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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] [Download PDF] [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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Gaus OV, Livzan MA, Gavrilenko DA. Risk factors for irritable bowel syndrome: A review. TERAPEVT ARKH 2024; 96:159-167. [DOI: 10.26442/00403660.2024.02.202597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/17/2024]
Abstract
Irritable bowel syndrome (IBS) is one of the most common diseases of the digestive tract from the group of disorders of interaction in the gut-brain axis. IBS has a negative impact of on patients' quality of life and the significant social and economic burden of the disease due to the low effectiveness of available treatment strategies, which are only symptomatic, without impacting factors and mechanisms of intestinal dysfunction. From this perspective, it is critical to study the factors contributing to the onset and persistence of IBS symptoms to improve the early diagnosis of the disease and implement targeted prevention technology in at-risk groups. The objective of this paper is to systematize data on the main risk factors for IBS, including hereditary predisposition, stress and psycho-emotional state, diet and eating habits, and acute intestinal infections.
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Li ZY, Mao YQ, Hua Q, Sun YH, Wang HY, Ye XG, Hu JX, Wang YJ, Jiang M. Serotonin receptor 2B induces visceral hyperalgesia in rat model and patients with diarrhea-predominant irritable bowel syndrome. World J Gastroenterol 2024; 30:1431-1449. [PMID: 38596485 PMCID: PMC11000090 DOI: 10.3748/wjg.v30.i10.1431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/29/2023] [Accepted: 02/06/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND Serotonin receptor 2B (5-HT2B receptor) plays a critical role in many chronic pain conditions. The possible involvement of the 5-HT2B receptor in the altered gut sensation of irritable bowel syndrome with diarrhea (IBS-D) was investigated in the present study. AIM To investigate the possible involvement of 5-HT2B receptor in the altered gut sensation in rat model and patients with IBS-D. METHODS Rectosigmoid biopsies were collected from 18 patients with IBS-D and 10 patients with irritable bowel syndrome with constipation who fulfilled the Rome IV criteria and 15 healthy controls. The expression level of the 5-HT2B receptor in colon tissue was measured using an enzyme-linked immunosorbent assay and correlated with abdominal pain scores. The IBS-D rat model was induced by intracolonic instillation of acetic acid and wrap restraint. Alterations in visceral sensitivity and 5-HT2B receptor and transient receptor potential vanilloid type 1 (TRPV1) expression were examined following 5-HT2B receptor antagonist administration. Changes in visceral sensitivity after administration of the TRPV1 antagonist were recorded. RESULTS Here, we observed greater expression of the 5-HT2B receptor in the colonic mucosa of patients with IBS-D than in that of controls, which was correlated with abdominal pain scores. Intracolonic instillation of acetic acid and wrap restraint induced obvious chronic visceral hypersensitivity and increased fecal weight and fecal water content. Exogenous 5-HT2B receptor agonist administration increased visceral hypersensitivity, which was alleviated by successive administration of a TRPV1 antagonist. IBS-D rats receiving the 5-HT2B receptor antagonist exhibited inhibited visceral hyperalgesia.Moreover, the percentage of 5-HT2B receptor-immunoreactive (IR) cells surrounded by TRPV1-positive cells (5-HT2B receptor I+) and total 5-HT2B receptor IR cells (5-HT2B receptor IT) in IBS-D rats was significantly reduced by the administration of a 5-HT2B receptor antagonist. CONCLUSION Our finding that increased expression of the 5-HT2B receptor contributes to visceral hyperalgesia by inducing TRPV1 expression in IBS-D patients provides important insights into the potential mechanisms underlying IBS-D-associated visceral hyperalgesia.
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Affiliation(s)
- Zheng-Yang Li
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Yu-Qing Mao
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Qian Hua
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Yong-Hong Sun
- Department of Gastroenterology, Dalian Friendship Hospital, Dalian 116001, Liaoning Province, China
| | - Hai-Yan Wang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Xuan-Guang Ye
- Department of Pathology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Jing-Xian Hu
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Ya-Jie Wang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
| | - Miao Jiang
- Department of Gastroenterology, Jinshan Hospital of Fudan University, Shanghai 201508, China
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Zhou GQ, Huang MJ, Yu X, Zhang NN, Tao S, Zhang M. Early life adverse exposures in irritable bowel syndrome: new insights and opportunities. Front Pediatr 2023; 11:1241801. [PMID: 37732013 PMCID: PMC10507713 DOI: 10.3389/fped.2023.1241801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 08/22/2023] [Indexed: 09/22/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder worldwide. Extensive research has identified multiple factors contributing to its development, including genetic predisposition, chronic infection, gut dysbiosis, aberrant serotonin metabolism, and brain dysfunction. Recent studies have emphasized the critical role of the early life stage as a susceptibility window for IBS. Current evidence suggests that diet can heighten the risk of IBS in offspring by influencing the microbiota composition, intestinal epithelium structure, gene expression, and brain-gut axis. The use of antibiotics during pregnancy and the neonatal period disrupts the normal gut microbiota structure, aligning it with the characteristics observed in IBS patients. Additionally, early life stress impacts susceptibility to IBS by modulating TLR4, NK1, and the hypothalamic-pituitary-adrenal (HPA) axis while compromising the offspring's immune system. Formula feeding facilitates the colonization of pathogenic bacteria in the intestines, concurrently reducing the presence of probiotics. This disruption of the Th1 and Th2 cell balance in the immune system weakens the intestinal epithelial barrier. Furthermore, studies suggest that delivery mode influences the occurrence of IBS by altering the composition of gut microbes. This review aims to provide a comprehensive summary of the existing evidence regarding the impact of adverse early life exposures on IBS during pregnancy, intrapartum, and neonatal period. By consolidating this knowledge, the review enhances our understanding of the direct and indirect mechanisms underlying early life-related IBS and offers new insights and research directions from childhood to adulthood.
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Affiliation(s)
| | | | | | | | | | - Ming Zhang
- Department of General Practice, Honghui Hospital, Xi'an Jiaotong University, Xi’an, China
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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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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] [MESH Headings] [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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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] [MESH Headings] [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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O'Malley D. Endocrine regulation of gut function - a role for glucagon-like peptide-1 in the pathophysiology of irritable bowel syndrome. Exp Physiol 2019; 104:3-10. [PMID: 30444291 DOI: 10.1113/ep087443] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [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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Hou RG, Fan L, Liu JJ, Cheng Y, Chang ZP, Wu B, Shao YY. Bile acid malabsorption is associated with diarrhea in acute phase of colitis. Can J Physiol Pharmacol 2018; 96:1328-1336. [PMID: 30383974 DOI: 10.1139/cjpp-2018-0017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The enterohepatic circulation of bile acids (BAs) critically depends on BA transporters and enzymes, which can be affected by inflammatory bowel disease. Diarrhea in colitis is believed to result in part from BA malabsorption. The work aimed to investigate whether diarrhea in colitis was associated with the expression of BA transporters, enzymes, and nuclear receptors. RT-qPCR and Western blot techniques were used to evaluate the gene and protein levels of Cyp7a1, Asbt, SHP, FXR, Ostβ in a 2,4,6-trinitrobenzenesulfonic-acid-induced rat model of colitis. The total BAs (TBAs) levels were assayed using ELISA kits, and the individual BAs were measured by LC-MS/MS. Results showed that the fecal excretions of TBAs were significantly increased by 1.6-fold in acute stage of colitis. In ileum, Asbt was significantly decreased; however, there was a compensatory increase in Cyp7a1 level in liver. Moreover, FXR has a decreased tendency and the downstream target gene SHP was downregulated. Contrary to acute stage, molecular changes were completely reversible during the remission phase. Our results indicated that the expression of Asbt and Cyp7a1 were altered in acute colitis, which performed vital roles in maintaining BA homeostasis. Early medical manipulation of BA transporters and enzymes may help prevent diarrhea.
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Affiliation(s)
- Rui-Gang Hou
- a School of Pharmaceutical, Shanxi Medical University, Shanxi 030000 China.,b Department of Pharmacy, Second Hospital of Shanxi Medical University, Shanxi 030000, China
| | - Lei Fan
- a School of Pharmaceutical, Shanxi Medical University, Shanxi 030000 China.,b Department of Pharmacy, Second Hospital of Shanxi Medical University, Shanxi 030000, China
| | - Jun-Jin Liu
- a School of Pharmaceutical, Shanxi Medical University, Shanxi 030000 China.,b Department of Pharmacy, Second Hospital of Shanxi Medical University, Shanxi 030000, China
| | - Yao Cheng
- a School of Pharmaceutical, Shanxi Medical University, Shanxi 030000 China.,b Department of Pharmacy, Second Hospital of Shanxi Medical University, Shanxi 030000, China
| | - Zhuang-Peng Chang
- a School of Pharmaceutical, Shanxi Medical University, Shanxi 030000 China.,b Department of Pharmacy, Second Hospital of Shanxi Medical University, Shanxi 030000, China
| | - Bei Wu
- a School of Pharmaceutical, Shanxi Medical University, Shanxi 030000 China.,b Department of Pharmacy, Second Hospital of Shanxi Medical University, Shanxi 030000, China
| | - Yun-Yun Shao
- a School of Pharmaceutical, Shanxi Medical University, Shanxi 030000 China.,b Department of Pharmacy, Second Hospital of Shanxi Medical University, Shanxi 030000, China
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Sadeghian M, Sadeghi O, Hassanzadeh Keshteli A, Daghaghzadeh H, Esmaillzadeh A, Adibi P. Physical activity in relation to irritable bowel syndrome among Iranian adults. PLoS One 2018; 13:e0205806. [PMID: 30335859 PMCID: PMC6193664 DOI: 10.1371/journal.pone.0205806] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Accepted: 10/02/2018] [Indexed: 12/12/2022] Open
Abstract
Background Irritable bowel syndrome (IBS) is the most prevalent functional gastrointestinal disorder worldwide. Physical activity in relation to IBS has been investigated in few studies and data in this regard are conflicting. Aim To investigate the association between physical activity and IBS in a large sample of Iranian adults. Methods This cross-sectional study was done on 4763 Iranian adults in the framework of SEPAHAN (The Study on the Epidemiology of Psycho-Alimentary Health and Nutrition) project. The physical activity of study participants was assessed using the General Practice Physical Activity Questionnaire (GPPAQ). Using a validated self-administered modified Rome III questionnaire, functional gastrointestinal disorders including irritable bowel syndrome was assessed. Results The mean age of study participants was 36.5 years. Irritable bowel syndrome was prevalent among 21.5% of participants. Compared with physically active individuals (≥ 1 hour/wk), those with sedentary physical activity (<1 hour/wk) had 1.27 times greater probability of suffering from IBS (OR: 1.27, 95% CI: 1.08–1.49). However, this association was attenuated after adjusting for age, sex, cigarette smoking and medical history of colitis and diabetes. When the analysis was additionally adjusted for diet-related practices and body mass index (BMI), a non-significant association was found between sedentary physical activity and IBS (OR: 1.18, 95% CI: 0.98–1.41). Gender-stratified analysis revealed similar findings in women either before (OR: 1.29, 95% CI: 1.04–1.61) or after controlling for covariates (OR: 1.27, 95% CI: 0.99–1.62). In BMI-stratified analysis, a significant positive association was seen between sedentary physical activity and IBS among individuals with normal BMI (OR: 1.38, 95% CI: 1.07–1.79). Conclusion We found a significant positive association between sedentary physical activity and IBS, particularly among women and individuals of normal weight.
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Affiliation(s)
- Mehdi Sadeghian
- Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Omid Sadeghi
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Hamed Daghaghzadeh
- Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ahmad Esmaillzadeh
- Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular -Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- * E-mail:
| | - Peyman Adibi
- Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
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Jia M, Lu X, Wang Z, Zhao L, Zhang S. Effects of Fengliao-Changweikang in Diarrhea-predominant Irritable Bowel Syndrome Rats and Its Mechanism Involving Colonic Motility. J Neurogastroenterol Motil 2018; 24:479-489. [PMID: 29715711 PMCID: PMC6034674 DOI: 10.5056/jnm17093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/21/2017] [Accepted: 11/20/2017] [Indexed: 12/13/2022] Open
Abstract
Background/Aims This study was designed to investigate the effect of Fengliao-Changweikang (FLCWK) in diarrhea-predominant irritable bowel syndrome (IBS-D) rats and explore its underlying mechanisms. Methods IBS-D model rats were induced by neonatal maternal separation (NMS) combined with restraint stress (RS). In in vivo experiments, the model rats were randomly divided into 5 groups: NMS + RS, FLCWK (low dose, middle dose, and high dose), and pinaverium bromide. The normal control (no handling) rats were classified as the NH group. The therapeutic effect of FLCWK was evaluated by fecal characteristics, electromyographic response and abdominal withdrawal reflex scores. In in vitro experiments, the model rats were randomly divided into 2 groups: NMS + RS, FLCWK (middle dose), and no handling rats were used as the NH group. The differences in basic tension and ACh-induced tension of isolated colonic longitudinal smooth muscle strips (CLSMs) among the 3 groups were observed. In addition, different inhibitors (nifedipine, TMB-8, L-NAME, methylene blue, and 4-AP) were pretreated to explore the underlying mechanisms. Results In in vivo experiments, fecal characteristics, electromyographic response, and abdominal withdrawal reflex scores significantly improved in the FLCWK group, compared with the NMS + RS group. In in vitro experiments, the basic tension and ACh-induced tension of CLSMs in IBS-D rats were significantly inhibited by FLCWK. After pre-treatment with different inhibitors, the ACh-induced tension of CLSMs in each group showed no significant difference. Conclusions FLCWK manifested curative effect in IBS-D rats by inhibiting colonic contraction. The underlying mechanisms may be related to regulatory pathway of nitric oxide/cGMP/Ca2+ and specific potassium channels.
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Affiliation(s)
- Mengdi Jia
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China
| | - Xiaofang Lu
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China
| | - Zhengfang Wang
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China
| | - Luqing Zhao
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China
| | - Shengsheng Zhang
- Digestive Disease Center, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China
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Lee JM, Ong JR, Vergnes L, de Aguiar Vallim TQ, Nolan J, Cantor RM, Walters JRF, Reue K. Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants. J Lipid Res 2018; 59:429-438. [PMID: 29295820 DOI: 10.1194/jlr.m078279] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 12/29/2017] [Indexed: 01/12/2023] Open
Abstract
Diet1 modulates intestinal production of the hormone, fibroblast growth factor (FGF)15, which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1-null mutation are resistant to hypercholesterolemia compared with wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1-/- mice on the C57BL/6J genetic background. C57BL/6J Diet1-/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant (rs12256835) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions.
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Affiliation(s)
- Jessica M Lee
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA
| | - Jessica R Ong
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA
| | - Laurent Vergnes
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA
| | - Thomas Q de Aguiar Vallim
- Department of Biological Chemistry and Division of Cardiology, University of California, Los Angeles, Los Angeles, CA
| | - Jonathan Nolan
- Department of Medicine, Section of Hepatology and Gastroenterology, Imperial College London and Imperial College Healthcare, London, United Kingdom
| | - Rita M Cantor
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA
| | - Julian R F Walters
- Department of Medicine, Section of Hepatology and Gastroenterology, Imperial College London and Imperial College Healthcare, London, United Kingdom
| | - Karen Reue
- Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA .,David Geffen School of Medicine, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA
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13
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Chatoo M, Li Y, Ma Z, Coote J, Du J, Chen X. Involvement of Corticotropin-Releasing Factor and Receptors in Immune Cells in Irritable Bowel Syndrome. Front Endocrinol (Lausanne) 2018; 9:21. [PMID: 29483895 PMCID: PMC5816029 DOI: 10.3389/fendo.2018.00021] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/18/2018] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder defined by ROME IV criteria as pain in the lower abdominal region, which is associated with altered bowel habit or defecation. The underlying mechanism of IBS is not completely understood. IBS seems to be a product of interactions between various factors with genetics, dietary/intestinal microbiota, low-grade inflammation, and stress playing a key role in the pathogenesis of this disease. The crosstalk between the immune system and stress in IBS mechanism is increasingly recognized. Corticotropin-releasing factor (CRF), a major mediator in the stress response, is involved in altered function in GI, including inflammatory processes, colonic transit time, contractile activity, defecation pattern, pain threshold, mucosal secretory function, and barrier functions. This mini review focuses on the recently establish local GI-CRF system, its involvement in modulating the immune response in IBS, and summarizes current IBS animal models and mapping of CRF, CRFR1, and CRFR2 expression in colon tissues. CRF and receptors might be a key molecule involving the immune and movement function via brain-gut axis in IBS.
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Affiliation(s)
- Mahanand Chatoo
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yi Li
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhiqiang Ma
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
| | - John Coote
- School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom
| | - Jizeng Du
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Medical Neurobiology of the Ministry of Health, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Medical Neurobiology of Zhejiang Province, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xuequn Chen
- Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Medical Neurobiology of the Ministry of Health, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Medical Neurobiology of Zhejiang Province, Institute of Neuroscience, School of Medicine, Zhejiang University, Hangzhou, China
- *Correspondence: Xuequn Chen,
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14
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Tsigaridas A, Papanikolaou IS, Vaiopoulou A, Anagnostopoulos AK, Viazis N, Karamanolis G, Karamanolis DG, Tsangaris GT, Mantzaris GJ, Gazouli M. Proteomics and irritable bowel syndrome. Expert Rev Proteomics 2017; 14:461-468. [PMID: 28395553 DOI: 10.1080/14789450.2017.1317600] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Irritable bowel syndrome (IBS) is a gastrointestinal disease that according to Rome IV criteria is subdivided into four subtypes. The pathophysiology of this disease is not well understood due to numerous factors playing multiple roles in disease development, such as diet, stress and hormones. IBS has a variety of symptoms and overlaps with many other gastrointestinal and non-gastrointestinal diseases. Area covered: This review aims to present an overview of implementation of proteomics in experimental studies in the field of IBS. Expert commentary: Proteomics is commonly used for biomarker discovery in and has also been extensively used in IBS research. The necessity of a sensitive and specific biomarker for IBS is apparent, but despite the intensive research performed in this field, an appropriate biomarker is not yet available.
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Affiliation(s)
| | - Ioannis S Papanikolaou
- b Hepatogastroenterology Unit, Second Department of Internal Medicine and Research Institute, Attikon University General Hospital, Medical School , National and Kapodistrian University of Athens , Athens , Greece
| | - Anna Vaiopoulou
- c Department of Basic Medical Sciences, Laboratory of Biology Medical School , National and Kapodistrian University of Athens , Athens , Greece
| | | | - Nikos Viazis
- a Gastroenterology Unit , Evangelismos Hospital , Athens , Greece
| | - George Karamanolis
- e Gastroenterology Unit, 2nd Department of Surgery, 'Aretaieio' University Hospital, Medical School , National and Kapodistrian University of Athens , Athens , Greece
| | | | - George T Tsangaris
- d Proteomics Research Unit , Biomedical Research Foundation of the Academy of Athens (IIBEAA) , Athens , Greece
| | | | - Maria Gazouli
- c Department of Basic Medical Sciences, Laboratory of Biology Medical School , National and Kapodistrian University of Athens , Athens , Greece
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Abstract
PURPOSE OF REVIEW To summarize the recent findings. RECENT FINDINGS Studies of changes in the plasma levels confirm the earlier concepts, but offer little proof of causal effect. It is increasingly realized that peptides produced in the gut have a paracrine role or an indirect effect via the gut-brain axis. Interest in prokinetic peptide agonists remains high despite the failure of two candidate drugs, but relamorelin and camicinal offer new hope. SUMMARY We review the original studies published since January 2013 on peptides produced in the gut and with an effect on gastrointestinal motility.
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Affiliation(s)
- Theo L Peeters
- Gut Peptide Laboratory, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium
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Chang FY. Irritable bowel syndrome: The evolution of multi-dimensional looking and multidisciplinary treatments. World J Gastroenterol 2014; 20:2499-2514. [PMID: 24627587 PMCID: PMC3949260 DOI: 10.3748/wjg.v20.i10.2499] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Revised: 10/16/2013] [Accepted: 01/02/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is common in the society. Among the putative pathogeneses, gut dysmotility results in pain and disturbed defecation. The latter is probably caused by the effect of abnormal gut water secretion. The interaction between abnormal gas accumulation, abdominal pain and bloating remains controversial. Visceral hypersensitivity and its modification along with the central transmission are the characteristics of IBS patients. The identification of biologic markers based on genetic polymorphisms is undetermined. Imbalanced gut microbiota may alter epithelial permeability to activate nociceptive sensory pathways which in turn lead to IBS. Certain food constituents may exacerbate bowel symptoms. The impact of adult and childhood abuses on IBS is underestimated. Using the concept of biopsychosocial dysfunction can integrate multidimensional pathogeneses. Antispasmodics plus stool consistency modifiers to treat the major symptoms and defecation are the first-line drug treatment. New drugs targeting receptors governing bowel motility, sensation and secretion can be considered, but clinicians must be aware of their potential serious side effects. Psychiatric drugs and modalities may be the final options for treating intractable subjects. Probiotics of multi-species preparations are safe and worth to be considered for the treatment. Antibiotics are promising but their long-term safety and effectiveness are unknown. Diet therapy including exclusion of certain food constituents is an economic measure. Using relatively safe complementary and alternative medicines (CAMs) may be optional to those patients who failed classical treatment. In conclusion, IBS is a heterogeneous disorder with multidimensional pathogeneses. Personalized medicines with multidisciplinary approaches using different classes of drugs, psychiatric measures, probiotics and antibiotics, dietary therapy, and finally CAMs, can be considered.
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Abstract
PURPOSE OF REVIEW To critically evaluate recent advances in the anatomy and physiology of colorectal motility and sensation and to discuss their potential clinical implications. RECENT FINDINGS Relatively noninvasive methods for the assessment of colonic transit have been developed and validated and high-resolution colonic and anorectal manometry as well as the barostat, despite their technical challenges, are beginning to show promise in clinical practice. At a more basic level, the importance of interstitial cells of Cajal as pacemakers, neuromodulators and stretch receptors has been revealed and their dysfunction associated with a number of disease states. Although the impact of a variety of biologically active agents on colonic sensorineural function in vitro has been described, the clinical implications of most of these effects remain unknown at this time. As the molecular bases of colonic motor and sensory function are identified, new disease entities are being described and novel therapeutic targets revealed. Equally important is the growing recognition of luminal factors and of the colonic microbiota, in particular, in the generation and modulation of colonic motility and sensation. SUMMARY The complexities of the basic physiology of colorectal motility and sensation continue to be revealed and our understanding of their regulation has progressed; clinical implications remain at a preliminary stage. Progress has been made, however, in the clinical assessment of colonic motor function.
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