An effective communication strategy between patients and health care professionals is essential to ensure early diagnosis and reduce both health care costs and overall disease burden. Treatment typically begins with lifestyle interventions and nonpharmacologic options, such as dietary interventions, fiber supplements, and osmotic laxatives. In patients with inadequate response to these therapies, 4 currently available therapies (lubiprostone, linaclotide, plecanatide, and tenapanor) approved by the US Food and Drug Administration may relieve IBS-C symptoms. These agents are generally well tolerated and efficacious in improving IBS-C symptoms, including constipation and abdominal pain. In patients with persistent abdominal pain and/or psychological symptoms, brain-gut behavioral therapy or neuromodulator therapy may be beneficial.
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Affiliation(s)
| | | | - Michael Cline
- Department of Gastroenterology, Cleveland Clinic, Cleveland, OH, USA
| | | | | | - Baharak Moshiree
- Division of Gastroenterology, Advocate Health Wake Forest Medical University, Charlotte, NC, USA
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Halloum W, Dughem YA, Beier D, Pellesi L. Glucagon-like peptide-1 (GLP-1) receptor agonists for headache and pain disorders: a systematic review. J Headache Pain 2024; 25:112. [PMID: 38997662 PMCID: PMC11241973 DOI: 10.1186/s10194-024-01821-3] [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: 06/17/2024] [Accepted: 07/03/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) plays a crucial role in metabolic disorders by enhancing insulin secretion, inhibiting glucagon release, and slowing gastric emptying, thereby improving glycemic control. In recent years, GLP-1 role in neuronal pathways has expanded its therapeutic potential. We aim to comprehensively evaluate the relevance of GLP-1 in headache and pain disorders. METHODS A systematic literature search was conducted on PubMed and Embase (Ovid) databases using the search terms "GLP-1" and "pain". Animal and human studies published in English language were included. Abstracts, reviews, and articles on other disorders than "pain" were excluded. RESULTS The search strategy identified 833 hits, of which 42 studies were included in the final review. The studies were categorized into four groups: inflammatory pain and osteoarthritis, headaches, neuropathic pain and diabetic neuropathy, and visceral pain and irritable bowel syndrome. GLP-1 receptor (GLP-1R) agonists, like liraglutide, have shown analgesic effects by modulating pain hypersensitivity in animal models of inflammatory and neuropathic pain. GLP-1 is involved in migraine mechanisms and GLP-1R agonists are beneficial in individuals with idiopathic intracranial hypertension. Additionally, GLP-1R agonists reduce visceral hypersensitivity and ameliorate symptoms in patients with irritable bowel syndrome. CONCLUSIONS The therapeutic scope of GLP-1R agonists is expanding beyond traditional metabolic targets, highlighting its potential for headache and pain disorders. Engineering bimodal molecules that integrate GLP-1R agonism with specific pain-related mechanisms may offer innovative therapeutic options.
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Affiliation(s)
- Wael Halloum
- Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Campusvej 55, Odense, 5230, Denmark
| | - Yousef Al Dughem
- Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Campusvej 55, Odense, 5230, Denmark
| | - Dagmar Beier
- Department of Neurology, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Lanfranco Pellesi
- Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Campusvej 55, Odense, 5230, Denmark.
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Huang L, Cao B, Geng Y, Zhou X, Yang Y, Ma T, Lin H, Huang Z, Zhuo L, Li J. A randomized double-blind phase Ib clinical trial of SY-009 in patients with type 2 diabetes mellitus. Eur J Pharm Sci 2024; 192:106644. [PMID: 37981049 DOI: 10.1016/j.ejps.2023.106644] [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: 11/11/2022] [Revised: 10/18/2023] [Accepted: 11/16/2023] [Indexed: 11/21/2023]
Abstract
INTRODUCTION SY-009 produces a hypoglycemic effect via inhibiting sodium/glucose cotransporter 1 (SGLT1) in type 2 diabetes mellitus (T2DM) patients. This randomized, double-blind, placebo-controlled, and multiple-dose escalation clinical trial aimed to evaluate the pharmacokinetic and pharmacodynamical characteristics as well as the safety and tolerability of SY-009 in T2DM patients. METHOD Fifty T2DM patients were randomized into experimental and placebo groups, and hospitalized for 9 days managed with a unified diet and rest management. Subjects were given SY-009 or placebo from day 1 to day 7 at different frequencies and dosages. Single dose cohort was defined as the first dose on day 1 and multiple dose cohort included all the dose from day 1 to 7. Blood samples were collected for pharmacokinetic analysis. Mixed meal tolerance tests were performed. Blood samples were collected to determine glucose, C-peptide, insulin, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP). RESULTS PK parameters were not obtained because blood SY-009 concentrations were below the limit of quantitation in all subjects. SY-009 decreased the postprandial glucose. Blood glucose was controlled within 4 hours after taking the drug. Short-term administration of SY-009 (7 days) had no significant effects on fasting glucose but reduced the secretion of C-peptide, insulin, and GIP and increased GLP-1 secretion. The most common adverse event was gastrointestinal disorder manifesting abdominal pain, diarrhea, and bloating. CONCLUSION Plasma exposure of SY-009 and its metabolites was fairly low in T2DM patients at doses of 1.0-4.0 mg. SY-009 reduced postprandial glucose, C-peptide, and insulin levels, showing relative safety and tolerability in the dose range of 1.0-4.0 mg. TRIALS REGISTRATION ClinicalTrials.gov Identifier: NCT04345107.
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Affiliation(s)
- Lei Huang
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Bei Cao
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Yan Geng
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Xiaoli Zhou
- Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou 215000, China
| | - Yuanxun Yang
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Tingting Ma
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Hui Lin
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China
| | - Zhijiang Huang
- Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou 215000, China
| | - Lang Zhuo
- Suzhou Yabao Pharmaceutical R&D Co., Ltd., Suzhou 215000, China.
| | - Juan Li
- Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China.
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Tang Y, Du J, Wu H, Wang M, Liu S, Tao F. Potential Therapeutic Effects of Short-Chain Fatty Acids on Chronic Pain. Curr Neuropharmacol 2024; 22:191-203. [PMID: 36173071 PMCID: PMC10788890 DOI: 10.2174/1570159x20666220927092016] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/03/2022] [Accepted: 09/13/2022] [Indexed: 11/22/2022] Open
Abstract
The intestinal homeostasis maintained by the gut microbiome and relevant metabolites is essential for health, and its disturbance leads to various intestinal or extraintestinal diseases. Recent studies suggest that gut microbiome-derived metabolites short-chain fatty acids (SCFAs) are involved in different neurological disorders (such as chronic pain). SCFAs are produced by bacterial fermentation of dietary fibers in the gut and contribute to multiple host processes, including gastrointestinal regulation, cardiovascular modulation, and neuroendocrine-immune homeostasis. Although SCFAs have been implicated in the modulation of chronic pain, the detailed mechanisms that underlie such roles of SCFAs remain to be further investigated. In this review, we summarize currently available research data regarding SCFAs as a potential therapeutic target for chronic pain treatment and discuss several possible mechanisms by which SCFAs modulate chronic pain.
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Affiliation(s)
- Yuanyuan Tang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
- Key Laboratory for Molecular Neurology of Xinxiang, Xinxiang, Henan, China
| | - Juan Du
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Hongfeng Wu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Mengyao Wang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, China
| | - Sufang Liu
- Department of Biomedical Sciences, College of Dentistry, Texas A&M University Dallas, Texas, USA
| | - Feng Tao
- Department of Biomedical Sciences, College of Dentistry, Texas A&M University Dallas, Texas, USA
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Yu L, Li Y. Involvement of Intestinal Enteroendocrine Cells in Neurological and Psychiatric Disorders. Biomedicines 2022; 10:biomedicines10102577. [PMID: 36289839 PMCID: PMC9599815 DOI: 10.3390/biomedicines10102577] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 09/21/2022] [Accepted: 09/21/2022] [Indexed: 11/24/2022] Open
Abstract
Neurological and psychiatric patients have increased dramatically in number in the past few decades. However, effective treatments for these diseases and disorders are limited due to heterogeneous and unclear pathogenic mechanisms. Therefore, further exploration of the biological aspects of the disease, and the identification of novel targets to develop alternative treatment strategies, is urgently required. Systems-level investigations have indicated the potential involvement of the brain–gut axis and intestinal microbiota in the pathogenesis and regulation of neurological and psychiatric disorders. While intestinal microbiota is crucial for maintaining host physiology, some important sensory and regulatory cells in the host should not be overlooked. Intestinal epithelial enteroendocrine cells (EECs) residing in the epithelium throughout intestine are the key regulators orchestrating the communication along the brain-gut-microbiota axis. On one hand, EECs sense changes in luminal microorganisms via microbial metabolites; on the other hand, they communicate with host body systems via neuroendocrine molecules. Therefore, EECs are believed to play important roles in neurological and psychiatric disorders. This review highlights the involvement of EECs and subtype cells, via secretion of endocrine molecules, in the development and regulation of neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, visceral pain, neuropathic pain, and depression. Moreover, the current paper summarizes the potential mechanism of EECs in contributing to disease pathogenesis. Examination of these mechanisms may inspire and lead to the development of new aspects of treatment strategies for neurological and psychiatric disorders in the future.
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Affiliation(s)
- Liangen Yu
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716, USA
| | - Yihang Li
- Department of Animal and Food Sciences, University of Delaware, Newark, DE 19716, USA
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
- Correspondence:
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Touny AA, Kenny E, Månsson M, Webb DL, Hellström PM. Pain relief and pain intensity response to GLP-1 receptor agonist ROSE-010 in irritable bowel syndrome; clinical study cross-analysis with respect to patient characteristics. Scand J Gastroenterol 2022; 57:783-791. [PMID: 35234561 DOI: 10.1080/00365521.2022.2041084] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Glucagon-like peptide-1 receptor agonist ROSE-010 has been studied for management of irritable bowel syndrome (IBS). ROSE-010 showed promising effects by reducing pain during attacks of IBS. In this exploratory substudy, we cross-analyzed earlier data to identify the most suitable subpopulation for treatment with ROSE-010. METHODS Data comprising 166 participants (116 females, 50 males) treated by subcutaneous injection with ROSE-010 at 100 µg and 300 µg versus placebo were broken down into subpopulations with recall of historical pain intensity, pain intensity immediately before treatment, gender, age, BMI, IBS subtype as well as pain intensity and pain relief of ROSE-010 with relationship to plasma glucose using visual analogue scores. Statistical cross-analysis was performed to detect optimal responders for adequate pain relief response. RESULTS ROSE-010 gave dose- and time-dependent effects with maximum pain relief at 300 µg relative 100 µg and placebo at 120 min post injection. Females had greater pain relief than males; age and BMI did not affect treatment response. IBS pain relief was greatest in constipation-dominant IBS (IBS-C) and mixed IBS (IBS-M) relative diarrhea-dominant and unspecified IBS. CONCLUSIONS Clinical trial data indicate that female participants are more likely than males to respond to ROSE-010 100 µg and 300 µg to achieve meaningful IBS pain relief. Maximum pain relief was achieved at 120 min with the higher dose, although this was accompanied with higher rates of nausea. Improvement of IBS pain attacks was most pronounced in IBS-C and IBS-M, suggesting these subgroups to be optimal ROSE-010 responders.
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Affiliation(s)
- Aya A Touny
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | | | - Dominic-Luc Webb
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Per M Hellström
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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10
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Gu Y, Li L, Yang M, Liu T, Song X, Qin X, Xu X, Liu J, Wang B, Cao H. Bile acid-gut microbiota crosstalk in irritable bowel syndrome. Crit Rev Microbiol 2022; 49:350-369. [PMID: 35389754 DOI: 10.1080/1040841x.2022.2058353] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with an increasing prevalence, and its precise aetiology remains unclear. Gut microbiota dysbiosis has been found to be associated with IBS pathogenesis. In addition, a high incidence of bile acid diarrhoea and disturbed bile acid metabolism has been observed in IBS patients. The abundant microorganisms inhabited in human gut have essential functions in bile acid biotransformation, and can immensely affect the size and constitution of bile acid pool. Meanwhile, the alterations of bile acid profile can inversely interfere with the gut microbiota. This review discussed the role of intricate correlations between bile acids and gut microbiota in IBS pathogenesis and delineated the possible molecular mechanisms, mainly the signalling induced by farnesoid X receptor and transmembrane G protein-coupled receptor 5. Besides, some biomarkers for identifying bile acid diarrhoea in IBS population were listed, assisting the diagnosis and classification of IBS. Moreover, it also assessed some therapeutic strategies for IBS that regulate the bile acid-gut microbiota axis, such as dietary modulation, probiotics/prebiotics, faecal microbiota transplantation, and antibiotics. Collectively, this article illustrated the relationship between bile acids and gut microbiota in IBS pathophysiology and might offer some novel therapeutic options for IBS.
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Affiliation(s)
- Yu Gu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lingfeng Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Min Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Tianyu Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xueli Song
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xiali Qin
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xin Xu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Jinghua Liu
- Department of Gastroenterology, Tianjin TEDA hospital, Tianjin, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
| | - Hailong Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
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Elwing JE, Atassi H, Rogers BD, Sayuk GS. Emerging therapies in the management of Irritable Bowel Syndrome (IBS). Expert Opin Emerg Drugs 2022; 27:55-73. [PMID: 35266839 DOI: 10.1080/14728214.2022.2052043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Irritable bowel syndrome (IBS) is a common, symptom-based disorder of chronic abdominal pain and altered bowel habits. The pathogenesis of IBS is multifactorial, leading to the potential for the development of multiple, diverse treatment strategies. This mechanistic heterogeneity also leads to the realization that available therapies are only effective in a subset of IBS suffers. Current US Food and Drug Administration (FDA) approved therapies for IBS with diarrhea (IBS-D) and IBS with constipation (IBS-C) are reviewed. Limited symptom responses and side effect experiences lead to considerable patient dissatisfaction with currently available IBS treatments. Only a small percentage of IBS patients are on prescription therapies underscoring the potential market and need for additional therapeutic options. AREAS COVERED : Expanding on currently available therapies, the serotonergic and endogenous opioid receptor systems continue to be a focus of future IBS treatment development. Additional novel emerging therapies include the endogenous cannabinoid system, bile acid secretion and sequestration, and exploit our enhanced understanding of visceral sensory signaling and intestinal secretomotor function. EXPERT OPINION While challenges remain for the future development of IBS therapies, the diverse etiologies underlying the disorder present an opportunity for novel therapies. Hence, great potential is anticipated for future IBS treatment options.
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Affiliation(s)
- Jill E Elwing
- St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA
| | - Hadi Atassi
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA
| | - Benjamin D Rogers
- Division of Gastroenterology, Hepatology, and Nutrition, University of Louisville School of Medicine, Louisville, KY, USA.,Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, USA
| | - Gregory S Sayuk
- St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA.,Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA
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Layer P, Andresen V, Allescher H, Bischoff SC, Claßen M, Elsenbruch S, Freitag M, Frieling T, Gebhard M, Goebel-Stengel M, Häuser W, Holtmann G, Keller J, Kreis ME, Kruis W, Langhorst J, Jansen PL, Madisch A, Mönnikes H, Müller-Lissner S, Niesler B, Pehl C, Pohl D, Raithel M, Röhrig-Herzog G, Schemann M, Schmiedel S, Schwille-Kiuntke J, Storr M, Preiß JC, Andus T, Buderus S, Ehlert U, Engel M, Enninger A, Fischbach W, Gillessen A, Gschossmann J, Gundling F, Haag S, Helwig U, Hollerbach S, Karaus M, Katschinski M, Krammer H, Kuhlbusch-Zicklam R, Matthes H, Menge D, Miehlke S, Posovszky MC, Schaefert R, Schmidt-Choudhury A, Schwandner O, Schweinlin A, Seidl H, Stengel A, Tesarz J, van der Voort I, Voderholzer W, von Boyen G, von Schönfeld J, Wedel T. Update S3-Leitlinie Reizdarmsyndrom: Definition, Pathophysiologie, Diagnostik und Therapie. Gemeinsame Leitlinie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Neurogastroenterologie und Motilität (DGNM) – Juni 2021 – AWMF-Registriernummer: 021/016. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2021; 59:1323-1415. [PMID: 34891206 DOI: 10.1055/a-1591-4794] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- P Layer
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - V Andresen
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - H Allescher
- Zentrum für Innere Medizin, Gastroent., Hepatologie u. Stoffwechsel, Klinikum Garmisch-Partenkirchen, Garmisch-Partenkirchen, Deutschland
| | - S C Bischoff
- Institut für Ernährungsmedizin, Universität Hohenheim, Stuttgart, Deutschland
| | - M Claßen
- Klinik für Kinder- und Jugendmedizin, Klinikum Links der Weser, Bremen, Deutschland
| | - S Elsenbruch
- Klinik für Neurologie, Translational Pain Research Unit, Universitätsklinikum Essen, Essen, Deutschland.,Abteilung für Medizinische Psychologie und Medizinische Soziologie, Ruhr-Universität Bochum, Bochum, Deutschland
| | - M Freitag
- Abteilung Allgemeinmedizin Department für Versorgungsforschung, Universität Oldenburg, Oldenburg, Deutschland
| | - T Frieling
- Medizinische Klinik II, Helios Klinikum Krefeld, Krefeld, Deutschland
| | - M Gebhard
- Gemeinschaftspraxis Pathologie-Hamburg, Hamburg, Deutschland
| | - M Goebel-Stengel
- Innere Medizin II, Helios Klinik Rottweil, Rottweil, und Innere Medizin VI, Psychosomat. Medizin u. Psychotherapie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - W Häuser
- Innere Medizin I mit Schwerpunkt Gastroenterologie, Klinikum Saarbrücken, Saarbrücken, Deutschland
| | - G Holtmann
- Faculty of Medicine & Faculty of Health & Behavioural Sciences, Princess Alexandra Hospital, Brisbane, Australien
| | - J Keller
- Medizinische Klinik, Israelitisches Krankenhaus, Hamburg, Deutschland
| | - M E Kreis
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
| | | | - J Langhorst
- Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Deutschland
| | - P Lynen Jansen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten, Berlin, Deutschland
| | - A Madisch
- Klinik für Gastroenterologie, interventionelle Endoskopie und Diabetologie, Klinikum Siloah, Klinikum Region Hannover, Hannover, Deutschland
| | - H Mönnikes
- Klinik für Innere Medizin, Martin-Luther-Krankenhaus, Berlin, Deutschland
| | | | - B Niesler
- Abteilung Molekulare Humangenetik Institut für Humangenetik, Universitätsklinikum Heidelberg, Heidelberg, Deutschland
| | - C Pehl
- Medizinische Klinik, Krankenhaus Vilsbiburg, Vilsbiburg, Deutschland
| | - D Pohl
- Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Schweiz
| | - M Raithel
- Medizinische Klinik II m.S. Gastroenterologie und Onkologie, Waldkrankenhaus St. Marien, Erlangen, Deutschland
| | | | - M Schemann
- Lehrstuhl für Humanbiologie, TU München, Deutschland
| | - S Schmiedel
- I. Medizinische Klinik und Poliklinik Gastroenterologie, Universitätsklinikum Hamburg-Eppendorf, Deutschland
| | - J Schwille-Kiuntke
- Abteilung für Psychosomatische Medizin und Psychotherapie, Medizinische Universitätsklinik Tübingen, Tübingen, Deutschland.,Institut für Arbeitsmedizin, Sozialmedizin und Versorgungsforschung, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - M Storr
- Zentrum für Endoskopie, Gesundheitszentrum Starnberger See, Starnberg, Deutschland
| | - J C Preiß
- Klinik für Innere Medizin - Gastroenterologie, Diabetologie und Hepatologie, Vivantes Klinikum Neukölln, Berlin, Deutschland
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Almario CV, Eberlein S, Khalil C, Spiegel BM. Determining patient treatment preferences for management of acute pain episodes in irritable bowel syndrome. Neurogastroenterol Motil 2021; 33:e14145. [PMID: 33797116 PMCID: PMC8486892 DOI: 10.1111/nmo.14145] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/19/2021] [Accepted: 03/16/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Many patients with irritable bowel syndrome (IBS) experience acute and unexpected pain episodes over and above chronic background symptoms, and there are emerging medications designed to treat such pain. We aimed to use conjoint analysis-a technique that elucidates how people make complex decisions-to examine patient preferences for emerging medicines for breakthrough IBS pain. METHODS We conducted a cross-sectional conjoint analysis survey among patients with Rome IV IBS and recurrent episodes of acute pain to assess the relative importance of medication attributes in their decision-making. We also assessed what respondents would require of subcutaneous (SQ) therapies to consider their use. KEY RESULTS Among 629 patients with Rome IV IBS, 606 (96.3%) reported ≥1 acute pain episodes in the past month. For the 461 participants with multiple attacks who completed the conjoint analysis, they prioritized medication efficacy (importance score 34.9%), avoidance of nausea (24.3%), and avoidance of constipation (12.2%) as most important in their decision-making. These were followed by route of administration (10.3%), avoidance of headache (9.3%), and avoidance of drowsiness (8.9%). Moreover, 431 (93.5%) participants would consider SQ therapies for their acute pain; they had varying expectations on the minimum pain decrease and onset and duration of pain relief needed for considering their use. CONCLUSIONS AND INFERENCES The vast majority of patients with IBS experience breakthrough pain, and when selecting among therapies, they prioritize efficacy and most are willing to use a rapid-acting SQ treatment. These results support development of novel, effective medications-oral or SQ-for management of acute pain attacks.
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Affiliation(s)
- Christopher V. Almario
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA
- Cedars-Sinai Center for Outcomes Research and Education (CS-CORE), Los Angeles, CA
- Division of Health Services Research, Cedars-Sinai Medical Center, Los Angeles, CA
- Division of Informatics, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Samuel Eberlein
- Cedars-Sinai Center for Outcomes Research and Education (CS-CORE), Los Angeles, CA
| | - Carine Khalil
- Cedars-Sinai Center for Outcomes Research and Education (CS-CORE), Los Angeles, CA
| | - Brennan M.R. Spiegel
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA
- Cedars-Sinai Center for Outcomes Research and Education (CS-CORE), Los Angeles, CA
- Division of Health Services Research, Cedars-Sinai Medical Center, Los Angeles, CA
- Department of Health Policy and Management, UCLA Fielding School of Public Health, Los Angeles, CA, USA
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14
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O'Brien R, Buckley MM, O'Malley D. Divergent effects of exendin-4 and interleukin-6 on rat colonic secretory and contractile activity are associated with changes in regional vagal afferent signaling. Neurogastroenterol Motil 2021; 33:e14160. [PMID: 33945195 DOI: 10.1111/nmo.14160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 03/10/2021] [Accepted: 03/24/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND The pro-inflammatory cytokine, interleukin (IL)-6 is elevated in individuals with the functional bowel disorder, irritable bowel syndrome (IBS). IL-6 can independently modify intestinal secreto-motor function, thereby contributing to IBS pathophysiology. Additionally, hormonal changes may underlie symptom flares. Post-prandial exacerbation of IBS symptoms has been linked to secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), which can also influence colonic secreto-motor activity. This study aimed to ascertain if the effects of GLP-1 on colonic secretory and contractile activity was impacted by elevated IL-6 levels and if sensory signals regarding such changes were reflected in altered vagal afferent activity. METHODS Colonic secretory currents and circular muscle contractile activity was investigated in Sprague Dawley rats using Ussing chamber and organ bath electrophysiology. Regional afferent signaling was assessed using extracellular electrophysiological recordings from colonic vagal afferents. KEY RESULTS Application of the GLP-1 receptor agonist, exendin-4 (Ex-4) in the presence of IL-6 potentiated colonic secretory currents and transepithelial resistance. Vagal afferent fibers originating in the submucosal layer exhibited larger responses to Ex-4 when IL-6 was also present. In contrast, co-application of Ex-4 and IL-6 to gut-bath chambers suppressed circular muscle contractile activity. The activity in extrinsic afferents originating in the colonic myenteric layer was similarly suppressed. CONCLUSIONS & INFERENCES Application of Ex-4 in the presence of IL-6 had divergent modulatory effects on colonic secretion and contractile activity. Similar patterns were observed in vagal afferent signaling originating in the submucosal and myenteric neuronal layers, indicating regional afferent activity reflected immune- and endocrine-mediated changes in colonic function.
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Affiliation(s)
- Rebecca O'Brien
- Department of Physiology, University College Cork, Cork, Ireland
| | - Maria M Buckley
- Department of Physiology, University College Cork, Cork, Ireland
| | - Dervla O'Malley
- Department of Physiology, University College Cork, Cork, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland
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15
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Radbakhsh S, Atkin SL, Simental-Mendia LE, Sahebkar A. The role of incretins and incretin-based drugs in autoimmune diseases. Int Immunopharmacol 2021; 98:107845. [PMID: 34126341 DOI: 10.1016/j.intimp.2021.107845] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 05/25/2021] [Accepted: 05/31/2021] [Indexed: 02/07/2023]
Abstract
Incretin hormones, including glucagon-like peptide (GLP)-1, GLP-2 and glucose-dependent insulinotropic polypeptide (GIP), are gastrointestinal peptides secreted from enteroendocrine cells. These hormones play significant roles in many physiological processes via binding to G-protein coupled receptors (GPCRs) on different organs and tissues; one of them is the immunomodulatory effect on the immune system and its molecular components such as cytokines and chemokines. Anti-inflammatory effects of incretins and dependent molecules involving long-acting analogs and DPP4 inhibitors through regulation of T and B cell activation may attenuate autoimmune diseases caused by immune system disorders in mistakenly recognizing self as the foreign agent. In this review, we investigate incretin effects on the immune system response and the potential benefits of incretin-based therapy for treating autoimmune diseases.
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Affiliation(s)
- Shabnam Radbakhsh
- Department of Medical Biotechnology and Nanotechnology, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Medicine, The University of Western Australia, Perth, Australia; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Cui X, Zhao X, Wang Y, Yang Y, Zhang H. Glucagon‑like peptide‑1 analogue exendin‑4 modulates serotonin transporter expression in intestinal epithelial cells. Mol Med Rep 2020; 21:1934-1940. [PMID: 32319618 PMCID: PMC7057813 DOI: 10.3892/mmr.2020.10976] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023] Open
Abstract
Serotonin-selective reuptake transporter (SERT) regulates extracellular availability of serotonin (5-hydroxytryptamine; 5-HT) and participates in the pathogenesis of functional disorders. Colonic SERT expression is decreased in colonic sensitized rats, and the glucagon-like peptide-1 analogue, exendin-4, reduces visceral hypersensitivity by decreasing 5-HT levels and increasing SERT expression. The present in vitro study aimed to further investigate the effects of exendin-4 on SERT expression, and to examine the role of GLP-1 and its receptor in the regulation of 5-HT. SERT mRNA and protein expression levels were detected by reverse transcription-quantitative PCR and western blotting. A [3H]−5-HT reuptake experiment was performed in IEC-6 rat intestinal epithelial cells treated with exendin-4. Effects on the adenosine cyclophosphate (AC)/PKA pathway were examined by variously treating cells with the AC activator forskolin, the protein kinase A (PKA) inhibitor H89 and the AC inhibitor SQ22536. Exendin-4 treatment upregulated SERT expression and enhanced 5-HT reuptake in IEC-6 cells. Also, PKA activity in IEC-6 cells was increased by both exendin-4 and forskolin, whereas these effects were abolished by the pre-treatment of exendin-9, which is a GLP-1R inhibitor, SQ22536 and H89. In conclusion, exendin-4 may be associated with the upregulation of SERT expression via the AC/PKA signaling pathway.
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Affiliation(s)
- Xiufang Cui
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xiaojing Zhao
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Ying Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Yan Yang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Hongjie Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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17
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O'Brien R, O'Malley D. The Glucagon-like peptide-1 receptor agonist, exendin-4, ameliorated gastrointestinal dysfunction in the Wistar Kyoto rat model of Irritable Bowel Syndrome. Neurogastroenterol Motil 2020; 32:e13738. [PMID: 31602785 DOI: 10.1111/nmo.13738] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 08/15/2019] [Accepted: 09/18/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) is beneficial in relieving pain-related symptoms of Irritable bowel syndrome (IBS), a prevalent, multi-factorial functional bowel disorder characterized by diarrhea and/or constipation, abdominal bloating, and pain. Activation of myenteric neurons has been implicated in the inhibitory effects of GLP-1 on gastrointestinal motility; however, the mechanisms of action underlying this are not clear. METHODS A rat model of IBS was used to examine physiological changes evoked by intraperitoneal administration of a GLP-1 receptor agonist, exendin-4. Behavioral and physiological analysis of stress-sensitive Wister Kyoto (WKY) rats was used to determine if administration of exendin-4, in the presence or absence of neutralizing interleukin-6 receptor monoclonal antibodies, modified IBS-like symptoms. Immunofluorescence, calcium imaging, and Western blotting techniques were used to investigate the potential role of enteric neural plexi and tight junction protein expression in this effect. KEY RESULTS Consistent with the expression of GLP-1 and interleukin-6 receptors in both submucosal and myenteric ganglia, exendin-4 and interleukin-6 stimulated calcium responses in these neurons. In vivo administration of exendin-4 normalized stress-induced defecation and visceral pain sensitivity in WKY rats. No additional changes were noted in rats co-treated with exendin-4 and anti-interleukin-6 receptor antibodies. Mucosal expression of occludin, a tight junction protein, was decreased by exendin-4. Centrally regulated anxiety-like behaviors were not modified. CONCLUSIONS AND INFERENCES These data suggest that intraperitoneal injection of exendin-4 improves bowel dysfunction in WKY rats without impacting on centrally regulated anxiety-like behaviors. Modulation of enteric neuronal function and tight junction expression appear to underlie the functional benefits of this intervention.
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Affiliation(s)
- Rebecca O'Brien
- Department of Physiology, University College Cork, Cork, Ireland
| | - Dervla O'Malley
- Department of Physiology, University College Cork, Cork, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland
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18
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Niewinna K, Zielińska A, Fichna J. Recent advances in the pharmacological management of constipation predominant irritable bowel syndrome. Expert Opin Pharmacother 2019; 21:73-84. [PMID: 31724881 DOI: 10.1080/14656566.2019.1688784] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Irritable bowel syndrome (IBS) is a complex functional gut disorder that typically manifests in early adult years. More than a third of IBS patients are diagnosed with predominant constipation subtype (IBS-C). This syndrome has a distressing impact on the quality of life and is challenging both for patients and physicians.Areas covered: This review focuses on the pathophysiology of constipation in IBS and presents current management options. It also covers the latest findings that may lead to novel pharmacological options in IBS-C management. The authors intend to highlight the results of published research including abstracts, records from the clinicaltrials.gov database (second and third phases of the study) and information from original FDA documents.Expert opinion: Current therapeutic options for IBS-C treatment are based on linaclotide, lubiprostone, plecanatide, and the reintroduced tegaserod. Drugs present on the market as well as those in pre-clinical development should increase the lower esophageal sphincter pressure, promote gastric motility, accelerate gastric emptying and improve gastro-duodenal coordination. Most significantly, they shall not induce severe side effects.
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Affiliation(s)
- Karolina Niewinna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Anna Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
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19
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Valencia-Rodríguez A, Aquino-Matus J, Vera-Barajas A, Qi X, Méndez-Sánchez N. New therapeutic options for bile acid malabsorption diarrhea. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:695. [PMID: 31930096 PMCID: PMC6944536 DOI: 10.21037/atm.2019.09.112] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
| | - Jorge Aquino-Matus
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
| | | | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
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20
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Buckley MM, O'Brien R, Buckley JM, O'Malley D. GHSR-1 agonist sensitizes rat colonic intrinsic and extrinsic neurons to exendin-4: A role in the manifestation of postprandial gastrointestinal symptoms in irritable bowel syndrome? Neurogastroenterol Motil 2019; 31:e13684. [PMID: 31311066 DOI: 10.1111/nmo.13684] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 06/19/2019] [Accepted: 07/08/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Patients with irritable bowel syndrome (IBS) may experience postprandial symptom exacerbation. Nutrients stimulate intestinal release of glucagon-like peptide 1 (GLP-1), an incretin hormone with known gastrointestinal effects. However, prior to the postprandial rise in GLP-1, levels of the hunger hormone, ghrelin, peak. The aims of this study were to determine if ghrelin sensitizes colonic intrinsic and extrinsic neurons to the stimulatory actions of a GLP-1 receptor agonist, and if this differs in a rat model of IBS. METHODS Calcium imaging of enteric neurons was compared between Sprague Dawley and Wistar Kyoto rats. Colonic contractile activity and vagal nerve recordings were also compared between strains. KEY RESULTS Circulating GLP-1 concentrations differ between IBS subtypes. Mechanistically, we have provided evidence that calcium responses evoked by exendin-4, a GLP-1 receptor agonist, are potentiated by a ghrelin receptor (GHSR-1) agonist, in both submucosal and myenteric neurons. Although basal patterns of colonic contractility varied between Sprague Dawley and Wister Kyoto rats, the capacity of exendin-4 to alter smooth muscle function was modified by a GHSR-1 agonist in both strains. Gut-brain signaling via GLP-1-mediated activation of vagal afferents was also potentiated by the GHSR-1 agonist. CONCLUSIONS & INFERENCES These findings support a temporal interaction between ghrelin and GLP-1, where the preprandial peak in ghrelin may temporarily sensitize colonic intrinsic and extrinsic neurons to the neurostimulatory actions of GLP-1. While the sensitizing effects of the GHSR-1 agonist were identified in both rat strains, in the rat model of IBS, underlying contractile activity was aberrant.
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Affiliation(s)
- Maria M Buckley
- Department of Physiology, University College Cork, Cork, Ireland.,APC Microbiome Ireland, Biosciences Institute, University College Cork, Cork, Ireland
| | - Rebecca O'Brien
- Department of Physiology, University College Cork, Cork, Ireland
| | - Julliette M Buckley
- Department of Surgery, University College Cork, Cork, and Mater Private Hospital, Cork, Ireland
| | - Dervla O'Malley
- Department of Physiology, University College Cork, Cork, Ireland.,APC Microbiome Ireland, Biosciences Institute, University College Cork, Cork, Ireland
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21
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Lomax AE, Pradhananga S, Sessenwein JL, O'Malley D. Bacterial modulation of visceral sensation: mediators and mechanisms. Am J Physiol Gastrointest Liver Physiol 2019; 317:G363-G372. [PMID: 31290688 DOI: 10.1152/ajpgi.00052.2019] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The potential role of the intestinal microbiota in modulating visceral pain has received increasing attention during recent years. This has led to the identification of signaling pathways that have been implicated in communication between gut bacteria and peripheral pain pathways. In addition to the well-characterized impact of the microbiota on the immune system, which in turn affects nociceptor excitability, bacteria can modulate visceral afferent pathways by effects on enterocytes, enteroendocrine cells, and the neurons themselves. Proteases produced by bacteria, or by host cells in response to bacteria, can increase or decrease the excitability of nociceptive dorsal root ganglion (DRG) neurons depending on the receptor activated. Short-chain fatty acids generated by colonic bacteria are involved in gut-brain communication, and intracolonic short-chain fatty acids have pronociceptive effects in rodents but may be antinociceptive in humans. Gut bacteria modulate the synthesis and release of enteroendocrine cell mediators, including serotonin and glucagon-like peptide-1, which activate extrinsic afferent neurons. Deciphering the complex interactions between visceral afferent neurons and the gut microbiota may lead to the development of improved probiotic therapies for visceral pain.
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Affiliation(s)
- Alan E Lomax
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Sabindra Pradhananga
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Jessica L Sessenwein
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Dervla O'Malley
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Physiology, University College Cork, Cork, Ireland
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22
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Yu Y, Villalobos-Hernandez EC, Pradhananga S, Baker CC, Keating C, Grundy D, Lomax AE, Reed DE. Deoxycholic acid activates colonic afferent nerves via 5-HT 3 receptor-dependent and -independent mechanisms. Am J Physiol Gastrointest Liver Physiol 2019; 317:G275-G284. [PMID: 31216174 DOI: 10.1152/ajpgi.00016.2019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Increased bile acids in the colon can evoke increased epithelial secretion resulting in diarrhea, but little is known about whether colonic bile acids contribute to abdominal pain. This study aimed to investigate the mechanisms underlying activation of colonic extrinsic afferent nerves and their neuronal cell bodies by a major secondary bile acid, deoxycholic acid (DCA). All experiments were performed on male C57BL/6 mice. Afferent sensitivity was evaluated using in vitro extracellular recordings from mesenteric nerves in the proximal colon (innervated by vagal and spinal afferents) and distal colon (spinal afferents only). Neuronal excitability of cultured dorsal root ganglion (DRG) and nodose ganglion (NG) neurons was examined with perforated patch clamp. Colonic 5-HT release was assessed using ELISA, and 5-HT immunoreactive enterochromaffin (EC) cells were quantified. Intraluminal DCA increased afferent nerve firing rate concentration dependently in both proximal and distal colon. This DCA-elicited increase was significantly inhibited by a 5-HT3 antagonist in the proximal colon but not in the distal colon, which may be in part due to lower 5-HT immunoreactive EC cell density and lower 5-HT levels in the distal colon following DCA stimulation. DCA increased the excitability of DRG neurons, whereas it decreased the excitability of NG neurons. DCA potentiated mechanosensitivity of high-threshold spinal afferents independent of 5-HT release. Together, this study suggests that DCA can excite colonic afferents via direct and indirect mechanisms but the predominant mechanism may differ between vagal and spinal afferents. Furthermore, DCA increased mechanosensitivity of high-threshold spinal afferents and may be a mechanism of visceral hypersensitivity.NEW & NOTEWORTHY Deoxycholic acid (DCA) directly excites spinal afferents and, to a lesser extent, indirectly via mucosal 5-HT release. DCA potentiates mechanosensitivity of high-threshold spinal afferents independent of 5-HT release. DCA increases vagal afferent firing in proximal colon via 5-HT release but directly inhibits the excitability of their cell bodies.
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Affiliation(s)
- Yang Yu
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | | | - Sabindra Pradhananga
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Corey C Baker
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - Christopher Keating
- Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
| | - David Grundy
- Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom
| | - Alan E Lomax
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
| | - David E Reed
- Gastrointestinal Diseases Research Unit, Queen's University, Kingston, Ontario, Canada
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23
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O'Brien R, Buckley MM, Kelliher A, O'Malley D. PI 3-kinase- and ERK-MAPK-dependent mechanisms underlie Glucagon-Like Peptide-1-mediated activation of Sprague Dawley colonic myenteric neurons. Neurogastroenterol Motil 2019; 31:e13631. [PMID: 31121089 DOI: 10.1111/nmo.13631] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 05/02/2019] [Accepted: 05/06/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Glucagon-like peptide (GLP-1) can modify colonic function, with beneficial effects reported in the functional bowel disorder, irritable bowel syndrome (IBS). IBS pathophysiology is characterized by hyper-activation of the hypothalamic-pituitary-adrenal stress axis and altered microbial profiles. This study aims to characterize the neuronal and functional effects of GLP-1 in healthy rat colons to aid understanding of its beneficial effects in moderating bowel dysfunction. METHODS Immunofluorescent and calcium imaging of myenteric neurons prepared from Sprague Dawley rat colons was carried out to elucidate the neuromodulatory actions of the GLP-1 receptor agonist, exendin-4 (Ex-4). Colonic contractile activity was assessed using organ bath physiological recordings. KEY RESULTS Ex-4 induced an elevation of intracellular calcium arising from store release and influx via voltage-gated calcium channels. Ex-4 activated both ERK-MAPK and PI 3-kinase signaling cascades. Neuronal activation was found to underlie suppression of contractile activity in colonic circular muscle. Although the stress hormone, corticotropin-releasing factor (CRF) potentiated the neuronal response to Ex-4, and the functional effects of Ex-4 on colonic circular muscle activity were not altered. CONCLUSIONS AND INFERENCES Ex-4 evoked neurally regulated suppression of rat colonic circular muscle activity. In myenteric neurons, the neurostimulatory effects of Ex-4 were dependent upon activation of PI 3-kinase and ERK-MAPK signaling cascades. No further change in circular muscle function was noted in the presence of CRF suggesting that stress does not impact on colonic function in health. Further studies in a model of IBS are needed to determine whether mechanisms are modified in the context of bowel dysfunction.
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Affiliation(s)
- Rebecca O'Brien
- Department of Physiology, University College Cork, Cork, Ireland
| | - Maria M Buckley
- Department of Physiology, University College Cork, Cork, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Amy Kelliher
- Department of Physiology, University College Cork, Cork, Ireland
| | - Dervla O'Malley
- Department of Physiology, University College Cork, Cork, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland
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24
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Kyriachenko Y, Falalyeyeva T, Korotkyi O, Molochek N, Kobyliak N. Crosstalk between gut microbiota and antidiabetic drug action. World J Diabetes 2019; 10:154-168. [PMID: 30891151 PMCID: PMC6422856 DOI: 10.4239/wjd.v10.i3.154] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 03/10/2019] [Accepted: 03/11/2019] [Indexed: 02/05/2023] Open
Abstract
Type 2 diabetes (T2D) is a disorder characterized by chronic inflated blood glucose levels (hyperglycemia), at first due to insulin resistance and unregulated insulin secretion but with tendency towards global spreading. The gut microbiota is recognized to have an influence on T2D, although surveys have not formed a clear overview to date. Because of the interactions between gut microbiota and host homeostasis, intestinal bacteria are believed to play a large role in various diseases, including metabolic syndrome, obesity and associated disease. In this review, we highlight the animal and human studies which have elucidated the roles of metformin, α-glucosidase inhibitors, glucagon-like peptide-1 agonists, peroxisome proliferator-activated receptors γ agonists, inhibitors of dipeptidyl peptidase-4, sodium/glucose cotransporter inhibitors, and other less studied medications on gut microbiota. This review is dedicated to one of the most widespread diseases, T2D, and the currently used antidiabetic drugs and most promising new findings. In general, the gut microbiota has been shown to have an influence on host metabolism, food consumption, satiety, glucose homoeostasis, and weight gain. Altered intestinal microbiota composition has been noticed in cardiovascular diseases, colon cancer, rheumatoid arthritis, T2D, and obesity. Therefore, the main effect of antidiabetic drugs is on the microbiome composition, basically increasing the short-chain fatty acids-producing bacteria, responsible for losing weight and suppressing inflammation.
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Affiliation(s)
- Yevheniia Kyriachenko
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Tetyana Falalyeyeva
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Oleksandr Korotkyi
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Nataliia Molochek
- Educational and Scientific Centre “Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
| | - Nazarii Kobyliak
- Endocrinology Department, Bogomolets National Medical University, Kyiv 01601, Ukraine
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25
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O'Malley D. Endocrine regulation of gut function - a role for glucagon-like peptide-1 in the pathophysiology of irritable bowel syndrome. Exp Physiol 2018; 104:3-10. [PMID: 30444291 DOI: 10.1113/ep087443] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 11/14/2018] [Indexed: 12/14/2022]
Abstract
NEW FINDINGS What is the topic of this review? Pathophysiological changes linked to irritable bowel syndrome (IBS) include stress and immune activation, changes in gastrointestinal microbial and bile acid profiles and sensitization of extrinsic and intrinsic gut neurons. This review explores the potential role for L-cells in these pathophysiological changes. What advances does it highlight? L-cells, which secrete glucagon-like peptide-1 in response to nutrients, microbial factors, bile acids and short-chain fatty acids, may sense IBS-related changes in the luminal environment. Glucagon-like peptide-1 can act as a hormone, a paracrine factor or a neuromodulatory factor and, through its actions on central or peripheral neurons, may play a role in gastrointestinal dysfunction. ABSTRACT The prevalent and debilitating functional bowel disorder, irritable bowel syndrome (IBS), is characterized by symptoms that include abdominal pain, bloating, diarrhoea and/or constipation. The heterogeneity of IBS underscores a complex multifactorial pathophysiology, which is not completely understood but involves dysfunction of the bi-directional signalling axis between the brain and the gut. This axis incorporates efferent and afferent branches of the autonomic nervous system, circulating endocrine hormones and immune factors, local paracrine and neurocrine factors and microbial metabolites. L-cells, which are electrically excitable biosensors embedded in the gastrointestinal epithelium, secrete glucagon-like peptide-1 (GLP-1) in response to nutrients in the small intestine. However, they appear to function in a different manner more distally in the gastrointestinal tract, where they are activated by luminal factors including short-chain fatty acids, bile acids and microbial metabolic products, all of which are altered in IBS patients. Glucagon-like peptide-1 can also interact with the hypothalamic-pituitary-adrenal stress axis and the immune system, both of which are activated in IBS. Given that a GLP-1 mimetic has been found to alleviate acute pain symptoms in IBS patients, GLP-1 might be important in the manifestation of IBS symptoms. This review assesses the current knowledge about the role of GLP-1 in IBS pathophysiology and its potential role as a signal transducer in the microbiome-gut-brain signalling axis.
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Affiliation(s)
- Dervla O'Malley
- Department of Physiology, University College Cork, Cork, Ireland
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26
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Fukudo S, Endo Y, Hongo M, Nakajima A, Abe T, Kobayashi H, Nakata T, Nakajima T, Sameshima K, Kaku K, Shoji E, Tarumi K, Nagaoka Y, Ooshima T, Ozawa K, Majima T, Kamata S, Tada T, Ishii H, Segawa Y, Miyazaki S, Yamamoto T, Yagi Y, Sawada H, Shirota S, Otsuka S, Yamada N, Suzuki R, Kurakata H, Nakai K, Syuji Y, Usui T, Yamamura M, Oishi T, Tanaka H. Safety and efficacy of the sodium-glucose cotransporter 1 inhibitor mizagliflozin for functional constipation: a randomised, placebo-controlled, double-blind phase 2 trial. Lancet Gastroenterol Hepatol 2018; 3:603-613. [DOI: 10.1016/s2468-1253(18)30165-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 05/02/2018] [Accepted: 05/03/2018] [Indexed: 12/11/2022]
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27
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Olivares M, Schüppel V, Hassan AM, Beaumont M, Neyrinck AM, Bindels LB, Benítez-Páez A, Sanz Y, Haller D, Holzer P, Delzenne NM. The Potential Role of the Dipeptidyl Peptidase-4-Like Activity From the Gut Microbiota on the Host Health. Front Microbiol 2018; 9:1900. [PMID: 30186247 PMCID: PMC6113382 DOI: 10.3389/fmicb.2018.01900] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 07/27/2018] [Indexed: 12/16/2022] Open
Abstract
The Dipeptidyl peptidase-4 (DPP-4) activity influences metabolic, behavioral and intestinal disorders through the cleavage of key hormones and peptides. Some studies describe the existence of human DPP-4 homologs in commensal bacteria, for instance in Prevotella or Lactobacillus. However, the role of the gut microbiota as a source of DPP-4-like activity has never been investigated. Through the comparison of the DPP-4 activity in the cecal content of germ-free mice (GFM) and gnotobiotic mice colonized with the gut microbiota of a healthy subject, we bring the proof of concept that a significant DPP-4-like activity occurs in the microbiota. By analyzing the existing literature, we propose that DPP-4-like activity encoded by the intestinal microbiome could constitute a novel mechanism to modulate protein digestion as well as host metabolism and behavior.
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Affiliation(s)
- Marta Olivares
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Valentina Schüppel
- ZIEL Institute for Food and Health, Technical University of Munich, Freising-Weihenstephan, Germany.,Chair of Nutrition and Immunology, Technical University of Munich, Freising-Weihenstephan, Germany
| | - Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Pharmacology Section, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Martin Beaumont
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
| | - Alfonso Benítez-Páez
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain
| | - Yolanda Sanz
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), Valencia, Spain
| | - Dirk Haller
- ZIEL Institute for Food and Health, Technical University of Munich, Freising-Weihenstephan, Germany.,Chair of Nutrition and Immunology, Technical University of Munich, Freising-Weihenstephan, Germany
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Pharmacology Section, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
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28
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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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29
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Spiller R. Inhibiting glucose absorption to treat constipation. Lancet Gastroenterol Hepatol 2018; 3:588-589. [PMID: 30056027 DOI: 10.1016/s2468-1253(18)30214-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 06/22/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Robin Spiller
- Nottingham Digestive Diseases Biomedical Research Unit, Nottingham Digestive Diseases Centre, Nottingham University Hospital, Nottingham NG2 7UH, UK.
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30
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Park SH, Lee JR, Jang SP, Park SH, Lee HJ, Hong JW, Suh HW. Antinociceptive profiles and mechanisms of centrally administered oxyntomodulin in various mouse pain models. Neuropeptides 2018; 68:7-14. [PMID: 29366515 DOI: 10.1016/j.npep.2018.01.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 01/15/2018] [Accepted: 01/15/2018] [Indexed: 11/26/2022]
Abstract
In the present study, the antinociceptive profiles of oxyntomodulin were examined in ICR mice. Oxyntomodulin administered intrathecally (i.t.) and intracerebroventricularly (i.c.v.) (from 1 to 5μg/5μl) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid-induced writhing test. Moreover, cumulative response time of nociceptive behaviors induced by intraplantar formalin injection was reduced by i.t. or i.c.v. treatment with oxyntomodulin during the second, but not the first phase. In addition, the cumulative nociceptive response time after i.t. injection with substance P (0.7μg), glutamate (20μg), and pro-inflammatory cytokines such as TNF-α, IL-β or IFN-γ (100pg/5μl) was diminished by spinally or supraspinally administered oxyntomodulin. However, i.t. and i.c.v. treatment with oxyntomodulin did not affect latencies of the tail-flick and hot-plate paw-licking responses. Furthermore, the i.t. pretreatment with yohimbine (adrenergic receptor antagonist), but not naloxone (an opioid receptor antagonist) or methysergide (a serotonergic receptor antagonist), attenuated antinociceptive effect induced by oxyntomodulin administered i.c.v. in the writhing test. The i.c.v. or i.t. pretreatment with oxyntomodulin attenuated formalin-induced increase of phosphorlated ERK (p-ERK) expression in the spinal cord. Our results suggest that centrally administered oxyntomodulin shows an antinociceptive property in various pain models except for thermal-induced nociception. Furthermore, supraspinally administered oxyntomodulin-induced antinociception may be mediated by spinal adrenergic receptors, but not serotonergic and opioidergic receptors. Furthermore, the antinociception induced by oxyntomodulin appears to be mediated by reduced formalin-induced p-ERK expression in the spinal cord.
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Affiliation(s)
- Soo-Hyun Park
- Front bio Co., Ltd., #405 1-dong, 32 Soyanggang-ro, Chuncheon, Gangwon-do 24232, Republic of Korea
| | - Jae-Ryeong Lee
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Sang-Pil Jang
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Seyung-Hwan Park
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Hee-Jung Lee
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Jung-Woo Hong
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Hong-Won Suh
- Department of Pharmacology, Institute of Natural Medicine, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do 24252, Republic of Korea.
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31
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Halim MA, Degerblad M, Sundbom M, Karlbom U, Holst JJ, Webb DL, Hellström PM. Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans. J Clin Endocrinol Metab 2018; 103:575-585. [PMID: 29177486 DOI: 10.1210/jc.2017-02006] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Accepted: 11/16/2017] [Indexed: 02/07/2023]
Abstract
CONTEXT Glucagon-like peptide-1 (GLP-1) secretion from l-cells and postprandial inhibition of gastrointestinal motility. OBJECTIVE Investigate whether physiological plasma concentrations of GLP-1 inhibit human postprandial motility and determine mechanism of action of GLP-1 and analog ROSE-010 action. DESIGN Single-blind parallel study. SETTING University hospital laboratory. PARTICIPANTS Healthy volunteers investigated with antroduodenal manometry. Human gastric and intestinal muscle strips. INTERVENTIONS Motility indices (MIs) obtained before and during GLP-1 or saline infusion. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips investigated for GLP-1- and ROSE-010-induced relaxation employing GLP-1 and GLP-2 and their receptor localization, and blockers exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2',5'-dideoxyadenosine (DDA), and tetrodotoxin (TTX) to reveal target mechanism of GLP-1 action. MAIN OUTCOME MEASURES Postprandial gastrointestinal relaxation by GLP-1. RESULTS In humans, food intake increased MI to 6.4 ± 0.3 (antrum), 5.7 ± 0.4 (duodenum), and 5.9 ± 0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg/min suppressed corresponding MI to 4.6 ± 0.2, 4.7 ± 0.4, and 5.0 ± 0.2, whereas 1.2 pmol/kg/min suppressed MI to 5.4 ± 0.2, 4.4 ± 0.3, and 5.4 ± 0.3 (P < 0.0001 to 0.005). In vitro, GLP-1 and ROSE-010 prevented contractions by bethanechol and electric field stimulation (P < 0.005 to 0.05). These effects were disinhibited by exendin(9-39)amide, L-NMMA, DDA, or TTX. GLP-1 and GLP-2 were localized to epithelial cells, GLP-1 also at myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle. CONCLUSIONS GLP-1 and ROSE-010 inhibit postprandial gastrointestinal motility through GLP-1R at myenteric neurons, involving nitrergic and cyclic adenosine monophosphate-dependent mechanisms.
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Affiliation(s)
- Md Abdul Halim
- Department of Medical Sciences, Gastroenterology Unit, Uppsala University, Uppsala, Sweden
| | - Marie Degerblad
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden
| | - Magnus Sundbom
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Urban Karlbom
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Jens Juul Holst
- NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Dominic-Luc Webb
- Department of Medical Sciences, Gastroenterology Unit, Uppsala University, Uppsala, Sweden
| | - Per M Hellström
- Department of Medical Sciences, Gastroenterology Unit, Uppsala University, Uppsala, Sweden
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32
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Nozu T, Miyagishi S, Kumei S, Nozu R, Takakusaki K, Okumura T. Glucagon-like peptide-1 analog, liraglutide, improves visceral sensation and gut permeability in rats. J Gastroenterol Hepatol 2018; 33:232-239. [PMID: 28440889 DOI: 10.1111/jgh.13808] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 04/08/2017] [Accepted: 04/19/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM A glucagon-like peptide-1 analog, liraglutide, has been reported to block inflammatory somatic pain. We hypothesized that liraglutide attenuates lipopolysaccharide (LPS)-induced and repeated water avoidance stress (WAS)-induced visceral hypersensitivity and tested the hypothesis in rats. METHODS The threshold of the visceromotor response induced by colonic balloon distention was measured to assess visceral sensation. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue spectrophotometrically, which was instilled in the proximal colon for 15 min. The interleukin-6 level in colonic mucosa was also quantified using ELISA. RESULTS Subcutaneously injected LPS (1 mg/kg) reduced the visceromotor response threshold after 3 h. Liraglutide (300 μg/kg subcutaneously) at 15 h and 30 min before injecting LPS eliminated LPS-induced allodynia. It also blocked the allodynia induced by repeated water avoidance stress for 1 h for three consecutive days. Neither vagotomy nor naloxone altered the antinociceptive effect of liraglutide, but NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, blocked it. LPS increased colonic permeability and the interleukin-6 level, and the analog significantly inhibited these responses. CONCLUSIONS This study suggests that liraglutide blocked LPS-induced visceral allodynia, which may be a nitric oxide-dependent response, and was probably mediated by inhibiting pro-inflammatory cytokine production and attenuating the increased gut permeability. Because the LPS-cytokine system is considered to contribute to altered visceral sensation in irritable bowel syndrome, these results indicate the possibility that liraglutide can be useful for treating this disease.
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Affiliation(s)
- Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Saori Miyagishi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Shima Kumei
- Department of General Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Rintaro Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Kaoru Takakusaki
- Research Center for Brain Function and Medical Engineering, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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33
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Holzer P, Farzi A, Hassan AM, Zenz G, Jačan A, Reichmann F. Visceral Inflammation and Immune Activation Stress the Brain. Front Immunol 2017; 8:1613. [PMID: 29213271 PMCID: PMC5702648 DOI: 10.3389/fimmu.2017.01613] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 11/07/2017] [Indexed: 12/20/2022] Open
Abstract
Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut-brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut-brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention.
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Affiliation(s)
- Peter Holzer
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed-Graz, Graz, Austria
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Ahmed M Hassan
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Geraldine Zenz
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
| | - Angela Jačan
- CBmed GmbH-Center for Biomarker Research in Medicine, Graz, Austria
| | - Florian Reichmann
- Research Unit of Translational Neurogastroenterology, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria
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Sinagra E, Morreale GC, Mohammadian G, Fusco G, Guarnotta V, Tomasello G, Cappello F, Rossi F, Amvrosiadis G, Raimondo D. New therapeutic perspectives in irritable bowel syndrome: Targeting low-grade inflammation, immuno-neuroendocrine axis, motility, secretion and beyond. World J Gastroenterol 2017; 23:6593-6627. [PMID: 29085207 PMCID: PMC5643283 DOI: 10.3748/wjg.v23.i36.6593] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/15/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a chronic, recurring, and remitting functional disorder of the gastrointestinal tract characterized by abdominal pain, distention, and changes in bowel habits. Although there are several drugs for IBS, effective and approved treatments for one or more of the symptoms for various IBS subtypes are needed. Improved understanding of pathophysiological mechanisms such as the role of impaired bile acid metabolism, neurohormonal regulation, immune dysfunction, the epithelial barrier and the secretory properties of the gut has led to advancements in the treatment of IBS. With regards to therapies for restoring intestinal permeability, multiple studies with prebiotics and probiotics are ongoing, even if to date their efficacy has been limited. In parallel, much progress has been made in targeting low-grade inflammation, especially through the introduction of drugs such as mesalazine and rifaximin, even if a better knowledge of the mechanisms underlying the low-grade inflammation in IBS may allow the design of clinical trials that test the efficacy and safety of such drugs. This literature review aims to summarize the findings related to new and investigational therapeutic agents for IBS, most recently developed in preclinical as well as Phase 1 and Phase 2 clinical studies.
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Affiliation(s)
- Emanuele Sinagra
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | | | - Ghazaleh Mohammadian
- Department of Medicine, Division of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Huddinge, 17176 Stockholm, Sweden
| | - Giorgio Fusco
- Unit of Internal Medicine, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, 90100 Palermo, Italy
| | - Valentina Guarnotta
- Section of Cardio-Respiratory and Endocrine-Metabolic Diseases, Biomedical Department of Internal and Specialist Medicine, University of Palermo, Palermo 90127, Italy
| | - Giovanni Tomasello
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | - Francesco Cappello
- Euro-Mediterranean Institute of Science and Technology, 90100 Palermo, Italy
- Department of Experimental Biomedicine and Clinical Neuroscience, Section of Human Anatomy, University of Palermo, 90100 Palermo, Italy
| | - Francesca Rossi
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
| | - Georgios Amvrosiadis
- Unit of Gastroenterology, Ospedali Riuniti Villa Sofia-Vincenzo Cervello, 90100 Palermo, Italy
| | - Dario Raimondo
- Gastroenterology and Endoscopy Unit, Fondazione Istituto Giuseppe Giglio, Contrada Pietra Pollastra Pisciotto, 90015 Cefalù, Italy
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Li ZY, Zhang N, Wen S, Zhang J, Sun XL, Fan XM, Sun YH. Decreased glucagon-like peptide-1 correlates with abdominal pain in patients with constipation-predominant irritable bowel syndrome. Clin Res Hepatol Gastroenterol 2017; 41:459-465. [PMID: 28215540 DOI: 10.1016/j.clinre.2016.12.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 10/26/2016] [Accepted: 12/15/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE The glucagon-like peptide-1 (GLP-1) analog, ROSE-010, plays a critical role in alleviating abdominal pain in patients with irritable bowel syndrome (IBS); however, the underling mechanism is unclear. In the present study, we determined the serum GLP-1 level in patients with constipation-predominant IBS (IBS-C). The relationship between GLP-1 and abdominal pain was investigated. In addition, the expression of the GLP-1 receptor in the colon was determined. METHODS Rectosigmoid biopsies were gathered from 38 patients with IBS-C who met the Rome III criteria, and 22 healthy controls. Abdominal pain was quantified by a validated questionnaire. Serum GLP-1 was measured by ELISA and correlated with abdominal pain scores. The presence of the GLP-1 receptor in the colonic mucosa was assessed by immunohistochemistry. RESULTS Serum GLP-1 was substantially decreased in patients with IBS-C. Decreased serum GLP-1 had a negative correlation with the abdominal pain scores. Biopsies from patients with IBS-C revealed a significant down-regulation of the GLP-1 receptor in colonic mucosa compared with control subjects. CONCLUSIONS Decreased serum GLP-1 correlates with abdominal pain in patients with IBS-C. Decreased expression of GLP-1 and GLP-1 receptor may be the basis for alleviation of abdominal pain in patients with IBS-C by ROSE-010.
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Affiliation(s)
- Zheng-Yang Li
- Department of Gastroenterology, Dalian friendship Hospital, Dalian, Liaoning 116001, PR China
| | - Na Zhang
- Department of Gastroenterology, Dalian friendship Hospital, Dalian, Liaoning 116001, PR China
| | - Shuang Wen
- Department of Gastroenterology, Dalian friendship Hospital, Dalian, Liaoning 116001, PR China
| | - Jing Zhang
- Department of Gastroenterology, Dalian friendship Hospital, Dalian, Liaoning 116001, PR China
| | - Xiu-Li Sun
- Department of Gastroenterology, Dalian friendship Hospital, Dalian, Liaoning 116001, PR China
| | - Xiao-Ming Fan
- Department of Gastroenterology, Jinshan hospital of Fudan University, Shanghai 201508, PR China.
| | - Yong-Hong Sun
- Department of Gastroenterology, Dalian friendship Hospital, Dalian, Liaoning 116001, PR China.
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McCullough R, McCullough J. Deciphering the pathophysiology of irritable bowel syndrome and functional gastrointestinal disorders-an alternative model for pathogenesis: cytokine controlled transepithelial multi-feedback loop. Transl Gastroenterol Hepatol 2017; 2:18. [PMID: 28447053 PMCID: PMC5388621 DOI: 10.21037/tgh.2017.03.02] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 02/23/2017] [Indexed: 12/12/2022] Open
Abstract
A working theoretical model for irritable bowel syndrome (IBS) and other functional gastrointestinal disorders (FGIDs) does not exist, hampered by the lack of any clear cut invention that address all symptom and signs of the disease. Reports of cessation of symptom and signs of both major types of IBS have been published using a non-systemic, topically active agent-high potency polymerized cross-linked sucralfate (HPPCLS). The unique clinical effect of this non-systemic agent restricted to the luminal surface of the gut provides opportunity to elaborate on an alternative working model for the pathogenesis of IBS and FGIDs. While the chemical determinants of HPPCLS and the mucosal lining contribute to the clinical effects, the sequence of events resides in the functional interplay among elements within the mucosa itself. The proposed model assumes that failure of a pre-existing genomic-controlled surveillance of the epithelium localized to the luminal surface triggers primary and secondary immune activation of inflammation intent on restoring epithelial homeostasis. Delayed restoration of homeostasis results in all the symptoms, signs and likely molecular events that characterize IBS and FGIDs.
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Affiliation(s)
- Ricky McCullough
- Translational Medicine Clinic and Research Center, Storrs CT 06368, USA
- Department of Medicine, Providence VA Medical Center, Brown University School of Medicine, Providence, RI, USA
| | - Jeremiah McCullough
- Medicinal Chemistry, School of Pharmacy, University of Connecticut, Storrs CT 06268, USA
- Department of Molecular and Cell Biology, University of Connecticut, Storrs CT 06268, USA
- Department of Physiology and Neurobiology, University of Connecticut, Storrs CT 06268, USA
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Mosaffa-Jahromi M, Lankarani KB, Pasalar M, Afsharypuor S, Tamaddon AM. Efficacy and safety of enteric coated capsules of anise oil to treat irritable bowel syndrome. JOURNAL OF ETHNOPHARMACOLOGY 2016; 194:937-946. [PMID: 27815079 DOI: 10.1016/j.jep.2016.10.083] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 10/07/2016] [Accepted: 10/29/2016] [Indexed: 02/08/2023]
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Abstract
Irritable bowel syndrome is a common functional bowel disorder whose incidence has a tendency to increase year by year. At present, the pathogenesis of irritable bowel syndrome is not completely clear, and treatments are mainly symptomatic. In recent years, with the better understanding of its pathogenesis, some new drugs and treatments have been developed, such as methods of improving intestinal micro-ecology (antibiotics, fecal transplantation), mesalazine, and new drugs of improving intestinal secretion, motiligy and sensitivity, plant drugs, some of which have been applied clinically. This article will make a review of the current progress in treatment of irritable bowel syndrome.
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Smits MM, van Raalte DH, Tonneijck L, Muskiet MHA, Kramer MHH, Cahen DL. GLP-1 based therapies: clinical implications for gastroenterologists. Gut 2016; 65:702-11. [PMID: 26786687 DOI: 10.1136/gutjnl-2015-310572] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 12/23/2015] [Indexed: 12/13/2022]
Abstract
The gut-derived incretin hormone, glucagon-like peptide 1 (GLP-1) lowers postprandial blood glucose levels by stimulating insulin and inhibiting glucagon secretion. Two novel antihyperglycaemic drug classes augment these effects; GLP-1 receptor agonists and inhibitors of the GLP-1 degrading enzyme dipeptidyl peptidase 4. These so called GLP-1 based or incretin based drugs are increasingly used to treat type 2 diabetes, because of a low risk of hypoglycaemia and favourable effect on body weight, blood pressure and lipid profiles. Besides glucose control, GLP-1 functions as an enterogastrone, causing a wide range of GI responses. Studies have shown that endogenous GLP-1 and its derived therapies slow down digestion by affecting the stomach, intestines, exocrine pancreas, gallbladder and liver. Understanding the GI actions of GLP-1 based therapies is clinically relevant; because GI side effects are common and need to be recognised, and because these drugs may be used to treat GI disease.
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Affiliation(s)
- Mark M Smits
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Daniel H van Raalte
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Lennart Tonneijck
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Marcel H A Muskiet
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Mark H H Kramer
- Department of Internal Medicine, Diabetes Center, VU University Medical Center, Amsterdam, The Netherlands
| | - Djuna L Cahen
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
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Mosińska P, Salaga M, Fichna J. Novel investigational drugs for constipation-predominant irritable bowel syndrome: a review. Expert Opin Investig Drugs 2016; 25:275-86. [PMID: 26765585 DOI: 10.1517/13543784.2016.1142532] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Constipation-predominant irritable bowel syndrome (IBS-C) is a functional gastrointestinal (GI) disorder with an unknown etiology. A number of the drugs tested for IBS-C have also been applied to chronic constipation and chronic idiopathic constipation. Unfortunately, due to severe adverse effects, many drugs envisioned for IBS-C had been withdrawn from the market. Nevertheless, a number of potential new agents for this indication are now under development. AREAS COVERED The following review describes the most recently developed agents in preclinical as well as Phase 1 and Phase 2 clinical studies. Information was obtained from published literature, abstracts and the latest results found in Clinicaltrial.gov database. The authors put a special interest on glucagon-like peptide 1 analogue, bile acid modulators, serotonergic agents, guanylate cyclase C and cannabinoid antagonists. EXPERT OPINION To enter the market, a newly-developed drug has to meet several criteria, such as good bioavailability or the absence of drug-related adverse events. Taking into account constipation and abdominal pain as the main symptoms in IBS-C, a novel successful drug is usually able to improve both at the same time. Four out of fifteen investigational drugs described in this paper belong to the serotonergic family and have a good prognosis to reach the market; still, more long-term clinical studies are warranted.
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Affiliation(s)
- Paula Mosińska
- a Department of Biochemistry, Faculty of Medicine , Medical University of Lodz , Lodz , Poland
| | - Maciej Salaga
- a Department of Biochemistry, Faculty of Medicine , Medical University of Lodz , Lodz , Poland
| | - Jakub Fichna
- a Department of Biochemistry, Faculty of Medicine , Medical University of Lodz , Lodz , Poland
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Abstract
Irritable bowel syndrome (IBS) affects about 15 % of the US population and results in significant morbidity and health care costs. There remains a significant unmet need for effective treatments particularly for the pain component of IBS and other functional gastrointestinal disorders (FGIDs). Progress made in our understanding of pathophysiological mechanisms such as the role of altered bile acid metabolism, neurohormonal regulation, immune dysfunction, the epithelial barrier and secretory properties of the gut has led to advancements in therapeutic armamentarium for IBS. This review discusses the new drugs for constipation and diarrhea-predominant IBS subtypes that have been tested or have been under investigation over the last 3-4 years. Overall, there is a promising pipeline of investigational drugs for the future treatment of IBS and related FGIDs.
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Affiliation(s)
- Akhilesh Wadhwa
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
| | - Madhusudan Grover
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Smits MM, Tonneijck L, Muskiet MHA, Hoekstra T, Kramer MHH, Pieters IC, Cahen DL, Diamant M, van Raalte DH. Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes. BMJ Open 2015; 5:e009579. [PMID: 26586327 PMCID: PMC4654309 DOI: 10.1136/bmjopen-2015-009579] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Incretin-based therapies, that is, glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, are relatively novel antihyperglycaemic drugs that are frequently used in type 2 diabetes management. Apart from glucose-lowering, these agents exhibit pleiotropic actions that may have favourable and unfavourable clinical consequences. Incretin-based therapies have been associated with heart rate acceleration, heart failure, acute renal failure and acute pancreatitis. Conversely, these agents may reduce blood pressure, glomerular hyperfiltration, albuminuria and hepatic steatosis. While large-sized cardiovascular safety trials can potentially identify the clinical significance of some of these pleiotropic actions, small-sized mechanistic studies are important to understand the (patho)physiological rationale of these findings. The current protocol describes a mechanistic study to assess cardiovascular, renal and gastrointestinal effects, and mechanisms of incretin-based therapies in type 2 diabetes. METHODS AND ANALYSES 60 patients with type 2 diabetes will undergo acute and prolonged randomised, double-blind, intervention studies. The acute intervention will consist of intravenous administration of the GLP-1 receptor agonist exenatide or placebo. For the prolonged intervention, patients will be randomised to 12-week treatment with the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebos. For each examined organ system, a primary end point is defined. Primary cardiovascular end point is change in resting heart rate variability assessed by beat-to-beat heart rate monitor and spectral analyses software. Primary renal end point is change in glomerular filtration rate assessed by the classic inulin clearance methodology. Primary gastrointestinal end points are change in pancreatic exocrine function assessed by MRI-techniques (acute intervention) and faecal elastase-1 levels (12-week intervention). Secondary end points include systemic haemodynamics, microvascular function, effective renal plasma flow, renal tubular function, pancreatic volume and gallbladder emptying-rate. MEDICAL ETHICS AND DISSEMINATION The study is approved by the local Ethics Review Board (VU University Medical Center, Amsterdam) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION NUMBER NCT01744236.
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Affiliation(s)
- Mark M Smits
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Lennart Tonneijck
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Marcel H A Muskiet
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Trynke Hoekstra
- Department of Health Sciences, EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam, The Netherlands
- Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
| | - Mark H H Kramer
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Indra C Pieters
- Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Djuna L Cahen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Michaela Diamant
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
| | - Daniël H van Raalte
- Department of Internal Medicine, Diabetes Centre, VU University Medical Center, Amsterdam, The Netherlands
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Mujagic Z, Keszthelyi D, Aziz Q, Reinisch W, Quetglas EG, De Leonardis F, Segerdahl M, Masclee AAM. Systematic review: instruments to assess abdominal pain in irritable bowel syndrome. Aliment Pharmacol Ther 2015; 42:1064-81. [PMID: 26290286 DOI: 10.1111/apt.13378] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 02/02/2015] [Accepted: 07/31/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Consensus on standard methods to assess chronic abdominal pain in patients with irritable bowel syndrome (IBS) is currently lacking. AIM To systematically review the literature with respect to instruments of measurement of chronic abdominal pain in IBS patients. METHODS Systematic literature search was performed in PubMed/Medline databases for studies using pain measurement instruments in patients with IBS. RESULTS One hundred and ten publications were reviewed. A multitude of different instruments is currently used to assess chronic abdominal pain in IBS patients. The single-item methods, e.g. the validated 10-point numeric rating scale (NRS), and questionnaires assessing gastrointestinal symptoms severity, focus mostly on the assessment of only the intensity of abdominal pain. Of these questionnaires, the validated IBS-Symptom Severity Scale includes the broadest measurement of pain-related aspects. General pain questionnaires and electronic momentary symptom assessment tools have been used to study abdominal pain in IBS patients, but have not yet been validated for this purpose. The evidence for the use of provocation tests, e.g. the rectal barostat with balloon distention, for measurement of abdominal pain in IBS is weak, due to the poor correlation between visceral pain thresholds assessed by provocation tests and abdominal pain as assessed by retrospective questionnaires. CONCLUSIONS The multitude of different instruments to measure chronic abdominal pain in IBS makes it difficult to compare endpoints of published studies. There is need for validated instruments to assess chronic abdominal pain in IBS patients, that overcome the limitations of the currently available methods.
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Affiliation(s)
- Z Mujagic
- Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - D Keszthelyi
- Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
| | - Q Aziz
- Centre for Digestive Diseases, Blizard Institute of Cell & Molecular Science, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - W Reinisch
- Department Internal Medicine III, Medical University of Vienna, Vienna, Austria.,McMaster University, Hamilton, ON, Canada
| | - E G Quetglas
- Medical Intelligence, Early Clinical Development, Grünenthal GmBH, Aachen, Germany
| | - F De Leonardis
- Medical Intelligence, Early Clinical Development, Grünenthal GmBH, Aachen, Germany
| | - M Segerdahl
- Medical Intelligence, Early Clinical Development, Grünenthal GmBH, Aachen, Germany.,Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - A A M Masclee
- Division Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands
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Jadallah KA, Kullab SM, Sanders DS. Constipation-predominant irritable bowel syndrome: A review of current and emerging drug therapies. World J Gastroenterol 2014; 20:8898-8909. [PMID: 25083062 PMCID: PMC4112860 DOI: 10.3748/wjg.v20.i27.8898] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 03/23/2014] [Accepted: 06/05/2014] [Indexed: 02/07/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent medical condition that adversely affects patient quality of life and constitutes a significant economic burden on healthcare resources. A large proportion of patients suffer from the constipation subtype of IBS (IBS-C), most commonly afflicting older individuals and those with a lower socioeconomic status. Conventional pharmacologic and nonpharmacologic treatment options have limited efficacies and/or significant adverse events, which lead to increased long-term health care expenditures. Failure to effectively treat IBS-C patients over the past decades has largely been due to a poor understanding of disease pathophysiology, lack of a global view of the patient, and an inappropriate selection of patients and treatment endpoints in clinical trials. In recent years, however, more effective and safer drugs have been developed for the treatment of IBS-C. The advancement in the area of pharmacologic treatment is based on new knowledge of the pathophysiologic basis of IBS-C and the development of drugs with increased selectivity within pharmacologic classes with recognized efficacies. This narrative review covers the spectrum of available drugs and their mechanisms of action, as well as the efficacy and safety profiles of each as determined in relevant clinical trials that have investigated treatment options for IBS-C and chronic constipation. A brief summary of laxative-based treatment options is presented, followed by up-to-date assessments for three classes of drugs: prokinetics, prosecretory agents, and bile acid modulators.
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Lazaraki G, Chatzimavroudis G, Katsinelos P. Recent advances in pharmacological treatment of irritable bowel syndrome. World J Gastroenterol 2014; 20:8867-8885. [PMID: 25083060 PMCID: PMC4112893 DOI: 10.3748/wjg.v20.i27.8867] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 03/13/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a highly prevalent functional disorder that reduces patients’ quality of life. It is a chronic disorder characterized by abdominal pain or discomfort associated with disordered defecation in the absence of identifiable structural or biochemical abnormalities. IBS imposes a significant economic burden to the healthcare system. Alteration in neurohumoral mechanisms and psychological factors, bacterial overgrowth, genetic factors, gut motility, visceral hypersensitivity, and immune system factors are currently believed to influence the pathogenesis of IBS. It is possible that there is an interaction of one or more of these etiologic factors leading to heterogeneous symptoms of IBS. IBS treatment is predicated upon the patient’s most bothersome symptoms. Despite the wide range of medications and the high prevalence of the disease, to date no completely effective remedy is available. This article reviews the literature from January 2008 to July 2013 on the subject of IBS peripherally acting pharmacological treatment. Drugs are categorized according to their administration for IBS-C, IBS-D or abdominal pain predominant IBS.
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Reed DE, Blackshaw LA. Inhibition of visceral nociceptors. Front Pharmacol 2014; 5:72. [PMID: 24782775 PMCID: PMC3995067 DOI: 10.3389/fphar.2014.00072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 03/27/2014] [Indexed: 12/12/2022] Open
Affiliation(s)
- David E Reed
- Neurogastroenterolohy Group, Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London London, UK
| | - L Ashley Blackshaw
- Neurogastroenterolohy Group, Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London London, UK
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Ducrotte P, Grimaud JC, Dapoigny M, Personnic S, O'Mahony V, Andro-Delestrain MC. On-demand treatment with alverine citrate/simeticone compared with standard treatments for irritable bowel syndrome: results of a randomised pragmatic study. Int J Clin Pract 2014; 68:245-54. [PMID: 24147869 PMCID: PMC4282257 DOI: 10.1111/ijcp.12333] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Accepted: 09/22/2013] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND In routine practice, irritable bowel syndrome (IBS) symptoms are often difficult to be relieved and impair significantly patients' quality of life (QoL). A randomised, double-blind, placebo-controlled study has shown the efficacy of alverine citrate/simeticone (ACS) combination for IBS symptom relief. AIM As IBS symptoms are often intermittent, this pragmatic study was designed to compare the efficacy of an on-demand ACS treatment vs. that of usual treatments. METHODS Rome III IBS patients were enrolled by 87 general practitioners who were randomly allocated to one of two therapeutic strategies: on-demand ACS or usual treatment chosen by the physician. The primary outcome measure was the improvement of the IBSQoL score between inclusion and month 6. RESULTS A total of 436 patients (mean age: 54.4 years; women: 73.4%) were included, 222 in the ACS arm and 214 patients in the usual treatment arm, which was mainly antispasmodics. At 6 months, improvement of IBSQoL was greater with ACS than with the usual treatment group (13.8 vs. 8.4; p < 0.0008). The IBS-severity symptom score (IBS-SSS) was lower with ACS than in the usual treatment arm with a mean (SE) decrease of 170.0 (6.6) vs. 110.7 (6.7), respectively (p = 0.0001). An IBS-SSS < 75 was more frequent in the ACS group (37.7% vs. 16.0%; p < 0.0001). Improvement of both abdominal pain and bloating severity was also greater with the on-demand ACS treatment, which was associated with both lower direct and indirect costs. CONCLUSIONS After 6 months, on-demand ACS treatment led to a greater improvement of QoL, reduced the burden of the disease and was more effective for IBS symptom relief than usual treatments.
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Affiliation(s)
- P Ducrotte
- Department of Gastroenterology, UMR 1073, Rouen University Hospital, University of Rouen, Rouen, France
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Siekmeier R, Hofmann T, Scheuch G, Pokorski M. Aerosolized GLP-1 for treatment of diabetes mellitus and irritable bowel syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2014; 849:23-38. [PMID: 25427821 DOI: 10.1007/5584_2014_94] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Diabetes is a global burden and the prevalence of the disease, in particular diabetes mellitus type 2 is rapidly increasing worldwide. After introduction of insulin into clinical therapy about 90 years ago a major number of pharmaceuticals has been developed for treatment of diabetes mellitus type 2. One of these, the incretin glucagon-like peptide 1 (GLP-1), like insulin, needs subcutaneous administration causing inconvenience to patients. However, administration of GLP-1 plays also a role for treatment of irritable bowel syndrome (IBS). To improve patient convenience inhaled insulin (Exubera(®)) was developed and approved but failed market acceptance some years ago. Recently, another inhalative insulin (Afrezza(®)) received market approval and GLP-1 may serve as another candidate drug for inhalative administration. This review analyzes the current literature investigating alternative administration of GLP-1 and GLP-1 analogs focusing on inhalation. Several formulations for inhalative administration of GLP-1 and analogs were investigated in animal studies, whereas there are only few clinical data. However, feasibility of GLP-1 inhalation has been shown and should be further investigated as such type of drug administration may serve for improvement of therapy in patients with diabetes mellitus or irritable bowel syndrome.
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Affiliation(s)
- Rüdiger Siekmeier
- Drug Regulatory Affairs, Pharmaceutical Institute, Bonn University, An der Immenburg 4, 53121, Bonn, Germany,
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Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a complex syndrome that is difficult to manage. Here we present the evidence supporting medication treatments for specific IBS symptoms, discuss evidence-based management of IBS with medications including dose regimens and adverse effects and review progress on research for new IBS treatments. SUMMARY Currently, there is evidence to support improvements in specific IBS symptoms following treatment with loperamide, psyllium, bran, lubiprostone, linaclotide, amitriptyline, trimipramine, desipramine, citalopram, fluoxetine, paroxetine, dicyclomine, peppermint oil, rifaximin, ketotifen, pregabalin, gabapentin and octreotide and there are many new medications being investigated for the treatment of IBS. Key Message: Of the medications with demonstrated improvements for IBS symptoms, rifaximin, lubiprostone, linaclotide, fiber supplementation and peppermint oil have the most reliable evidence supporting their use for the treatment of IBS. Onset of efficacy for the various medications has been noted to be as early as 6 days after initiation; however, the efficacy of most medications was not assessed prospectively at predefined periods. Additional studies of currently available and new medications are ongoing and are needed to better define their place in therapy and expand therapeutic options for the treatment of IBS. The most promising new medications for IBS include a variety of novel pharmacologic approaches, most notably the dual μ-opioid receptor agonist and δ-opioid antagonist, JNJ-27018966.
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Affiliation(s)
- Katy E Trinkley
- University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, Colo., USA
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Camilleri M. Pharmacological agents currently in clinical trials for disorders in neurogastroenterology. J Clin Invest 2013; 123:4111-20. [PMID: 24084743 DOI: 10.1172/jci70837] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Esophageal, gastrointestinal, and colonic diseases resulting from disorders of the motor and sensory functions represent almost half the patients presenting to gastroenterologists. There have been significant advances in understanding the mechanisms of these disorders, through basic and translational research, and in targeting the receptors or mediators involved, through clinical trials involving biomarkers and patient responses. These advances have led to relief of patients' symptoms and improved quality of life, although there are still significant unmet needs. This article reviews the pipeline of medications in development for esophageal sensorimotor disorders, gastroparesis, chronic diarrhea, chronic constipation (including opioid-induced constipation), and visceral pain.
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