Part I Literature Review and Hypothesis Chapter Spectrum of Irritable Bowel Syndrome and Brain-Gut Axis 1.1 Introduction The irritable bowel syndrome (IBS) is a common disorder producing abdominal pain, bloating and altered bowel habits, which can be associated with significant disability and health care costs IBS is defined by symptoms, which are markedly influenced by psychological factors and stressful life situations, in the absence of structural pathology No life threatening or significant disease such as infections, inflammatory bowel disease or bowel cancer have been found in majority of IBS patients on appropriate investigations With the accumulation of knowledge from epidemiology, physiology, psychology and neuroscience during the last decade, IBS is now believed to result from a dysregulation of brain-gut axis which involves the alterations in intestinal motor, sensory, and central nervous system (CNS) The histories of patients with IBS show considerable variation in symptom experience and behavior Though most of these patients only have relatively mild to moderate symptoms, some suffer severe symptoms that can restrict social activities and substantially reduce quality of life and cause serious consequence It can affect employment, leisure travel, sexual function, diet and co-morbid with sleep, depression and anxiety Patients with IBS have three times work absenteeism than other employees (Drossman et al, 1993), and based on the large proportion of the population affected, IBS patients consume tremendous healthcare services IBS accounts for an estimated 2.4-3.5 million physician visits per year in the United States (Everhart and Renault, 1991) and for an estimated 2.2 million medication prescriptions (Sandler, 1990) Patients with IBS undergo numerous diagnostic tests and procedures (many unnecessary), and may retain a maladaptive illness belief that some other diagnosis is still being missed Some of them are also more likely to undergo surgery (Longstreth et al, 1990) The cost of health services for patients with IBS is significantly higher than that for controls and is estimated at eight billion dollars per year for the white population of the United States (Talley et al, 1995) Because of poor understanding of the cause of the disorder, lack of common-accepted diagnostic criteria and a biopsychosocial model of the disease, there is still no encouraging strategy for cure and the optimal treatment for IBS remains controversial As such, we face many problems and challenges and there is clearly a need for more research on this disorder 1.2 Epidemiology In general, large epidemiological studies from United States, United Kingdom, and China show that IBS affects about 11%-20% of people in the community (Farthing, 1995) The prevalence of IBS varies across different epidemiological studies; presumably due to the diversity of definitional criteria, differences in the specific questions used to elicit the information, different target population and other factors A survey using Manning criteria found that 22% of the British population aged between 20 and 90 years have IBS (Jones and Lydeard, 1992) Another study using the same diagnostic criteria but in a different age group (30 to 64 years), reported a prevalence of approximately 17% (Talley et al, 1991) Using the more restrictive Rome criteria, IBS symptoms was only detected in 9.4% of the United States population (Drossman et al, 1993) It has also been documented that only a proportion of those with IBS symptoms consult physicians While a study done by Talley et al (1991) reported that only 14% of patients with IBS symptoms had consulted a physician, a survey conducted by Jones and Lydeard (1992) revealed that only one-third IBS patients had seen a doctor for their symptoms There are marked differences in the prevalence of IBS in women as compared with men IBS affects females approximately twice as often as males In the U.S Householder Survey (Drossman et al, 1993), IBS was present in 14.5% of women but in only 7.7% of men Similar differences in prevalence have been reported in other studies from western countries (Hislop, 1971; Talley et al, 1991; Heaton et al, 1992; Jones and Lydeard, 1992) Contrary to findings by the abovementioned studies done in the western countries, studies from India and Sri lanka reported a preponderance of men having IBS (Kapoor et al,1985; Mendis et al, 1982) The disparity of IBS prevalence between the western and Indian reports may be attributed to different healthcare seeking tendency between men and women in the two different societies (Thompson et al, 1989) 1.3 Etiology and pathophysiology The pathophysiology of IBS remains largely unknown Several mechanisms have been postulated as the basis for the cause and development of IBS These mechanisms include dysregulation of brain-gut interactions, psychological factors, abnormal motility, enhanced visceral sensitivity and autonomic system imbalance However, no mechanism unique to IBS has been identified 1.3.1 The brain-gut axis Currently, more and more attention has been put on the dysregulation of brain-gut interactions The brain-gut axis refers to the continuous back and forth interactions of information and feedback that take place between the gastrointestinal tract, and the brain and spinal cord These interrelated feedback circuits can influence brain processes and bowel functions including pain perception, gut sensitivity, secretions, inflammatory responses, and motility The brain-gut circuits can be activated by an external or internal factor or stimulus that makes a demand on the system, such as a stressful event Symptoms, such as abdominal pain and altered motility and bowel habits in IBS patients can arise from dysregulation of activity in one or more of the stations in the bidirectional communication pathways between the GI system (the enteric nervous system, ENS) and the spinal cord and brain (the central nervous system, CNS) Through the use of modern imaging techniques, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), researchers have been able to evaluate cerebral blood flow or oxygen desaturation respectively, in areas of active brain functioning in response to real or anticipated pain from visceral balloon distention A fMRI study found increased anterior cingulated cortex (ACC) activation in IBS patients compared to healthy controls as well as activation of prefrontal, insular and thalamus in most subjects in response to painful rectal distention (Mertz et al, 2000) However, using PET, it was also revealed that unlike healthy controls, IBS patients failed to activate the ACC during painful rectal distention (Silverman et al, 1997) Such differences might suggest these findings are related to anxiety and uncertainty among the patients In spite of these inconsistent results, these data at least provided an objective evidence to support the hypothesis of the dysregulation of brain-gut communication, and such dysregulation are especially manifested in the abnormal descending pain inhibitory modulation Numerous neurotransmitters found in the brain and gut act as messengers that regulate brain-gut communication under stress These messengers, including serotonin (5-HT), cholecystokinin, substance P, enkephalins, calcitonin gene related polypeptide, nitric oxide, and others, have varied and integrated effects on pain modulation, gastrointestinal motility, emotional behavior, and immunity (Mayer and Gebhart, 1994) Given the complex relationship between inflammatory mediators, gut hypersensitivity, motility, and pain experience, the results of recent research strongly suggest that alterations in neuroimmune and neuroendocrine communications at the enteric and CNS levels may trigger a series of events that gives rise to chronic changes in visceral sensitivity and central mechanisms controlling pain, as evidence of dysregulation of the brain-gut axis Several kinds of events could trigger the dysregulation of the brain-gut axis in patients with IBS Among these are psychological experiences, such as life stress, psychological co-morbidity, or sexual and physical abuse, and inflammation (Drossman et al, 1996; Gwee et al, 1999) 1.3.2 Stress Stress, defined as an acute threat to the homeostasis of an organism by real (physical, ‘interoceptive’; e.g gut infection, cold water immersion, visceral distention) or perceived (psychological, ‘exteroceptive’; e.g dichotomous listening, mental arithmetic, life events) events, initiates adaptive physiologic and behavioral changes that serve to defend the stability of the internal environment (Monnikes et al, 2001; Selye,1998; Selye, 1976; Chrousos and Gold, 1992) Certain physical and psychological stresses have been associated with the onset or symptom exacerbation in functional gastrointestinal disorders (FGD), especially IBS Such association in patients with IBS was observed in some well-designed surveys (Gwee et al, 1999; Bennett and Tennant et al, 1998; Whitehead et al, 1992; Welgan et al 1985) Patients with FGD are exposed to one or more stressors much more often than normal controls (98% versus 36%) (Bennett and Piesse et al, 1998) Meanwhile, the symptoms are improved with the acquisition of more effective stress management skills (Guthrie et al, 1993; Shaw et al, 1991) Furthermore, evidences from animal studies have shown that various stressors caused delayed gastric emptying, inhibited small bowel transit and accelerated colonic transit (Williams et al, 1988; Tache et al, 1999; Tsukada et al, 2002) Some investigators also observed increased responses of distal colonic motility in response to stress in IBS patients (Welgan et al, 1988; Fukudo et al, 1993; Narducci et al, 1985) Recently, a study group reported decreased rectal pain thresholds in patients with IBS but not in normal controls during acute laboratorial physical (cold water hand immersion) and psychological (dichotomous listening) stress (Murray et al, 2004) By contrast, a variety of stressful stimuli has been shown to produce analgesia, a phenomenon often referred to as stress-induced analgesia (SIA) (Bodnar, 1986; Hayes and Katayama, 1986; Watkins et al, 1982) Studies using different stressors (e.g cold stress pain, ischemic pain and noxious heat) significantly produced analgesia in healthy subjects (Washington et al, 2000; Willer et al, 1989; Pertovaara et al, 1982) However, this “stress inhibiting pain” phenomenon has never been reported in patients with IBS Taken together, all these data may imply an altered stress regulatory mechanism in IBS patients, especially endogenous pain modulation, which change the sensory and motility of the bowel These changes in turn could cause visceral hyperalgesia, abdominal symptoms and altered stool habits Compared with the knowledge in physiology, the role of central functions in stress and thereby the interactions between neural networks and gut remains poorly understood Sawchenko et al pointed out that there are some similar principal circuits underlying the stress response in spite of the different types of stress (Sawchenko and Li, 2000) The limbic forebrain including the lateral and medial prefrontal cortex, hippocampus, and amygdale may participate in central processing psychological stress (Sawchenko and Li, 2000) A recent study observed significant group differences in the frontal brain among healthy controls and IBS patients with respect to the event-related potentials in the brain during exposure to everyday words with emotional content (Blomhoff et al, 2000) Using electroencephalograms (EEG), Nomura et al also showed significantly greater EEG abnormality in the IBS patients (29.2%) than in the controls (4.2%) under mental arithmetic stress and the administration of neostigmine (Nomura et al, 1999) All these data suggest a possible involvement of the CNS in the pathophysiology of IBS, especially under the stress situation 1.3.3 Psychopathology Some chronic and acute psychosocial factors including early life experiences, conditioning factors (Levy et al, 2000; Whitehead et al, 1994), psychological stress (which has been introduced in the section 1.3.1), personal and social coping systems (Drossman et al, 2000), and psychological distress and co-morbidity, are important in the pathophysiology of IBS A whole variety of chronic psychopathologies have been described in secondary care IBS patients although anxiety and depression are by far the commonest, accounting for at least 60% (Whitehead and Crowell, 1991) of them Abnormal illness behavior and illness attitude have also been reported as being more common in IBS than healthy controls (Drossman et al, 1988; Levy et al, 2000) Compared with healthy controls, patients with IBS are observed to have higher scores for anxiety, depression, hostile feelings, sadness, interpersonal sensitivity, as well as more sleep disturbance (Whitehead et al, 1980; Svedlund et al, 1985; Gomborone et al, 1995; Ford et al, 1987) All of these factors could cause chronic stress in IBS subjects This opinion was furthere supported by the finding that many patients with IBS have counterproductive coping styles, such as cognitions that "catastrophize" symptoms and life events (Drossman et al, 2000) In another study, psychological factors were reported to predict the development IBS after an episode of acute gastroenteritis in previously asymptomatic individuals (Gwee et al, 1999) The prevalence of psychiatric diagnoses in IBS ranges between 40% and 100% depending on the population, settings, and diagnostic criteria (Hochstrasser and Angst, 1996; 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brain- gut interactions The brain- gut axis refers to the continuous back and forth interactions of information... Effects of melatonin on brain- gut axis and IBS related conditions Since the structural identification of melatonin and the availability of a few melatonin agonists and antagonists in the last fifteen... 3.3.4 Gastrointestinal regulation function of melatonin 3.3.4.1 Gastrointestinal melatonin The finding that the concentration of melatonin in the gastrointestinal tissues surpasses that in the blood