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Irritable Bowel Syndrome : Pathophysiology, Symptoms and Biomarkers

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Irritable Bowel Syndrome : Pathophysiology, Symptoms and Biomarkers Irritable bowel syndrome : pathophysiology, symptoms and biomarkers Citation for published version (APA): Mujagic, Z. (2015). Irritable bowel syndrome : pathophysiology, symptoms and biomarkers. Uitgeverij BOXPress || Proefschriftmaken.nl. https://doi.org/10.26481/dis.20151221zm Document status and date: Published: 01/01/2015 DOI: 10.26481/dis.20151221zm Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 06 Oct. 2021 IRRITABLE BOWEL SYNDROME Pathophysiology, Symptoms and Biomarkers © Copyright Zlatan Mujagić, Maastricht 2015 Layout: Tiny Wouters Cover: Stefani Wiatowski Printed by: Uitgeverij BOXPress || Proefschriftmaken.nl ISBN: 978‐94‐6295‐402‐1 The studies presented in this thesis were performed within the framework of NUTRIM School of Nutrition and Translational Research in Metabolism (Maastricht University), which participates in the Graduate School VLAG (Food Technology, Agrobiotechnology, Nutrition and Health Sciences), accredited by the Royal Netherlands Academy of Arts and Sciences. Furthermore, a part of the research presented in this thesis has been funded by the Top Institute for Food and Nutrition (TIFN), Wageningen. Printing of this thesis was financially supported by: Grünenthal GmbH, Aachen, Germany – Medische Laboratoria Dr. Stein & Collegae, Maastricht, The Netherlands – Euro Diagnostica, Malmö, Sweden – Nederlandse Vereniging voor Gastroenterologie (NVGE) – Maastricht University Medical Center+. IRRITABLE BOWEL SYNDROME Pathophysiology, Symptoms and Biomarkers ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Universiteit Maastricht, op gezag van de Rector Magnificus, Prof. dr. L.L.G. Soete volgens het besluit van het College van Decanen, in het openbaar te verdedigen op maandag 21 december 2015, om 12:00 uur. door Zlatan Mujagić Promotor Prof. dr. A.A.M. Masclee Prof. dr. F.J. van Schooten Copromotor Dr. D.M.A.E. Jonkers Beoordelingscommissie Prof. dr. C.H.C. Dejong; voorzitter Prof. dr. A.M. Schols Prof. dr. R.C. Spiller, Queen's Medical Centre, Nottingham, UK Prof. dr. H.W.M. Steinbusch Dr. P.J.J. van der Veek, Medisch Centrum Haaglanden, Den Haag Table of contents Chapter 1 Introduction 7 Part I Pathophysiology 23 Chapter 2 Intestinal permeability in IBS 25 Chapter 3 Effects of L. plantarum on intestinal mucosa 47 Chapter 4 Effects of L. plantarum on immunity 71 Chapter 5 Markers for visceral hypersensitivity in IBS 99 Chapter 6 Biological markers for visceral hypersensitivity in IBS 115 Chapter 7 Serotonin metabolism in IBS 131 Part II Symptoms 153 Chapter 8 Systematic review: Measurement of abdominal pain in IBS 155 Chapter 9 ESM ‐ a new digital tool for symptom assessment in IBS 189 Part III Biomarkers 207 Chapter 10 A novel faecal and plasma biomarker panel for IBS 209 Chapter 11 Novel breath biomarkers for IBS; a metabolomic approach 229 Chapter 12 General discussion 247 Summary 261 Samenvatting 269 Valorisation 277 List of publications 285 Dankwoord 291 Curriculum vitae 301 Chapter 1 General introduction 7 Chapter 1 8 General introduction General introduction Functional Gastrointestinal Disorders Functional gastrointestinal disorder (FGID) is an umbrella term for a broad spectrum of disorders of the gastrointestinal (GI) tract, for which no clearcut organic cause can be identified.1,2 FGIDs are among the most prevalent disorders worldwide. Since only a minority of people who experience functional GI symptoms seek medical attention,3 the exact prevalence of FGIDs among the general population is not well established. In a large general population based prospective cohort study in the USA, Halder et al. found that 42% of the included subjects had one or more FGIDs, as observed over a 12 year time period.4 The first FGID to be described in 1818, was a disorder characterized by abdominal pain, now referred to as irritable bowel syndrome (IBS).5 In the past decades, several terms have been used for IBS, mostly based on altered motility and sensitivity of the colon as the presumed main pathophysiological mechanism, such as spastic colon, nervous colon or irritable colon syndrome.6 The term IBS was first introduced in 1967 by DeLor.7 In 1978, Manning and colleagues described the first criteria based on symptoms to aid the diagnostic process for IBS (i.e. the Manning criteria).8 In 1989, the Rome Committee published new criteria for IBS,9 which were revised several times, resulting in the currently generally accepted ‘gold standard’ Rome III criteria. Meanwhile, discussion is ongoing, which should lead to the development of the Rome IV criteria in the nearby future.10 Irritable Bowel Syndrome The diagnosis of IBS, as described by the Rome III criteria, is based on recurrent abdominal pain or discomfort, which patients experience at least 3 days per month, and is associated with changes in stool frequency, consistency, and/or improvement with defecation. Furthermore, symptom onset must be at least 6 months before making the diagnosis. Furthermore, ‘red flags’ that could indicate the presence of an organic disorder, should be absent. Based on a meta‐analysis, a pooled estimate of 11% has been reported for the global prevalence of IBS among the general population, with a female predominance (1:2 ratio).11 Next to abdominal pain or discomfort, several other GI symptoms, such as bloating, flatulence, constipation and/or diarrhoea, nausea and belching, have been associated with IBS, but their presence and severity vary between patients. IBS can be divided into four subtypes according to predominant bowel habits, i.e. diarrhoea (IBS‐D) and constipation (IBS‐C) predominant and mixed (IBS‐M) subtypes, or those with unspecified stool pattern (IBS‐U).1 Furthermore, the IBS patient population is characterised by a large diversity in lifestyle, dietary patterns and use of medication. Altogether, this reflects the distinct heterogeneity of the IBS patient population. 9 Chapter 1 From a clinical perspective, IBS is not considered a severe medical condition, nor is it a risk factor or predisposing to other more severe disorders. Nevertheless, the disease burden in affected subjects is high, leading to considerable impairment of quality of life and work absenteeism,12 and high health care costs.13 High costs are reflected by extensive diagnostic investigations, as well as the lack of standardised treatment protocols.13 Although the Rome III criteria emphasize that IBS is not a diagnosis of exclusion and should be based on symptom criteria,1 in daily clinical practice most physicians (>70%) frequently employ endoscopy, CT or ultrasound imaging, blood, faecal or other analyses to exclude organic disorders.14 Objective non‐invasive biomarkers that could aid the diagnostic process of IBS in daily clinical practice are currently not available.15 Furthermore, standardized treatments for IBS are lacking. The efficacy of currently available therapeutic strategies is moderate.16 This is partly due to a lack of insight into pathophysiological mechanisms that underlie generation of GI symptoms in IBS. Pathophysiology of IBS Although IBS is a symptom‐based diagnosis without a clear organic cause, several pathophysiological mechanisms have been associated with the disorder. This has led to the generally accepted concept of multifactorial aetiology in IBS. Alterations may occur in many intestinal processes, in bidirectional signalling between the central nervous system and the GI tract, in processing of signals by the brain, in prevalent psychological comorbidity and in genetic susceptibility. Through complex interaction all these factors contribute to the development of IBS, as is shown in Figure 1.1.16,17 Genetics A role for host genetics in IBS originates from findings in family studies. IBS patients were reported to be twice more likely to have relatives with IBS compared to non‐IBS subjects.18 However, this association may also result from Figure
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