View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Jagiellonian Univeristy Repository © Med Sci Monit, 2004; 10(6): RA125-131 WWW.MEDSCIMONIT.COM PMID: 15173682 Review Article Received: 2004.02.17 Accepted: 2004.03.15 The brain-gut axis in irritable bowel syndrome Published: 2004.06.03 – clinical aspects Tomasz Mach Department of Infectious Diseases and Hepatology, Jagiellonian University School of Medicine, Cracow, Poland Source of support: Self financing. RA Summary Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal (GI) disorder, affecting about 20% of the world’s population. Chronic abdominal pain or discomfort relieved by defecation and associated with altered bowel habits are the mainstay in diagnosis. The pathophysiology of IBS remains unknown. This biopsychosocial disorder involves dysregula- tion of the nervous system, altered intestinal motility, and increased visceral sensitivity. All of these result from dysregulation of the bidirectional communication between the gut with its enteric nervous system and the brain (the brain-gut axis), modulated by various psychosocial and environmental factors (e.g. infection, inflammation). Numerous neurotransmitters are found in the brain and gut that regulate GI activities, including 5-hydroxytryptamine (5-HT, serotonin) and its 5-HT3 and 5-HT4 receptors. The current approach to IBS patients is based on a positive diagnosis of the symptom complex, exclusion of underlying organic disease, and institution of a therapeutic trial. Traditional symptomatic treatment has included antidiar- rheals, laxatives and bulking agents/fiber, low-dose tricyclic antidepressants, antispasmodics for pain, and ‘alternative’ therapies (e.g. psychotherapy, hypnotherapy). The scientific evi- dence supporting this therapy is limited. Novel approaches include visceral analgesics and serotonin agonists and antagonists. In patients with severe diarrhea, 5-HT3 receptor antago- nists (e.g. alosetron) and selective M3-type anticholinergics are indicated, in constipation 5- HT4 agonists (e.g. tegaserod), and in pain alfa2-adrenergics (e.g. clonidine), cholecystokinin antagonists, kappa-opioid agonists (e.g. fedotozine), and neurokinin antagonists; some of these agents are still being investigated. Understanding the brain-gut axis is crucial in the development of effective therapies for IBS. key words: brain-gut axis • irritable bowel syndrome • pathophysiology • serotonin • treatment Full-text PDF: http://www.MedSciMonit.com/pub/vol_10/no_6/5095.pdf Word count: 3482 Tables: 3 Figures: — References: 35 Author’s address: Dr hab. med. Tomasz Mach, Department of Infectious Diseases and Hepatology, Jagiellonian University School of Medicine, ul. Śniadeckich 10, 31-153 Kraków, Poland, e-mail: [email protected] RA125 Review Article Med Sci Monit, 2004; 10(6): RA125-131 BACKGROUND tures: beginning of symptoms at an age over 50 years, progression or worsening of symptoms without periods Irritable bowel syndrome (IBS) is a chronic disorder of of relief, nighttime symptoms, rectal bleeding, anemia, the gastrointestinal (GI) function characterized by con- hypoalbuminemia, anorexia, unexplained weight loss, tinuous or remittent abdominal pain and is associated recurrent vomiting, family history of colon cancer, with altered bowel habits, diarrhea or constipation or abnormal physical findings (e.g. mass), and extraintesti- both, and bloating [1]. The disorder cannot be explained nal manifestations as seen in inflammatory bowel disease by specific pathophysiologic mechanisms, or structural [8]. The presence of any of these features is usually an or known biochemical abnormalities. IBS symptoms are indication for further investigations (Table 1) [10]. multi-determined and are generated from dysregulation at multiple levels of the brain-gut axis (BGA). They are EPIDEMIOLOGY manifested by abdominal motor reactivity to various stimuli and low sensation and pain thresholds. Psycho- Epidemiologic studies are difficult to interpret because social factors also have an important role in modulating there is a lack of clear pathologic features of IBS [1]. both the disease experience and clinical outcome. IBS is The investigated population may vary according to the highly prevalent and can be associated with significant nature and interpretation of the diagnostic criteria. IBS emotional distress, impaired health-related quality of seems to be as common in American and Asian as it is in life, disability, and high health care costs [2,3]. European countries. Prevalence seems to be similar in whites, blacks, and Hispanics [2]. The overall prevalence IBS is one of the most common clinical problems from questionnaire studies is 2.9%, but population- encountered by the general practitioners and gastroen- based studies in the USA estimate the prevalence of IBS terologists [4,5]. Approximately 10–15% of the general between 5% and 25% [2,3,5]. The precise incidence of population has IBS, and more than 40% of IBS patients IBS is unclear, but it has been estimated at 1–2% per have such frequent and severe symptoms as to lead to a year [5]. Although the majority of people with IBS do reduction in quality of life and result in numerous visits not consult a physician, approximately 10–25% of to physicians. The economic impact of IBS is large [5]. patients seek family practice and 1% is referred to a gas- The estimated health care costs of IBS in the United troenterologist [6,14]. The prevalence of IBS is 3–4 States are very high, with $19.2 billion annual indirect times greater in women than men, and female patients costs (e.g. work absenteeism, reduced productivity) and seem to have more frequent and severe symptoms and $1.6 billion direct medical expenses (e.g. visits to health- they seek health care more often [1–3]. care providers, diagnostic workups, treatment) [2,5,6]. IBS can affect people at any age, but the prevalence of There are no specific laboratory tests or physical mark- IBS declines with age [15]. Approximately 50% of peo- ers that are pathognomonic for IBS. Therefore the ple with IBS report beginning of symptoms before the diagnosis is based on symptoms and clinical features as age of 35 [3]. Traditionally, IBS is not diagnosed in peo- well as an absence of any alarm indicators [3,7,8]. In ple after the age of 60, when organic diseases of the gut 1978, Manning and associates established six criteria to become more frequent [1,3,5,15]. distinguish IBS from organic bowel disease. Talley and co-workers showed that the Manning criteria are sensi- IBS does not increase mortality or the risk of inflamma- tive in 58% and specific in 74% of cases in discriminat- tory bowel disease or cancer. Patients with IBS who seek ing IBS from organic GI diseases [9,10]. These criteria medical attention are more disturbed psychologically, were updated in 1999, and the Rome criteria have come more likely to have abnormal personality profiles, are to be accepted as the state-of-the-art criteria for research more concerned about their health and fearful of illness studies and clinical practice [3]. According to the Rome [5]. criteria, IBS is defined on the basis of abdominal pain and alteration of bowel habits. The symptoms are used PATHOPHYSIOLOGY to differentiate three subgroups of patients: those with constipation-predominant IBS, those with diarrhea-pre- The pathophysiology of IBS is heterogeneous and not dominant, and those with alternating bowel movements fully elucidated. Recent studies have led to a greater [11]. The Rome criteria have a positive predictive value understanding of the association between the gut and of approximately 98% and additional diagnostic tests CNS. Currently, the model for IBS incorporates have a yield of 2% or less [7]. However, many authors enhanced motility, abnormal sensation, and autonomic suggest that the diagnostic criteria for IBS need further reactivity modulated by CNS-enteric nervous system validation [10,12]. (ENS) interaction, or the BGA. Moreover, enteric infec- tion, immune activation, and inflammation of the colonic IBS is heterogeneous in nature, and patients experience mucosa as well as the enteric neuro-muscular apparatus not only abdominal discomfort and bowel problems, but play a role in the pathophysiology of IBS [4,16]. sometimes many other symptoms, including heartburn, back pain, headache, urinary frequency, muscle pains, IBS is recognized as a biopsychosocial disease in which menorrhagia, dyspareunia, anxiety, and depression [1]. several major mechanisms interact, including enhanced It is essential to differentiate between organic and func- visceral sensation (visceral hypersensation), central per- tional causes of symptoms. An organic pathology may be ception of visceral events, abnormal intestinal motility, suspected in a patient with any of the so-called alarm fea- and abnormal psychosocial factors [3,4]. RA126 Med Sci Monit, 2004; 10(6): RA125-131 Mach T – Brain-gut axis in irritable bowel syndrome Table 1. The Manning and Rome II diagnostic criteria for irritable bowel syndrome [13,14]. Manning criteria Rome II criteria Onset of pain associated with more frequent bowel movements At least 12 weeks, which need not be consecutive, in the preceding 12 Onset of pain associated with looser bowel movements months of abdominal discomfort or pain that has 2 of 3 features: Pain relieved by defecation 1. Relieved with defecation; and/or Visible abdominal distention 2. Onset associated with a change in frequency of stool; and/or Subjective