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Sulaimi F, Ong TSK, Tang ASP, Quek J, Pillay RM, Low DT, Lee CKL, Siah KTH, Ng QX. Risk factors for developing irritable bowel syndrome: systematic umbrella review of reviews. BMC Med 2025; 23:103. [PMID: 39985070 PMCID: PMC11846330 DOI: 10.1186/s12916-025-03930-5] [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: 06/29/2024] [Accepted: 02/06/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a debilitating disorder affecting 4-9% of the global population. It is a multifaceted disorder with complex and varied causes. This review aims to consolidate the evidence regarding IBS risk factors by examining existing systematic reviews and meta-analyses, covering potential genetic, immunological, psychological, and dietary causes. METHODS Systematic literature searches were conducted in MEDLINE, Embase and Cochrane library databases. Study selection and data extraction were conducted independently by four authors, with discrepancies resolved by consensus with a senior author. Systematic reviews examining risk factors of IBS development were eligible for review. Results were narratively synthesized. Quality of reviews were analysed using AMSTAR 2, and evidence were appraised using GRADE methodology. RESULTS A total of 69 systematic reviews were included in this study. Most reviews were of "critically low" quality, while the remaining were "low" quality. Common shortcomings included the absence of a list of excluded studies with justifications for their exclusion and inadequate consideration of the risk of bias in individual studies. Eight major categories of risk factors for IBS identified were as follows: dietary, genetic, environmental, psychological, gut microbiome, socio-economic, physiological, and pathological, albeit overlaps exist. The most frequently reported risk factors for IBS development were female gender and anxiety disorders, with overall GRADE evaluation of "low"; depression and gastroenteritis, with overall GRADE evaluation of "moderate". CONCLUSIONS Clinical practice should prioritize recognition of these risk factors. Future reviews should improve their reporting of results based on the PRISMA guidelines, to enhance the quality of research in this field. PROTOCOL REGISTRATION PROSPERO CRD42023493739.
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Affiliation(s)
- Farisah Sulaimi
- School of Medical Sciences, Wallace Wurth Building, University of New South Wales, Sydney, NSW, Australia
| | - Timothy Sheng Khai Ong
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ansel Shao Pin Tang
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jingxuan Quek
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Renish M Pillay
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Damien Tianle Low
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Charisse Kai Ling Lee
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Kewin Tien Ho Siah
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology & Hepatology, University Medicine Cluster, National University Hospital, Singapore, Singapore
| | - Qin Xiang Ng
- NUS Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
- SingHealth Duke-NUS Global Health Institute, Duke-NUS Medical School, Singapore, Singapore.
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García Mansilla MJ, Rodríguez Sojo MJ, Lista AR, Ayala Mosqueda CV, Ruiz Malagón AJ, Gálvez J, Rodríguez Nogales A, Rodríguez Sánchez MJ. Exploring Gut Microbiota Imbalance in Irritable Bowel Syndrome: Potential Therapeutic Effects of Probiotics and Their Metabolites. Nutrients 2024; 17:155. [PMID: 39796588 PMCID: PMC11723002 DOI: 10.3390/nu17010155] [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: 12/04/2024] [Revised: 12/24/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025] Open
Abstract
Irritable bowel syndrome is a common functional gastrointestinal disorder characterized by recurrent abdominal discomfort, bloating, cramping, flatulence, and changes in bowel movements. The pathophysiology of IBS involves a complex interaction between motor, sensory, microbiological, immunological, and psychological factors. Diversity, stability, and metabolic activity of the gut microbiota are frequently altered in IBS, thus leading to a situation of gut dysbiosis. Therefore, the use of probiotics and probiotic-derived metabolites may be helpful in balancing the gut microbiota and alleviating irritable bowel syndrome symptoms. This review aimed to report and consolidate recent progress in understanding the role of gut dysbiosis in the pathophysiology of IBS, as well as the current studies that have focused on the use of probiotics and their metabolites, providing a foundation for their potential beneficial effects as a complementary and alternative therapeutic strategy for this condition due to the current absence of effective and safe treatments.
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Affiliation(s)
- María José García Mansilla
- Department of Pharmacology, Centro de investigación Biomédica (CIBM), University of Granada, 18071 Granada, Spain; (M.J.G.M.); (M.J.R.S.); (J.G.); (A.R.N.); (M.J.R.S.)
| | - María Jesús Rodríguez Sojo
- Department of Pharmacology, Centro de investigación Biomédica (CIBM), University of Granada, 18071 Granada, Spain; (M.J.G.M.); (M.J.R.S.); (J.G.); (A.R.N.); (M.J.R.S.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; (A.R.L.); (C.V.A.M.)
| | - Andrea Roxana Lista
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; (A.R.L.); (C.V.A.M.)
| | | | - Antonio Jesús Ruiz Malagón
- Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Málaga, Spain
| | - Julio Gálvez
- Department of Pharmacology, Centro de investigación Biomédica (CIBM), University of Granada, 18071 Granada, Spain; (M.J.G.M.); (M.J.R.S.); (J.G.); (A.R.N.); (M.J.R.S.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; (A.R.L.); (C.V.A.M.)
- CIBER de Enfermedades Hepáticas y Digestivas (CIBER-EHD), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Alba Rodríguez Nogales
- Department of Pharmacology, Centro de investigación Biomédica (CIBM), University of Granada, 18071 Granada, Spain; (M.J.G.M.); (M.J.R.S.); (J.G.); (A.R.N.); (M.J.R.S.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; (A.R.L.); (C.V.A.M.)
| | - María José Rodríguez Sánchez
- Department of Pharmacology, Centro de investigación Biomédica (CIBM), University of Granada, 18071 Granada, Spain; (M.J.G.M.); (M.J.R.S.); (J.G.); (A.R.N.); (M.J.R.S.)
- Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain; (A.R.L.); (C.V.A.M.)
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Pastras P, Aggeletopoulou I, Triantos C. Impact of Enteric Nervous Cells on Irritable Bowel Syndrome: Potential Treatment Options. Microorganisms 2024; 12:2036. [PMID: 39458345 PMCID: PMC11510338 DOI: 10.3390/microorganisms12102036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/04/2024] [Accepted: 10/05/2024] [Indexed: 10/28/2024] Open
Abstract
Irritable bowel syndrome (IBS) is a condition that significantly impacts the lifestyle, health, and habits of numerous individuals worldwide. Its diagnosis and classification are based on the Rome criteria, updated periodically to reflect new research findings in this field. IBS can be classified into different types based on symptoms, each with distinct treatment approaches and some differences in their pathophysiology. The exact pathological background of IBS remains unclear, with many aspects still unknown. Recent research developments suggest that disorders in the brain-gut-microbiota axis are key contributors to the symptoms and severity of IBS. The central nervous system (CNS) interacts bidirectionally with intestinal processes within the lumen and the intestinal wall, with the autonomic nervous system, particularly the vagus nerve, playing an important role. However, the enteric nervous system (ENS) is also crucial in the pathophysiological pathway of IBS. The apeline-corticotropin-releasing factor (CRF)-toll-like receptor 4 (TLR4) signaling route via enteric glia and serotonin production in enteroendocrine cells at the enteric barrier are among the most well-understood new findings that affect IBS through the ENS. Additionally, the microbiota regulates neuronal signals, modifying enteric function by altering the number of enteric bacteria and other mechanisms. Given the limited therapeutic options currently available, it is essential to identify new treatment targets, with the brain-gut axis, particularly the enteric nervous system, being a promising focus. This study aims to delineate the molecular mechanisms that induce IBS and to suggest potential targets for future research and treatment of this potentially debilitating disease.
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Affiliation(s)
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, 26504 Patras, Greece; (P.P.); (C.T.)
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Trush EA, Karchevskaya AE, Maslennikov RV, Poluektova EA, Shifrin OS, Ivashkin VT. Single Nucleotide Polymorphisms, Associated with Increased Risk of Irritable Bowel Syndrome with Predominant Constipation: A Meta Analysis. RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 34:62-77. [DOI: 10.22416/1382-4376-2024-34-3-62-77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
Introduction. Genetic predisposition in combination with environmental factors and the patient’s psychological and emotional state play a key role in the development of irritable bowel syndrome (IBS). Studies of association between genetic polymorphisms and IBS can help in understanding the key pathophysiological mechanisms. To date, 11 meta-analyses on this issue have been published, however, none of them comprehensively summarize the data on the prevalence of genetic polymorphisms in IBS with predominant constipation (IBS-C).Aim: to summarize the published data on the impact of genetic polymorphisms on the risk of IBS-C.Materials and methods. A literature search was performed in the PubMed and Scopus databases. Identified studies were used for a meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Publications investigating genetic polymorphisms in patients with IBS-C were included in this analysis.Results. A total of 34 studies met the inclusion criteria. The collected data were sufficient to conduct a meta-analysis on polymorphisms of three of the listed genes: SLC6A4 (10 articles), GNB3 (5 articles), ADRA2A (4 articles). No significant association was found between the SLC6A4 (5-HTTLPR) polymorphism, GNB3 c.825C > T (rs5443) polymorphism and either IBS or IBS-C. It was found that ADRA2A 1291C>G polymorphism was significantly associated with both IBS and IBS-C.Conclusions. Our meta-analysis revealed that ADRA2A 1291C>G polymorphism was significantly associated with both IBS and IBS-C in the mixed population. Neither homozygous nor heterozygous variants of the SLC6A4 (5-HTTLPR) polymorphism and GNB3 C825T polymorphism were associated with either IBS-C or IBS as a whole.
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Affiliation(s)
- E. A. Trush
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - A. E. Karchevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - R. V. Maslennikov
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - E. A. Poluektova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. S. Shifrin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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Camilleri M, Jencks K. Pharmacogenetics in IBS: update and impact of GWAS studies in drug targets and metabolism. Expert Opin Drug Metab Toxicol 2024; 20:319-332. [PMID: 38785066 PMCID: PMC11139426 DOI: 10.1080/17425255.2024.2349716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 04/26/2024] [Indexed: 05/25/2024]
Abstract
INTRODUCTION Medications are frequently prescribed for patients with irritable bowel syndrome (IBS) or disorders of gut brain interaction. The level of drug metabolism and modifications in drug targets determine medication efficacy to modify motor or sensory function as well as patient response outcomes. AREAS COVERED The literature search included PubMed searches with the terms: pharmacokinetics, pharmacogenomics, epigenetics, clinical trials, irritable bowel syndrome, disorders of gut brain interaction, and genome-wide association studies. The main topics covered in relation to irritable bowel syndrome were precision medicine, pharmacogenomics related to drug metabolism, pharmacogenomics related to mechanistic targets, and epigenetics. EXPERT OPINION Pharmacogenomics impacting drug metabolism [CYP 2D6 (cytochrome P450 2D6) or 2C19 (cytochrome P450 2C19)] is the most practical approach to precision medicine in the treatment of IBS. Although there are proof of concept studies that have documented the importance of genetic modification of transmitters or receptors in altering responses to medications in IBS, these principles have rarely been applied in patient response outcomes. Genome-wide association (GWAS) studies have now documented the association of symptoms with genetic variation but not the evaluation of treatment responses. Considerably more research, particularly focused on patient response outcomes and epigenetics, is essential to impact this field in clinical medicine.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Kara Jencks
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Marginean CM, Popescu M, Drocas AI, Cazacu SM, Mitrut R, Marginean IC, Iacob GA, Popescu MS, Docea AO, Mitrut P. Gut–Brain Axis, Microbiota and Probiotics—Current Knowledge on Their Role in Irritable Bowel Syndrome: A Review. GASTROINTESTINAL DISORDERS 2023; 5:517-535. [DOI: 10.3390/gidisord5040043] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
Irritable bowel syndrome (IBS) is a common digestive disorder with a significant impact on both individuals and society in terms of quality of life and healthcare costs. A growing body of research has identified various communication pathways between the microbiota and the brain in relation to motility disorders, with the gut–brain axis being key to the pathogenesis of IBS. Multiple factors contribute to the pathogenetic pathways in IBS, including immune mechanisms, psychosocial factors, increased oxidative stress and pro-inflammatory cytokine release, as well as genetic and hormonal factors. Increased permeability of the normal intestinal barrier allows bacterial products to access the lamina propria, providing a mechanism for perpetuating chronic inflammation and characteristic symptoms. The microbiota influences inflammatory processes in IBS by altering the balance between pro-inflammatory factors and host defence. Probiotics modulate the pathophysiological mechanisms involved in IBS by influencing the composition of the microbiota and improving intestinal motility disorders, visceral hypersensitivity, immune function of the intestinal epithelium, metabolic processes in the intestinal lumen, dysfunction of the microbiota-GBA, and are recognised as effective and safe in IBS therapy. Our study aimed to provide a comprehensive overview of the relationship between the gut–brain axis, microbiota, and IBS, based on current information.
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Affiliation(s)
- Cristina Maria Marginean
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mihaela Popescu
- Department of Endocrinology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Andrei Ioan Drocas
- Department of Urology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Sergiu Marian Cazacu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Radu Mitrut
- Department of Cardiology, University and Emergency Hospital, 050098 Bucharest, Romania
| | | | - George Alexandru Iacob
- Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Marian Sorin Popescu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Anca Oana Docea
- Department of Toxicology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Paul Mitrut
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
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Di Nardo G, Cremon C, Staiano A, Stanghellini V, Borrelli O, Strisciuglio C, Romano C, Mallardo S, Scarpato E, Marasco G, Salvatore S, Zenzeri L, Felici E, Pensabene L, Sestito S, Francavilla R, Quitadamo P, Baldassarre M, Giorgio V, Tambucci R, Ziparo C, Parisi P, Barbaro MR, Barbara G. Role of inflammation in pediatric irritable bowel syndrome. Neurogastroenterol Motil 2023; 35:e14365. [PMID: 35340083 DOI: 10.1111/nmo.14365] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 02/09/2022] [Accepted: 03/15/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND IBS affects a large number of children throughout the world and is thought to be the result of disturbed neuroimmune function along with the brain-gut axis. Although the underlying pathophysiologic mechanisms are not clear, the role of low-grade inflammation and mucosal immune activation in IBS symptom generation has become evident also in subsets of pediatric patients. Animal models provided meaningful insight in the causal relationship between abnormal mucosal immune activation and changes in gastrointestinal (GI) sensory-motor function. Likewise, the development of long-standing GI symptoms fulfilling the current criteria for functional GI disorders after infection gastroenteritis and in patients with IBD or celiac disease in remission further supports this hypothesis. Immune activation, its impact on gut sensory-motor function, and potential implications for symptom generation emerged in both children and adults with IBS. PURPOSE The aim of this review is to summarize the main evidence on the presence of low-grade inflammation and immune activation in children with IBS, its possible role in symptom generation, and its potential implication for new therapeutic strategies.
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Affiliation(s)
- Giovanni Di Nardo
- NESMOS Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Cesare Cremon
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Annamaria Staiano
- Department of Translational Medical Science, "Federico II", University of Naples, Naples, Italy
| | | | - Osvaldo Borrelli
- Division of Neurogastroenterology and Motility, Department of Paediatric Gastroenterology, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialistic Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Claudio Romano
- Pediatric Gastroenterology Unit, Department of Human Pathology in Adulthood and Childhood "G. Barresi", University of Messina, Messina, Italy
| | - Saverio Mallardo
- Pediatric Department, Santa Maria Goretti Hospital, Sapienza University of Rome, Latina, Italy
| | - Elena Scarpato
- Department of Translational Medical Science, "Federico II", University of Naples, Naples, Italy
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Silvia Salvatore
- Pediatric Department, Ospedale "F. Del Ponte", University of Insubria, Varese, Italy
| | - Letizia Zenzeri
- NESMOS Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
- Pediatric Emergency Unit, Santobono-Pausilipon Children's Hospital, Naples, Italy
| | - Enrico Felici
- Pediatric and Pediatric Emergency Unit, "Umberto Bosio" Center for Digestive Diseases, The Children Hospital, AO SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
| | - Licia Pensabene
- Department of Medical and Surgical Sciences, Pediatric Unit, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Simona Sestito
- Department of Medical and Surgical Sciences, Pediatric Unit, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Ruggiero Francavilla
- Pediatric Section, Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Paolo Quitadamo
- Department of Pediatrics, A.O.R.N. Santobono-Pausilipon, Naples, Italy
| | - Mariella Baldassarre
- Neonatology and Neonatal Intensive Care Unit, Department of Biomedical Science and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | | | - Renato Tambucci
- Digestive Endoscopy and Surgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Chiara Ziparo
- NESMOS Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | - Pasquale Parisi
- NESMOS Department, Faculty of Medicine and Psychology, Sant'Andrea University Hospital, Sapienza University of Rome, Rome, Italy
| | | | - Giovanni Barbara
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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Fritz N, Berens S, Dong Y, Martínez C, Schmitteckert S, Houghton LA, Goebel-Stengel M, Wahl V, Kabisch M, Götze D, D’Amato M, Zheng T, Röth R, Mönnikes H, Tesarz J, Engel F, Gauss A, Raithel M, Andresen V, Keller J, Frieling T, Pehl C, Stein-Thöringer C, Clarke G, Kennedy PJ, Cryan JF, Dinan TG, Quigley EMM, Spiller R, Beltrán C, Madrid AM, Torres V, Mayer EA, Sayuk G, Gazouli M, Karamanolis G, Bustamante M, Estivil X, Rabionet R, Hoffmann P, Nöthen MM, Heilmann-Heimbach S, Schmidt B, Franke A, Lieb W, Herzog W, Boeckxstaens G, Wouters MM, Simrén M, Rappold GA, Vicario M, Santos J, Schaefert R, Lorenzo-Bermejo J, Niesler B. The serotonin receptor 3E variant is a risk factor for female IBS-D. J Mol Med (Berl) 2022; 100:1617-1627. [PMID: 36121467 PMCID: PMC9592668 DOI: 10.1007/s00109-022-02244-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/18/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022]
Abstract
Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.
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Affiliation(s)
- Nikola Fritz
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Sabrina Berens
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Yuanjun Dong
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Cristina Martínez
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.420395.90000 0004 0425 020XInstitut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain ,Lleida Institute for Biomedical Research Dr, Pifarré Foundation (IRBLleida), Lleida, Spain
| | - Stefanie Schmitteckert
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Lesley A. Houghton
- grid.443984.60000 0000 8813 7132University of Leeds, St. James’s University Hospital, Leeds, UK ,grid.417467.70000 0004 0443 9942Mayo Clinic, Jacksonville, FL USA
| | - Miriam Goebel-Stengel
- grid.411544.10000 0001 0196 8249Department of Psychosomatic Medicine, University Hospital Tübingen, Tübingen, Germany ,Department of Internal Medicine and Gastroenterology, HELIOS Clinic Rottweil, Rottweil, Germany
| | - Verena Wahl
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Maria Kabisch
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Dorothea Götze
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Mauro D’Amato
- grid.4714.60000 0004 1937 0626Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden ,grid.420175.50000 0004 0639 2420Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Bilbao, Derio Spain ,grid.424810.b0000 0004 0467 2314IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Tenghao Zheng
- grid.4714.60000 0004 1937 0626Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ralph Röth
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.5253.10000 0001 0328 4908nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Hubert Mönnikes
- grid.461755.40000 0004 0581 3852Martin-Luther-Hospital, Berlin, Germany
| | - Jonas Tesarz
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Felicitas Engel
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Annika Gauss
- grid.7700.00000 0001 2190 4373Department of Gastroenterology, Infectious Diseases and Intoxications, Heidelberg University, Heidelberg, Germany
| | - Martin Raithel
- grid.5330.50000 0001 2107 3311University of Erlangen, Erlangen, Germany
| | - Viola Andresen
- grid.414844.90000 0004 0436 8670Israelitisches Krankenhaus, Hamburg, Germany
| | - Jutta Keller
- grid.414844.90000 0004 0436 8670Israelitisches Krankenhaus, Hamburg, Germany
| | | | | | | | - Gerard Clarke
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Paul J. Kennedy
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - John F. Cryan
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Eamonn M. M. Quigley
- grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland ,grid.63368.380000 0004 0445 0041Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX USA
| | - Robin Spiller
- grid.4563.40000 0004 1936 8868Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Caroll Beltrán
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Ana María Madrid
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Verónica Torres
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Emeran A. Mayer
- grid.19006.3e0000 0000 9632 6718Oppenheimer Center for Neurobiology of Stress, University of California, Los Angeles, CA USA
| | - Gregory Sayuk
- grid.4367.60000 0001 2355 7002Washington University School of Medicine, St. Louis, MO USA
| | - Maria Gazouli
- grid.5216.00000 0001 2155 0800Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George Karamanolis
- grid.5216.00000 0001 2155 0800Academic Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Mariona Bustamante
- grid.11478.3b0000 0004 1766 3695CRG, Centre for Genomic Regulation, Barcelona, Spain ,grid.434607.20000 0004 1763 3517ISGlobal, Barcelona, Spain
| | - Xavier Estivil
- grid.5841.80000 0004 1937 0247Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain
| | - Raquel Rabionet
- grid.5841.80000 0004 1937 0247Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain
| | - Per Hoffmann
- grid.435715.10000 0004 0436 7643Life and Brain Center, Bonn, Germany
| | - Markus M. Nöthen
- grid.435715.10000 0004 0436 7643Life and Brain Center, Bonn, Germany
| | | | - Börge Schmidt
- grid.410718.b0000 0001 0262 7331Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
| | - André Franke
- Institute of Clinical Molecular Biology, Kiel, Germany
| | - Wolfgang Lieb
- grid.417834.dInstitute of Epidemiology, Kiel, Germany
| | - Wolfgang Herzog
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Guy Boeckxstaens
- grid.410569.f0000 0004 0626 3338TARGID, University Hospital Leuven, Louvain, Belgium
| | - Mira M. Wouters
- grid.410569.f0000 0004 0626 3338TARGID, University Hospital Leuven, Louvain, Belgium
| | - Magnus Simrén
- grid.8761.80000 0000 9919 9582Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Gudrun A. Rappold
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
| | - Maria Vicario
- grid.411083.f0000 0001 0675 8654Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain ,grid.419905.00000 0001 0066 4948Nestlé Institute of Health Sciences, Nestlé Research, Société Des Produits Nestlé S.A, Vers-chez-les-Blanc, Lausanne, Switzerland
| | - Javier Santos
- grid.411083.f0000 0001 0675 8654Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain
| | - Rainer Schaefert
- grid.410567.1Department of Psychosomatic Medicine, Division of Theragnostics, University Hospital Basel, Basel, Switzerland ,grid.6612.30000 0004 1937 0642Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Justo Lorenzo-Bermejo
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Beate Niesler
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.5253.10000 0001 0328 4908nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
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9
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The Associations of Single Nucleotide Polymorphisms with Risk and Symptoms of Irritable Bowel Syndrome. J Pers Med 2022; 12:jpm12020142. [PMID: 35207633 PMCID: PMC8878682 DOI: 10.3390/jpm12020142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/10/2022] [Accepted: 01/17/2022] [Indexed: 12/12/2022] Open
Abstract
Although several risk single nucleotide polymorphisms (SNPs) have been found to play an important role in etiology of irritable bowel syndrome (IBS), the findings are inconsistent. A descriptive correlational design was used to analyze the baseline data of a randomized controlled trial including participants with IBS and healthy controls (HC). Pain severity and interference, anxiety, sleep, and fatigue were measured using the Brief Pain Inventory (BPI) and patient-reported outcomes measurement information system (PROMIS). Fisher’s exact test and multivariate linear regression were used to investigate the associations between IBS risk alleles and IBS symptoms. Participants were predominantly female, white, and had an average age of 21.13 ± 2.42 years. Polymorphisms within TNFSF15 (rs4263839), SLC6A4 5-HTTLPR, HTR3A (rs1062613), and OXTR (rs2254298) were associated with IBS risk, and TNFSF15 (rs4263839), COMT (rs6269), SLC6A4 5-HTTLPR polymorphisms were associated with pain severity. TNFSF15 (rs4263839) and COMT (rs4680; rs4633) genotypes were associated with sleep disturbance, and the ADRA1D SNP rs1556832 was associated with fatigue in both IBS and HC groups. Genotypic differences were associated with IBS risk and symptoms including abdominal pain, sleep disturbance, and fatigue. Further investigation is warranted to reveal the mechanisms by which these genetic variations influence the dynamic nature of IBS symptoms over time.
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10
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Tang HY, Jiang AJ, Wang XY, Wang H, Guan YY, Li F, Shen GM. Uncovering the pathophysiology of irritable bowel syndrome by exploring the gut-brain axis: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1187. [PMID: 34430628 PMCID: PMC8350700 DOI: 10.21037/atm-21-2779] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022]
Abstract
Objective To improve the pathophysiological understanding of irritable bowel syndrome (IBS) by exploring the gut-brain axis. Background Disorders of gut-brain interaction (DGBIs) are gastrointestinal (GI) disorders in which alterations in bowel functions occur. IBS, which is one of the most studied DGBIs, is linked with abdominal distress or pain without obvious structural or biochemical anomalies. Methods The etiology of IBS has not been clearly described but is known to be multifactorial, involving GI motility changes, post-infectious reactivity, visceral hypersensitivity, gut-brain interactions, microbiota dysbiosis, small intestinal bacterial overgrowth, food sensitivity, carbohydrate malabsorption, and intestinal inflammation. Conclusions One of the main features of IBS is the occurrence of structural and functional disruptions in the gut-brain axis, which alter reflective and perceptual nervous system reactions. Herein, we provide a brief summary of this topic. Furthermore, we discuss animal models, which are important in the study of IBS, especially as it is linked with stressors. These animal models cannot fully represent the human disease but serve as important tools for understanding this complicated disorder. In the future, technologies, such as organ-on-a-chip models and metabolomics, will provide novel information regarding the pathophysiology of IBS, which will play an important role in treatment development. Finally, we take a brief glance at how acupuncture treatments may hold potential for patients with IBS.
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Affiliation(s)
- He-Yong Tang
- Graduate School of Anhui University of Chinese Medicine, Hefei, China
| | - Ai-Juan Jiang
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Xi-Yang Wang
- Graduate School of Anhui University of Chinese Medicine, Hefei, China
| | - Hao Wang
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Yuan-Yuan Guan
- Department of Acupuncture and Moxibustion, The First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Fei Li
- Department of Rehabilitation, Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Guo-Ming Shen
- School of Integrated Traditional Chinese and Western Medicine, Anhui University of Traditional Chinese Medicine, Hefei, China
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11
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Mohr S, Fritz N, Hammer C, Martínez C, Berens S, Schmitteckert S, Wahl V, Schmidt M, Houghton LA, Goebel‐Stengel M, Kabisch M, Götze D, Milovač I, D’Amato M, Zheng T, Röth R, Mönnikes H, Engel F, Gauss A, Tesarz J, Raithel M, Andresen V, Frieling T, Keller J, Pehl C, Stein‐Thöringer C, Clarke G, Kennedy PJ, Cryan JF, Dinan TG, Quigley EMM, Spiller R, Beltrán C, Madrid AM, Torres V, Pérez de Arce E, Herzog W, Mayer EA, Sayuk G, Gazouli M, Karamanolis G, Kapur‐Pojskič L, Bustamante M, Rabionet R, Estivil X, Franke A, Lieb W, Boeckxstaens G, Wouters MM, Simrén M, Rappold GA, Vicario M, Santos J, Schaefert R, Lorenzo‐Bermejo J, Niesler B. The alternative serotonin transporter promoter P2 impacts gene function in females with irritable bowel syndrome. J Cell Mol Med 2021; 25:8047-8061. [PMID: 34165249 PMCID: PMC8358858 DOI: 10.1111/jcmm.16736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/20/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a gut-brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation-predominant IBS (IBS-C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta-analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS-C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow-up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS-C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.
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12
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Vasant DH, Paine PA, Black CJ, Houghton LA, Everitt HA, Corsetti M, Agrawal A, Aziz I, Farmer AD, Eugenicos MP, Moss-Morris R, Yiannakou Y, Ford AC. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut 2021; 70:1214-1240. [PMID: 33903147 DOI: 10.1136/gutjnl-2021-324598] [Citation(s) in RCA: 267] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 03/30/2021] [Accepted: 04/06/2021] [Indexed: 12/11/2022]
Abstract
Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.
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Affiliation(s)
- Dipesh H Vasant
- Neurogastroenterology Unit, Gastroenterology, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.,Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
| | - Peter A Paine
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK.,Gastroenterology, Salford Royal Foundation Trust, Salford, UK
| | - Christopher J Black
- Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK.,Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Lesley A Houghton
- Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.,Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida, USA
| | - Hazel A Everitt
- Primary Care and Population Sciences, University of Southampton, Southampton, UK
| | - Maura Corsetti
- Nottingham Digestive Diseases Biomedical Research Unit, University of Nottingham, Nottingham, UK
| | - Anurag Agrawal
- Gastroenterology, Doncaster and Bassetlaw Hospitals NHS Trust, Armthorpe Road, Doncaster, UK
| | - Imran Aziz
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.,Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
| | - Adam D Farmer
- Department of Gastroenterology, University Hospitals of North Midlands NHS Trust, Stoke-on-Trent, UK.,School of Medicine, Keele University, Keele, UK
| | - Maria P Eugenicos
- Department of Gastroenterology, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Rona Moss-Morris
- Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Yan Yiannakou
- Department of Gastroenterology, County Durham and Darlington NHS Foundation Trust, Durham, UK
| | - Alexander C Ford
- Leeds Gastroenterology Institute, Leeds Teaching Hospitals NHS Trust, Leeds, UK .,Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
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13
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Fukudo S, Okumura T, Inamori M, Okuyama Y, Kanazawa M, Kamiya T, Sato K, Shiotani A, Naito Y, Fujikawa Y, Hokari R, Masaoka T, Fujimoto K, Kaneko H, Torii A, Matsueda K, Miwa H, Enomoto N, Shimosegawa T, Koike K. Evidence-based clinical practice guidelines for irritable bowel syndrome 2020. J Gastroenterol 2021; 56:193-217. [PMID: 33538894 PMCID: PMC7932982 DOI: 10.1007/s00535-020-01746-z] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.
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Affiliation(s)
- Shin Fukudo
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan.
- Department of Behavioral Medicine Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
| | - Toshikatsu Okumura
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Masahiko Inamori
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yusuke Okuyama
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Motoyori Kanazawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Takeshi Kamiya
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ken Sato
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akiko Shiotani
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yuji Naito
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Yoshiko Fujikawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Ryota Hokari
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tastuhiro Masaoka
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuma Fujimoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroshi Kaneko
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Akira Torii
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kei Matsueda
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Nobuyuki Enomoto
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
| | - Kazuhiko Koike
- Guidelines Committee for Creating and Evaluating the "Evidence-Based Clinical Practice Guidelines for Irritable Bowel Syndrome", The Japanese Society of Gastroenterology, 6F Shimbashi i-MARK Building, 2-6-2 Shimbashi, Minato-ku, Tokyo, 105-0004, Japan
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14
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Ledergerber M, Lang BM, Heinrich H, Biedermann L, Begré S, Zeitz J, Krupka N, Rickenbacher A, Turina M, Greuter T, Schreiner P, Roth R, Siebenhüner A, Vavricka SR, Rogler G, Beerenwinkel N, Misselwitz B. Abdominal pain in patients with inflammatory bowel disease: association with single-nucleotide polymorphisms prevalent in irritable bowel syndrome and clinical management. BMC Gastroenterol 2021; 21:53. [PMID: 33546600 PMCID: PMC7866750 DOI: 10.1186/s12876-021-01622-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 01/20/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Abdominal pain is a frequent symptom in patients with inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Pain can result from ongoing inflammation or functional disorders imitating irritable bowel syndrome (IBS). Several single-nucleotide polymorphisms (SNPs) have been associated with IBS. However, the impact of IBS genetics on the clinical course of IBD, especially pain levels of patients remains unclear. METHODS Data of 857 UC and 1206 CD patients from the Swiss IBD Cohort Study were analysed. We tested the association of the maximum of the abdominal pain item of disease activity indices in UC and CD over the study period with 16 IBS-associated SNPs, using multivariate ANOVA models. RESULTS In UC patients, the SNPs rs1042713 (located on the ADRB2 gene) and rs4663866 (close to the HES6 gene) were associated with higher abdominal pain levels (P = 0.044; P = 0.037, respectively). Abdominal pain was not associated with any markers of patient management in a model adjusted for confounders. In CD patients, higher levels of abdominal pain correlated with the number of physician contacts (P < 10-15), examinations (P < 10-12), medical therapies (P = 0.023) and weeks of hospitalisation (P = 0.0013) in a multivariate model. CONCLUSIONS We detected an association between maximal abdominal pain in UC patients and two IBS-associated SNPs. Abdominal pain levels had a pronounced impact on diagnostic and therapeutic procedures in CD but not in UC patients.
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Affiliation(s)
- Martina Ledergerber
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - Brian M Lang
- Department of Biosystems Science and Engineering, ETH Basel, Basel, Switzerland.,SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Henriette Heinrich
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - Stefan Begré
- Department of Biomedical Research, Neurology, Inselspital and University Clinic of Bern, Bern, Switzerland
| | - Jonas Zeitz
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland.,Center of Gastroenterology, Clinic Hirslanden, Zurich, Switzerland
| | - Niklas Krupka
- Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, Bern, Switzerland
| | - Andreas Rickenbacher
- Department of Visceral Surgery, University Hospital Zurich (USZ), Zurich, Switzerland
| | - Matthias Turina
- Department of Visceral Surgery, University Hospital Zurich (USZ), Zurich, Switzerland
| | - Thomas Greuter
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - Philipp Schreiner
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - René Roth
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - Alexander Siebenhüner
- Department of Oncology, Center of Hematology and Oncology University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - Stephan R Vavricka
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland
| | - Niko Beerenwinkel
- Department of Biosystems Science and Engineering, ETH Basel, Basel, Switzerland.,SIB Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Benjamin Misselwitz
- Department of Gastroenterology, University Hospital Zurich (USZ), Zurich University, Zurich, Switzerland. .,Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, Bern, Switzerland.
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15
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Szałwińska P, Włodarczyk J, Spinelli A, Fichna J, Włodarczyk M. IBS-Symptoms in IBD Patients-Manifestation of Concomitant or Different Entities. J Clin Med 2020; 10:jcm10010031. [PMID: 33374388 PMCID: PMC7794700 DOI: 10.3390/jcm10010031] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 12/14/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a functional heterogenous disease with a multifactorial pathogenesis. It is characterized by abdominal pain, discomfort, and alteration in gut motility. The occurrence of similar symptoms was observed in patients in clinical remission of inflammatory bowel diseases (IBD) that is Crohn's disease (CD) and ulcerative colitis (UC), which pathogenesis is also not fully understood. Hence, arose the question if these symptoms are "true IBS" imposed on IBD, or is it a subclinical form of IBD or even pre-IBD? In this article, based on a narrative overview of the literature, we try to find an answer to this query by discussing the pathogenesis and overlaps between these conditions.
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Affiliation(s)
- Patrycja Szałwińska
- Department of Biochemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland; (P.S.); (J.W.); (J.F.)
| | - Jakub Włodarczyk
- Department of Biochemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland; (P.S.); (J.W.); (J.F.)
- Department of General and Colorectal Surgery, Medical University of Lodz, Haller Square 1, 90-624 Lodz, Poland
| | - Antonino Spinelli
- Colon and Rectal Surgery Division, Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milano, Italy;
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20090 Milano, Italy
| | - Jakub Fichna
- Department of Biochemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland; (P.S.); (J.W.); (J.F.)
| | - Marcin Włodarczyk
- Department of General and Colorectal Surgery, Medical University of Lodz, Haller Square 1, 90-624 Lodz, Poland
- Correspondence:
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16
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Akhmedov VA, Sargsyan AK, Gaus OV. Prospects for the use of biomarkers in the diagnosis of irritable bowel syndrome. ACTA ACUST UNITED AC 2020. [DOI: 10.31146/1682-8658-ecg-175-3-94-101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Irritable bowel syndrome is a chronic functional disorder of the intestine, manifested by altered intestinal habits and recurrent abdominal pain in combination with two or more criteria: association with defecation, association with a change in the frequency of defecation, association with a change in the appearance of the stool. To date, IBS remains a diagnosis of exclusion that needs to be differentiated from a wide range of organic diseases. In recent years, a large number of publications have appeared on the research of etiopathogenesis, diagnosis and treatment of IBS. This literary review highlights the problems of searching for biomarkers of IBS as a way to solve the problem of diagnosis of this pathology and understanding the causes of its occurrence.
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Affiliation(s)
- V. A. Akhmedov
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| | - A. K. Sargsyan
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
| | - O. V. Gaus
- Federal State Educational Establishment of Higher Education Omsk State Medical University of the Ministry of Health of the Russian Federation
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17
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Xiao QY, Fang XC, Li XQ, Fei GJ. Ethnic differences in genetic polymorphism associated with irritable bowel syndrome. World J Gastroenterol 2020; 26:2049-2063. [PMID: 32536774 PMCID: PMC7267697 DOI: 10.3748/wjg.v26.i17.2049] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/25/2020] [Accepted: 04/04/2020] [Indexed: 02/06/2023] Open
Abstract
Genetic polymorphism is associated with irritable bowel syndrome (IBS) in terms of susceptibility and clinical manifestations. Previous studies have shown that genetic polymorphism might play a key role in the onset and progression of IBS by modulating components of its pathogenesis such as the gut-brain axis, gastrointestinal motility, inflammatory activity, and immune status. Although underlying pathophysiological mechanisms have not been fully clarified, the potential ethnic differences that are present in worldwide genetic studies of IBS deserve attention. This review surveyed numerous studies focusing on IBS-associated single nucleotide polymorphisms, and investigated the ethnic disparities revealed by them. The results demonstrate the need for more attention on ethnic factors in IBS-related genetic studies. Taking ethnic backgrounds into accounts and placing emphasis on disparities potentially ascribed to ethnicity could help lay a solid and generalized foundation for transcultural, multi-ethnic, or secondary analyses in IBS, for example, a meta-analysis. Broader genetic studies considering ethnic factors are greatly needed to obtain a better understanding of the pathophysiological mechanisms of IBS and to improve the prevention, intervention, and treatment of this disease.
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Affiliation(s)
- Qi-Yun Xiao
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiu-Cai Fang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiao-Qing Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Gui-Jun Fei
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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18
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Effect of the interleukin 10 polymorphisms on interleukin 10 production and visceral hypersensitivity in Chinese patients with diarrhea-predominant irritable bowel syndrome. Chin Med J (Engl) 2020; 132:1524-1532. [PMID: 31205078 PMCID: PMC6616227 DOI: 10.1097/cm9.0000000000000306] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Background: Irritable bowel syndrome (IBS), a functional gastrointestinal disorder, is characterized by cytokine imbalance. Previously, decreased plasma interleukin 10 (IL-10) level was reported in patients with IBS, which may be due to genetic polymorphisms. However, there are no reports correlating the IL-10 polymorphisms with IL-10 production in patients with IBS. This study aimed to analyze the effect of IL-10 polymorphisms on IL-10 production and its correlation with the clinical symptoms in Chinese patients with diarrhea-predominant IBS (IBS-D). Methods: Two IL-10 single nucleotide polymorphisms (rs1800871 and rs1800896) were detected in 120 patients with IBS-D and 144 healthy controls (HC) using SNaPshot. IBS symptom severity score, Bristol scale, hospital anxiety, and depressive scale (HADS) were used to evaluate the clinical symptoms, as well as the psychological status and visceral sensitivity of the subjects. IL-10 levels in the plasma and peripheral blood mononuclear cell (PBMC) culture supernatant were measured using enzyme-linked immunosorbent assay, while those in ileal and colonic mucosal biopsies were measured using immunohistochemistry. Results: The frequency of rs1800896 C allele was significantly lower in the patients with IBS-D than that in the HC (odds ratio: 0.49, 95% confidence interval: 0.27–0.92, P = 0.0240). The IL-10 levels in the plasma (P = 0.0030) and PBMC culture supernatant (P = 0.0500) of the CT genotype subjects were significantly higher than those in the TT genotype subjects. The CT genotype subjects exhibited a higher pain threshold in the rectal distention test than the TT genotype subjects. Moreover, IL-10 rs1800871 GG genotype subjects showed an increase in the HADS score compared to other genotype subjects. Conclusions: IL-10 rs1800896 C allele is correlated with higher IL-10 levels in the plasma and the PBMC culture supernatant, which is associated with a higher pain threshold in the Chinese patients with IBS-D. This study provides an explicit relationship of IL-10 polymorphisms with IL-10 production, which might help in understanding the pathogenesis of IBS-D.
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19
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Mahurkar-Joshi S, Chang L. Epigenetic Mechanisms in Irritable Bowel Syndrome. Front Psychiatry 2020; 11:805. [PMID: 32922317 PMCID: PMC7456856 DOI: 10.3389/fpsyt.2020.00805] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a brain-gut axis disorder characterized by abdominal pain and altered bowel habits. IBS is a multifactorial, stress-sensitive disorder with evidence for familial clustering attributed to genetic or shared environmental factors. However, there are weak genetic associations reported with IBS and a lack of evidence to suggest that major genetic factor(s) contribute to IBS pathophysiology. Studies on animal models of stress, including early life stress, suggest a role for environmental factors, specifically, stress associated with dysregulation of corticotropin releasing factor and hypothalamus-pituitary-adrenal (HPA) axis pathways in the pathophysiology of IBS. Recent evidence suggests that epigenetic mechanisms, which constitute molecular changes not driven by a change in gene sequence, can mediate environmental effects on central and peripheral function. Epigenetic alterations including DNA methylation changes, histone modifications, and differential expression of non-coding RNAs (microRNA [miRNA] and long non-coding RNA) have been associated with several diseases. The objective of this review is to elucidate the molecular factors in the pathophysiology of IBS with an emphasis on epigenetic mechanisms. Emerging evidence for epigenetic changes in IBS includes changes in DNA methylation in animal models of IBS and patients with IBS, and various miRNAs that have been associated with IBS and endophenotypes, such as increased visceral sensitivity and intestinal permeability. DNA methylation, in particular, is an emerging field in the realm of complex diseases and a promising mechanism which can provide important insights into IBS pathogenesis and identify potential targets for treatment.
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Affiliation(s)
- Swapna Mahurkar-Joshi
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, Division of Digestive Diseases, Department of Medicine at UCLA, Los Angeles, CA, United States
| | - Lin Chang
- G. Oppenheimer Center for Neurobiology of Stress and Resilience, Division of Digestive Diseases, Department of Medicine at UCLA, Los Angeles, CA, United States
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20
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Zhu S, Wang B, Jia Q, Duan L. Candidate single nucleotide polymorphisms of irritable bowel syndrome: a systemic review and meta-analysis. BMC Gastroenterol 2019; 19:165. [PMID: 31615448 PMCID: PMC6792237 DOI: 10.1186/s12876-019-1084-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 10/01/2019] [Indexed: 12/19/2022] Open
Abstract
Background Genetic factors increase the risk of irritable bowel syndrome (IBS). Analysis of single nucleotide polymorphisms (SNPs) has been used in IBS patients, but the findings are inconsistent. The goal of this review was to synthesize all the published SNPs studies of IBS through meta-analysis to objectively evaluate the relevance of SNPs to IBS risks. Methods IBS - related polymorphisms studies from 2000 to 2018 were searched. Pooled odds ratios with a 95% confidence interval for each SNP were evaluated through five genetic models. Ethnicity, ROME criteria and IBS subtypes were defined for subgroup analyze. Results Ten relevant genes were evaluated. SNPs rs4263839 and rs6478108 of TNFSF15 associated with an increased risk of IBS; IL6 rs1800795 increased the risk for Caucasian IBS patients which diagnosed by Rome III criteria; and IL23R rs11465804 increased the risk for IBS-C patients. IL10 rs1800896 GG genotype associated with a decreased risk of IBS. No evidence supported the association of GNβ3 rs5443, TNFα rs1800629, and IL10 rs1800871 to IBS in this study. Conclusions This meta-analysis presents an in-depth overview for IBS SNPs analysis. It was confirmed that polymorphisms of TNFSF15 associated with increased IBS risk, while IL10 rs1800896 associated with decreased IBS risk. It might offer some insights into polymorphisms of inflammation factors which might affect IBS susceptibility. Moreover, the analysis also emphasizes the importance of diagnostic criteria and phenotype homogeneity in IBS genetic studies.
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Affiliation(s)
- Shiwei Zhu
- Department of Gastroenterology, Peking University Third Hospital, No.49 North Garden Rd., Haidian District, Beijing, 100191, China
| | - Ben Wang
- Department of Gastroenterology, Peking University Third Hospital, No.49 North Garden Rd., Haidian District, Beijing, 100191, China
| | - Qiong Jia
- Department of Gastroenterology, Peking University Third Hospital, No.49 North Garden Rd., Haidian District, Beijing, 100191, China
| | - Liping Duan
- Department of Gastroenterology, Peking University Third Hospital, No.49 North Garden Rd., Haidian District, Beijing, 100191, China.
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21
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Chong PP, Chin VK, Looi CY, Wong WF, Madhavan P, Yong VC. The Microbiome and Irritable Bowel Syndrome - A Review on the Pathophysiology, Current Research and Future Therapy. Front Microbiol 2019; 10:1136. [PMID: 31244784 PMCID: PMC6579922 DOI: 10.3389/fmicb.2019.01136] [Citation(s) in RCA: 174] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 05/06/2019] [Indexed: 11/16/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a functional disorder which affects a large proportion of the population globally. The precise etiology of IBS is still unknown, although consensus understanding proposes IBS to be of multifactorial origin with yet undefined subtypes. Genetic and epigenetic factors, stress-related nervous and endocrine systems, immune dysregulation and the brain-gut axis seem to be contributing factors that predispose individuals to IBS. In addition to food hypersensitivity, toxins and adverse life events, chronic infections and dysbiotic gut microbiota have been suggested to trigger IBS symptoms in tandem with the predisposing factors. This review will summarize the pathophysiology of IBS and the role of gut microbiota in relation to IBS. Current methodologies for microbiome studies in IBS such as genome sequencing, metagenomics, culturomics and animal models will be discussed. The myriad of therapy options such as immunoglobulins (immune-based therapy), probiotics and prebiotics, dietary modifications including FODMAP restriction diet and gluten-free diet, as well as fecal transplantation will be reviewed. Finally this review will highlight future directions in IBS therapy research, including identification of new molecular targets, application of 3-D gut model, gut-on-a-chip and personalized therapy.
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Affiliation(s)
- Pei Pei Chong
- School of Biosciences, Taylor's University, Subang Jaya, Malaysia
| | - Voon Kin Chin
- School of Biosciences, Taylor's University, Subang Jaya, Malaysia
| | - Chung Yeng Looi
- School of Biosciences, Taylor's University, Subang Jaya, Malaysia
| | - Won Fen Wong
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Priya Madhavan
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, Subang Jaya, Malaysia
| | - Voon Chen Yong
- School of Biosciences, Taylor's University, Subang Jaya, Malaysia
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22
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Manzella C, Singhal M, Alrefai WA, Saksena S, Dudeja PK, Gill RK. Serotonin is an endogenous regulator of intestinal CYP1A1 via AhR. Sci Rep 2018; 8:6103. [PMID: 29666456 PMCID: PMC5904159 DOI: 10.1038/s41598-018-24213-5] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 03/28/2018] [Indexed: 02/07/2023] Open
Abstract
Aryl hydrocarbon receptor (AhR) is a nuclear receptor that controls xenobiotic detoxification via induction of cytochrome P450 1A1 (CYP1A1) and regulates immune responses in the intestine. Metabolites of L-tryptophan activate AhR, which confers protection against intestinal inflammation. We tested the hypothesis that serotonin (5-HT) is an endogenous activator of AhR in intestinal epithelial cells. Treatment of Caco-2 monolayers with 5-HT induced CYP1A1 mRNA in a time- and concentration-dependent manner and also stimulated CYP1A1 activity. CYP1A1 induction by 5-HT was dependent upon uptake via serotonin transporter (SERT). Antagonism of AhR and knockdown of AhR and its binding partner aryl hydrocarbon receptor nuclear translocator (ARNT) attenuated CYP1A1 induction by 5-HT. Activation of AhR was evident by its nuclear translocation after 5-HT treatment and by induction of an AhR-responsive luciferase reporter. In vivo studies showed a dramatic decrease in CYP1A1 expression and other AhR target genes in SERT KO ileal mucosa by microarray analysis. These results suggest that intracellular accumulation of 5-HT via SERT induces CYP1A1 expression via AhR in intestinal epithelial cells, and SERT deficiency in vivo impairs activation of AhR. Our studies provide a novel link between the serotonergic and AhR pathways which has implications in xenobiotic metabolism and intestinal inflammation.
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Affiliation(s)
- Christopher Manzella
- Department of Physiology & Biophysics, University of Illinois at Chicago, Chicago, IL, United States
| | - Megha Singhal
- Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, IL, United States
| | - Waddah A Alrefai
- Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, IL, United States
- Jesse Brown VA Medical Center, Chicago, IL, United States
| | - Seema Saksena
- Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, IL, United States
- Jesse Brown VA Medical Center, Chicago, IL, United States
| | - Pradeep K Dudeja
- Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, IL, United States
- Jesse Brown VA Medical Center, Chicago, IL, United States
| | - Ravinder K Gill
- Division of Gastroenterology & Hepatology, University of Illinois at Chicago, Chicago, IL, United States.
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23
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Lazaridis N, Germanidis G. Current insights into the innate immune system dysfunction in irritable bowel syndrome. Ann Gastroenterol 2018; 31:171-187. [PMID: 29507464 PMCID: PMC5825947 DOI: 10.20524/aog.2018.0229] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/22/2017] [Indexed: 12/12/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a functional bowel disorder associated with abdominal pain and alterations in bowel habits. The presence of IBS greatly impairs patients' quality of life and imposes a high economic burden on the community; thus, there is intense pressure to reveal its elusive pathogenesis. Many etiological mechanisms have been implicated, but the pathophysiology of the syndrome remains unclear. As a result, novel drug development has been slow and no pharmacological intervention is universally accepted. A growing evidence implicates the role of low-grade inflammation and innate immune system dysfunction, although contradictory results have frequently been presented. Mast cells (MC), eosinophils and other key immune cells together with their mediators seem to play an important role, at least in subgroups of IBS patients. Cytokine imbalance in the systematic circulation and in the intestinal mucosa may also characterize IBS presentation. Toll-like receptors and their emerging role in pathogen recognition have also been highlighted recently, as dysregulation has been reported to occur in patients with IBS. This review summarizes the current knowledge regarding the involvement of any immunological alteration in the development of IBS. There is substantial evidence to support innate immune system dysfunction in several IBS phenotypes, but additional studies are required to better clarify the underlying pathogenetic pathways. IBS heterogeneity could potentially be attributed to multiple causes that lead to different disease phenotypes, thus explaining the variability found between study results.
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Affiliation(s)
- Nikolaos Lazaridis
- Gastroenterology Department, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Georgios Germanidis
- Gastroenterology Department, AHEPA University General Hospital of Thessaloniki, Thessaloniki, Greece
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24
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Popa SL, Dumitrascu DL, Vulturar R, Niesler B. Genetic studies in irritable bowel syndrome-status quo. World J Meta-Anal 2018; 6:1-8. [DOI: 10.13105/wjma.v6.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 01/17/2018] [Accepted: 03/01/2018] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the most common studied genetic polymorphisms that may have an etiological role in irritable bowel syndrome (IBS).
METHODS The data base PubMed was searched for studies analyzing the association between gene polymorphisms and IBS. All original full papers, written in English, were retained for further analysis. The retrieved papers were further systematized according to those polymorphisms that have been detected in IBS.
RESULTS Considering these criteria, our literature search found 12 polymorphisms, residing in 10 genes, which were reported to be consistently associated with IBS. The initial search identified 189 articles, out of which 48 potentially appropriate articles were reviewed. Of these 48 articles, 41 articles were included in the review. These articles were published between 2002 and 2016. Out of these 41 studies, 17 reported analysis of the serotonin transporter (SERT) gene (SLC6A4), eight on guanine nucleotide-binding protein subunit beta-3 (GNbeta3), six on the serotonin type 3 receptor genes (HTR3A), four on (HTR3E), three on (HTR2A), three the tumor necrosis factor superfamily member TL1A gene (TNFSF15), and ten on genetic polymorphisms with limited evidence.
CONCLUSION Current evidence for the relation between genetic polymorphisms and IBS is limited owing to the fact that high-quality prospective studies and detailed phenotyping of patients suffering from IBS and matched controls were lacking in the past.
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Affiliation(s)
- Stefan-Lucian Popa
- Department of 2nd Medical, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400006, Romania
| | - Dan L Dumitrascu
- Department of 2nd Medical, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400006, Romania
| | - Romana Vulturar
- Department of Cell and Molecular Biology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400006, Romania
| | - Beate Niesler
- Department of Human Molecular Genetics, Heidelberg University, Heidelberg 69120, Germany
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25
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Szilagyi A, Xue X. Comparison of geographic distributions of Irritable Bowel Syndrome with Inflammatory Bowel Disease fail to support common evolutionary roots: Irritable Bowel Syndrome and Inflammatory Bowel Diseases are not related by evolution. Med Hypotheses 2017; 110:31-37. [PMID: 29317064 DOI: 10.1016/j.mehy.2017.10.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 10/22/2017] [Indexed: 02/07/2023]
Abstract
Irritable Bowel Syndrome (IBS) shares overlapping symptoms and some features of pathogenesis with Inflammatory Bowel Diseases (IBD: Crohn's disease [CD], and Ulcerative Colitis [UC]). Geographic markers such as latitude/sunshine and more recently lactase population distributions are found to be correlated with IBD. As a result of clinical and pathogenic similarities between the 2 conditions, some authorities questioned whether a connection exists between them. We compare IBS directly with IBD, and indirectly with geographic markers associated with IBD, in order to evaluate possible evolutionary links between IBS and IBD. Similar correlations may link IBS as a precursor to IBD and possibly other conditions which are geographically connected with IBD. Data from four systematic reviews on IBD incidence and prevalence, IBS prevalence, and lactase distributions were included. Pearson's correlations were used for comparisons, with IBD values log-transformed because of skewed distribution. The articles provided 18-28 complete set of national data. Direct comparison between IBS and IBD showed no significant correlations (r = -0.14, r = -0.06 for CD and UC prevalence, r = -0.10 for CD incidence). Indirect comparisons also failed to show correlations of IBS with lactase distributions (r = -0.17), sunshine (r = -0.2) or latitude (r = 0.097); however, there was significant correlation between lactase distributions and CD incidence (r = -0.84), prevalence (r = -0.55) and UC prevalence (r = -0.59). Both sunshine (r= -0.53) and latitude (r = 0.58) are also significantly related to CD incidence. It is concluded that IBS and IBD do not follow similar global geographic patterns. This suggests a lack of an evolutionary genetic background coincident with emergence of lactase persistence. As well, vitamin D has no obvious impact on development of IBS. Similarities with IBD may result from sub groups (not yet identified) within the current Rome criteria of IBS. Alternatively limited intestinal gut-brain responses to host microbial interactions may result in similar overlap features in both.
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Affiliation(s)
- Andrew Szilagyi
- Department of Internal Medicine, Division of Gastroenterology, Jewish General Hospital, McGill University School of Medicine, Canada.
| | - Xiaoqing Xue
- Department of Emergency Medicine, Biostatistics, Jewish General Hospital, McGill University School of Medicine, Canada
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26
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Interleukin-6 in irritable bowel syndrome: A systematic review and meta-analysis of IL-6 (-G174C) and circulating IL-6 levels. Cytokine 2017; 99:132-138. [PMID: 28886490 DOI: 10.1016/j.cyto.2017.08.017] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 08/03/2017] [Accepted: 08/21/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which presents with abdominal pain and alterations of the bowel habits. The pathophysiology of IBS is not well-recognized. Low grade inflammation has been suggested as one of the underlying mechanisms of IBS. Variations in the circulating pro-inflammatory interleukin-6 (IL-6) levels and IL-6 gene polymorphisms have been demonstrated in IBS. However, the results of published studies are not consistent, probably due to their small sample sizes. To address this inconsistency, we conducted the current systematic review and meta-analysis on serum/plasma IL-6 levels and IL-6 (-G174C; rs1800795) gene polymorphism in IBS. METHODS PubMed was searched in July 2016. Case-control studies on serum/plasma IL-6 levels and IL-6 (-G174C) gene polymorphisms in IBS versus control were retrieved. The quality of studies was evaluated based on the modified Newcastle-Ottawa Scale (NOS) with 0 indicating the lowest and 9 as the highest score. Results were pooled using: (a) the standardized mean difference (SMD) for IL-6 levels which was considered statistically significant when the 0 value was not within the 95% confidence interval (CI), or (b) odds ratio (OR; 95% CI) through converting and pooling the IL-6 (-G174C) genotypes and alleles data into individual 2×2 tables. Heterogeneity was assessed based on I2 values; where I2≤50% and I2>50% designated using fixed and random effect models, respectively. RESULTS Circulating IL-6 levels are higher in IBS patients compared to controls (SMD: 2.40 [95%CI: 0.53-4.28]; p=0.01). Categorizing data based on IBS subtypes, showed that IL-6 level is significantly higher in diarrhea predominant IBS (IBS-D) compared to control (SMD: 2.62 [95%CI: 0.29-4.95]; p=0.03), while it is comparable in constipation predominant IBS (IBS-C) and alternating IBS (IBS-A) patients with healthy controls. The meta-analysis of IL-6 (-G174C) polymorphism in IBS and based on IBS subtypes showed no difference in the distribution of genotypes or alleles compared to control. CONCLUSION The higher IL-6 levels in IBS and more specifically in IBS-D suggests a pro-inflammatory phenotype in these patients, while this phenomenon is not supported by the polymorphism of IL-6 (-G174C). Increased IL-6 in IBS might be an acquired phenomenon or mediated by other genotypes. Any potential association between gene polymorphisms and IL-6 levels in IBS should be tested by assessing both IL-6 levels and IL-6 (-G174C) simultaneously in the same IBS subjects compared to their healthy controls. Categorizing patients based on their circulating IL-6 levels may introduce a new opportunity for personalized anti-inflammatory therapies of IBS.
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Halawi H, Camilleri M. Pharmacogenetics and the treatment of functional gastrointestinal disorders. Pharmacogenomics 2017; 18:1085-1094. [PMID: 28686075 PMCID: PMC5591464 DOI: 10.2217/pgs-2017-0049] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 05/10/2017] [Indexed: 12/12/2022] Open
Abstract
The diagnosis and management of functional gastrointestinal disorders (FGIDs) remain very challenging. In the era of precision medicine, it is important to individualize the treatment of these conditions by providing targeted and effective therapies while minimizing the risk of medication side effects. By using genetic information that predicts and affects the responses to specific medications, it is anticipated that the science of pharmacogenetics in FGIDs will advance the practice of precision medicine. The pathophysiology of FGIDs is complex, involving the interaction between predisposing genetic and environmental factors. Studies have shown that genetic polymorphisms may contribute to the variable responses to specific medications among individuals with FGIDs. Genetic variations in the CYP450 system can affect the metabolism and, hence, the pharmacokinetics of drugs used to treat FGIDs. Polymorphisms in the genes controlling proteins that are involved in the direct action of medications targeting the serotonergic, cannabinoid, adrenergic and bile acid pathways can affect the pharmacologic effects of the medications. In this review, we summarize the published literature on the pharmacogenetics of FGIDs and address the potential clinical utility and future challenges in this field. Since it was the dominant topic in the majority of the articles relevant to FGIDs, our review will focus on irritable bowel syndrome.
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Affiliation(s)
- Houssam Halawi
- Clinical Enteric Neuroscience Translational & Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational & Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN 55905, USA
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Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol 2016; 1:133-146. [DOI: 10.1016/s2468-1253(16)30023-1] [Citation(s) in RCA: 256] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 06/20/2016] [Accepted: 06/24/2016] [Indexed: 11/25/2022]
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Abstract
The acute phase of IBD with inflamed gut and often ulcerated mucosa is clearly different from the apparently normal mucosa characteristic of IBS. However, more detailed assessment has detected immune activation, increased gut permeability, increased mucosal serotonin availability, abnormalities of enteric nerve structure and function, and dysbiosis in gut microbiota in IBS - all features seen in IBD. Furthermore, as treatments for inflammation in IBD have become more effective it is now apparent that ∼1 in 3 patients with IBD in remission from inflammation still have persistent abnormalities of sensation, motility and gut microbiota, which might cause IBS-like symptoms. This Perspective explores the overlap between IBS and IBD and their treatments, proposing future directions for research in this stimulating area.
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Affiliation(s)
- Robin Spiller
- NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and The University of Nottingham, Queens Medical Centre, E Floor West Block, Nottingham NG7 2UH, UK
| | - Giles Major
- NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and The University of Nottingham, Queens Medical Centre, E Floor West Block, Nottingham NG7 2UH, UK
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Chang L, Heitkemper MM, Wiley JW, Camilleri M. 2015 James W. Freston Single Topic Conference: A Renaissance in the Understanding and Management of Irritable Bowel Syndrome. Gastroenterology 2016; 151:e1-8. [PMID: 27215658 PMCID: PMC5410382 DOI: 10.1053/j.gastro.2016.05.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Lin Chang
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California.
| | - Margaret M. Heitkemper
- Department of Biobehavioral Nursing & Health Systems, School of Nursing, Division of Gastroenterology, School of Medicine, University of Washington, Seattle, Washington
| | - John W. Wiley
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Michael Camilleri
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Chang L, Heitkemper MM, Wiley JW, Camilleri M. 2015 James W. Freston Single Topic Conference: A Renaissance in the Understanding and Management of Irritable Bowel Syndrome. Clin Gastroenterol Hepatol 2016; 14:e77-86. [PMID: 27237431 DOI: 10.1016/j.cgh.2016.05.027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Lin Chang
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California.
| | - Margaret M Heitkemper
- Department of Biobehavioral Nursing & Health Systems, School of Nursing, Division of Gastroenterology, School of Medicine, University of Washington, Seattle, Washington
| | - John W Wiley
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Michael Camilleri
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Chang L, Heitkemper MM, Wiley JW, Camilleri M. 2015 James W. Freston Single Topic Conference: A Renaissance in the Understanding and Management of Irritable Bowel Syndrome. Cell Mol Gastroenterol Hepatol 2016; 2:394-399.e2. [PMID: 28174725 PMCID: PMC5042595 DOI: 10.1016/j.jcmgh.2016.05.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Lin Chang
- Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California,Correspondence Address correspondence to: Lin Chang, MD, G. Oppenheimer Center for Neurobiology of Stress and Resilience, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, CHS 42-210, Los Angeles, California 90095-7378.G. Oppenheimer Center for Neurobiology of Stress and ResilienceDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLA10833 Le Conte Avenue, CHS 42-210Los AngelesCalifornia 90095-7378
| | - Margaret M. Heitkemper
- Department of Biobehavioral Nursing & Health Systems, School of Nursing, Division of Gastroenterology, School of Medicine, University of Washington, Seattle, Washington
| | - John W. Wiley
- Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan
| | - Michael Camilleri
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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Henström M, D'Amato M. Genetics of irritable bowel syndrome. Mol Cell Pediatr 2016; 3:7. [PMID: 26873717 PMCID: PMC4752571 DOI: 10.1186/s40348-016-0038-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 02/05/2016] [Indexed: 12/31/2022] Open
Abstract
Irritable bowel syndrome (IBS) is a common condition with a complex and largely unknown etiology. There is no cure, and treatment options are mainly directed to the amelioration of symptoms. IBS causes reduced quality of life and poses considerable repercussions on health and socioeconomic systems. There is a heritable component in IBS, and genetic research is a valuable tool for the identification of causative pathways, which will provide important insight into the pathophysiology. However, although some gene-hunting efforts have been conducted and a few risk genes proposed, IBS genetic research is lagging behind compared to other complex diseases. In this mini-review, we briefly summarize existing genetic studies, discuss the main challenges in IBS genetic research, and propose strategies to overcome these challenges for IBS gene discovery.
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Affiliation(s)
- Maria Henström
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
| | - Mauro D'Amato
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. .,BioCruces Health Research Institute and Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
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Gazouli M, Wouters MM, Kapur-Pojskić L, Bengtson MB, Friedman E, Nikčević G, Demetriou CA, Mulak A, Santos J, Niesler B. Lessons learned--resolving the enigma of genetic factors in IBS. Nat Rev Gastroenterol Hepatol 2016; 13:77-87. [PMID: 26726033 DOI: 10.1038/nrgastro.2015.206] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
IBS is the most prevalent functional gastrointestinal disorder and phenotypically characterized by chronic abdominal discomfort, pain and altered defecation patterns. The pathophysiology of IBS is multifactorial, albeit with a substantial genetic component. To date, studies using various methodologies, ranging from family and twin studies to candidate gene approaches and genome-wide association studies, have identified several genetic variants in the context of IBS. Yet, despite enlarged sample sizes, increased statistical power and meta-analyses in the past 7 years, positive associations are still scarce and/or have not been reproduced. In addition, epigenetic and pharmacogenetic approaches remain in their infancy. A major hurdle is the lack of large homogenized case-control cohorts recruited according to standardized and harmonized criteria. The COST Action BM1106 GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope) has been established to address these obstacles. In this Review, the (epi)genetic working group of GENIEUR reports on the current state-of-the-art in the field, highlights fundamental flaws and pitfalls in current IBS (epi)genetic research and provides a vision on how to address and improve (epi)genetic approaches in this complex disorder in the future.
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Affiliation(s)
- Maria Gazouli
- Department of Basic Sciences, Laboratory of Biology, School of Medicine, University of Athens, Michalakopoulou 176, 11527 Athens, Greece
| | - Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Herestraat 49, Leuven 3000, Belgium
| | - Lejla Kapur-Pojskić
- Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Kemalbegova 10, 71.000 Sarajevo, Bosnia and Herzegovina
| | - May-Bente Bengtson
- Vestfold Hospital Trust, Tønsberg, Department of Internal Medicine, Division of Gastroenterology, P.O. Box 2168, 3103 Tønsberg, Norway
| | - Eitan Friedman
- The Suzanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Centre, 52621 Tel-Hashomer, Israel
| | - Gordana Nikčević
- Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 23 11010 Belgrade, Serbia
| | - Christiana A Demetriou
- Department of Electron Microscopy / Molecular Pathology, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus
| | - Agata Mulak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
| | - Javier Santos
- Neuro-immuno-gastroenterology Lab, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca. Department of Gastroenterology, Hospital Universitari Vall d'Hebron &Facultat de Medicina, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Beate Niesler
- Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
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Camilleri M. Review article: biomarkers and personalised therapy in functional lower gastrointestinal disorders. Aliment Pharmacol Ther 2015; 42:818-28. [PMID: 26264216 PMCID: PMC4558225 DOI: 10.1111/apt.13351] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 07/09/2015] [Accepted: 07/17/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Treatment of IBS and functional lower gastrointestinal disorders is still based predominantly on symptoms; biomarkers that reflect the mechanism or pathophysiology have been identified. Given the diverse mechanisms that result in the same clinical phenotype of IBS, it is hypothesised that identification of biomarkers may lead to individualisation of medical therapy. AIM To review the biomarkers that have been appraised in IBS. METHODS A single author reviewed the published literature on biomarkers appraised in IBS. RESULTS The current literature suggests that these biomarkers are insufficiently sensitive or specific to differentiate IBS from health or from other diseases causing similar symptoms, such as coeliac disease or inflammatory bowel disease. Most of the proposed biomarkers are not actionable, that is, they do not lead to an efficacious therapy based on the biological inference of the biomarker itself. However, among proposed biomarkers in IBS, some are actionable, as they specifically reflect a quantitative difference in a mediator of dysfunction or result in a quantifiable disturbance of function that can be specifically treated. Such biomarkers may potentially identify relevant subgroups that respond to specific therapy. The most promising actionable biomarkers are measurement of colonic transit (leading to treatments that reverse the abnormal transit) and measurements of bile acid diarrhoea to identify responders to bile acid sequestrants. CONCLUSIONS Therefore, although biomarkers are not ready for prime time as diagnostic tests in IBS, some biomarkers could identify subgroups of patients with IBS for inclusion in clinical trials that target specific dysfunctions. Such an approach may enhance treatment efficacy, and may ultimately help reduce costs in drug development and in the management of patients in clinical practice.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, Minnesota
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Abstract
Irritable bowel syndrome (IBS) is a chronic disease characterized by complex interactions between genetic predisposition and the environment. Current treatments for IBS are characterized by a highly variable response. Gene variations may result from insertions or deletions, gene rearrangements, splice variants or copy number variants, or, more commonly, from substitutions in the DNA of one (single nucleotide polymorphism [SNPs]) or more than one nucleotide. The objective of this editorial is to review the potential importance of pharmacogenetics in the treatment of IBS based on current evidence.
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Affiliation(s)
- Andres Acosta
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic , Charlton 8-110, 200 First St. S.W, chester, MN 55905, Rochester, MN , USA +1 507 266 2305 ;
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