Irritable Bowel Syndrome

Motility and Functional Bowel Disease

Irritable bowel syndrome

Using the Rome criteria, IBS affects 5–10% of the population, with a female preponderance and a peak incidence in the third and fourth decades. The estimated direct costs of healthcare of IBS in the USA in 1998 were around $1.6 billion, and it is the second most important reason for loss of time from work in the UK. IBS sufferers have considerable impairment in quality of life, with effects on social and emotional functioning comparable to depression, and on physical function which are, on average, worse than both diabetes and hypertension.2

Anna L Forbes J O Hunter

A condition which arises in the nervous system? Abstract

It has long been widely believed that IBS sufferers endure gut complaints as a result of mental turmoil. A strong correlation between IBS and psychiatric disorders lead to the conclusion that all patients with IBS are psychologically abnormal.3 ­Correlations between IBS and mental health are hampered, however, by the lack of any true measure of IBS illness severity, and the fact that the majority of IBS sufferers do not seek health care.4 Neverthe­ less, adverse life events often precede its development, and these may be distant (from childhood) or recent (such as marital separa­ tion). There are higher rates of reported physical and sexual abuse in IBS sufferers than in controls. Anxiety and depression are the most frequent psychiatric disorders in IBS. They exacerbate symptoms and adversely influence prognosis.5 The evidence for a cerebral cause of IBS may be summarized as follows. • Psychosocial factors may affect IBS via a central nervous ­system (CNS) route. • Centrally active treatments, such as psychotherapy, hypnosis and antidepressants, are beneficial in some cases of IBS. • Symptoms are absent during sleep when the CNS is less ­active. • Differences in CNS blood flow have been detected on ­functional brain scans in IBS patients. • IBS patients have a higher prevalence of other functional and psychomotor disorders which could have a common cause from CNS malfunction.6

Irritable bowel syndrome (IBS) is characterized by a number of ­symptoms including diarrhoea, constipation, wind and bloating. Despite many years of research, IBS still has an uncertain aetiology. The Rome criteria have been devised to ensure recruitment consistency in studies. This contribution looks into the possible causes of IBS and now it may be managed.

Keywords colonic malfermentation; constipation; diarrhoea; irritable bowel syndrome

Irritable bowel syndrome (IBS) is the complaint encountered most frequently in gastroenterological clinics in the Western world – and the most poorly understood. Patients suffer persistent abdominal pain with diarrhoea or constipation, wind and bloating for which, despite intensive investigation, no cause can be discovered. The prognosis of IBS is benign, but its symptoms may mimic those of more serious conditions, such as inflammatory bowel disease or colon cancer. These must be excluded in every case, and certain danger signals, which may herald the presence of more serious diseases, are listed in Table 1, together with those investigations necessary to exclude organic ­pathology. IBS is remarkable in that, despite many years of research, it is still unclear whether it is primarily a condition of the brain and enteric nervous system, which affects the gut, or a disorder of the gut, which may influence the brain. This is partly because the lack of objective diagnostic criteria has caused a tendency for physicians to lump all cases of abdominal pain with no apparent cause into a common category of ‘IBS’, producing considerable confusion. Abdominal pain may, of course, arise for many reasons not only within, but also beyond the gut, such as anxiety and depression, or musculoskeletal problems. The Rome criteria (Table 2) devised by an international co-coordinating committee have latterly been widely applied in an attempt to ensure recruitment consistency in both surveys and pathophysiological studies.1

Alarm symptoms (not present in IBS) and investigations

Anna L Forbes BMedSci BMBS is a Junior Doctor at the West Suffolk Hospital in Bury St Edmunds, UK. She graduated from Nottingham University, UK. Her current research interests include irritable bowel syndrome. Competing interests: none declared. J O Hunter MA MD FRCP FACG AGAF is Consultant Physician at the Gastroenterology Research Unit, Addenbrooke’s Hospital, Cambridge, UK. Competing interests: none declared.

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Alarm symptoms

Suggested investigations

Rectal bleeding Weight loss Nocturnal abdominal pain or diarrhoea Anaemia Fever

Full blood count Urea and electrolytes Liver function tests Thyroid function Serum albumin and calcium C-reactive protein Tissue transglutaminase Stool culture and microscopy Endoscopy or radiology of colon in those aged >45 years.

Table 1

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Motility and Functional Bowel Disease

The Rome II criteria

Proportion feeling pain %

Visceral hypersensitivity in irritable bowel syndrome

At least 12 weeks or more, which need not be consecutive, in the preceding 12 months, of abdominal discomfort or pain having two out of the following features: • relieved by defecation • onset associated with a change in the frequency of stool • onset associated with a change in the form/appearance of stool. Other features that were part of the more complex Rome I criteria are no longer required but are often present, including: • abnormal stool frequency • abnormal stool form • abnormal passage of stool (straining, urgency or feeling of incomplete evacuation) • passage of mucus • bloating or feeling of abdominal distension.

100 80 60

Normal subjects Irritable bowel subjects

40 20 0 20

40

60

100

200

300

Balloon inflation volume (ml) Pain is induced by the distension of a rectal balloon to a lower pressure than in health. Reproduced with kind permission of the BMJ Publishing Group from Ritchie J. Gut 1973; 14: 125–32.8

Figure 1

Table 2

Brain imaging technology now allows for the measurement of changes in regional blood flow during stimulation by functional magnetic resonance and positron emission tomography (PET). Brain areas receiving higher blood flow are generally more meta­ bolically active. Increased activation of the anterior cingulate cortex together with impaired activation of brainstem nuclei with both active and sham balloon distention has been demonstrated in IBS (Figure 2). Recent research also suggests the possibility of defective anti-nociceptive mechanisms in IBS, which might result in sufferers perceiving normal gut sensations as painful. Pain perception may be inhibited by activity in descending tracts arising from the mid-brain, which reduce the response of spinal nerves to nociceptive stimuli. These include both serotonergic and noradrenergic nerves whose activity is reduced in depression, and it is possible that some of the benefits of antidepressants and 5-HT agonists in IBS might be due to their effects on these pathways.11

Proposed mechanisms underlying gut symptoms The bowel reacts to luminal conditions independently of input from the CNS as a result of the activity of the enteric nervous system (ENS). This is a complex and independent nervous system which resembles the CNS rather than peripheral nerves in its anatomy, chemistry and ability to control its own behaviour independently. Intrinsic primary afferent neurons (IPANs) activate peristaltic and secretory reflexes and in response to luminal stimuli may be excited by paracrine secretions from enteroendocrine cells, particularly serotonin (5-HT).7 5-HT is released after meals, stimulating the peristaltic reflex and intestinal secretions. The effect of 5-HT is terminated by reuptake into the gut cells, a process mediated by the serotonin reuptake transporter (SERT). Transgenic mice lacking SERT have changes in stool weight and rectal motility leading to alternating diarrhoea and constipation similar to that of IBS. An increasingly popular theory proposes changes in the processing by the CNS of sensations arising in the gut as a cause of IBS symptoms. Increased visceral hypersensitivity, which may be demonstrated by distension of a balloon placed in the rectum, could arise from local changes in the gut or could equally be mediated in the brain stem or spinal cord (Figure 1).8 Cerebral effects are certainly important, as in some IBS patients there is anticipation of discomfort, so that even sham balloon distensions may provoke pain. Patients who do not initially show hypersensitivity may develop it after repeated painful distensions in the sigmoid colon, whereas normal individuals often become habituated to this. Altered sensitivity might then exacerbate motility disturbances in the gut by up-regulating sensorimotor reflex loops, leading to painful colonic spasm.9 A possible mechanism for stress-induced hypersensitivity is the release of corticotrophin-releasing factor (CRF) from the hypothalamus. The triggering of cortisol release is responsible for stress-induced increases in stool output and colonic motility in animals. Intraventricular CRF antagonists can inhibit the effect of stress on gastrointestinal motility. An abnormal stressCRF response might possibly underlie the marked increase in colonic motility seen in IBS patients.10

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A condition which arises in the gut? Damage to the colonic microflora The incidence of IBS is greater after gut infections, with an ­incidence one year after an episode of bacterial gastroenteritis of 4–12%, and a relative risk 12 times that of healthy controls. Similarly, there is a relative risk of 4 for the development of IBS ­during the year following a course of antibiotics.12 Both infection and antibiotics may damage the faecal flora, which in IBS has been shown to be abnormal.13 No specific pathogen has been detected, but compared to controls there is an unstable flora, with reduced numbers of Lactobacilli and Bifido­ bacteria, and an overgrowth of facultative anaerobes. These are rarely present in more than 105-6/g faeces in health, but may reach 108 in IBS, rising as high as 1010 after food challenge. Although the possible role of Candida albicans in IBS has been strongly advocated by alternative practitioners, no difference in numbers of this organism was found between patients and healthy controls,14 and no evidence exists of improvement of IBS after antifungal drugs. 268

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Motility and Functional Bowel Disease

Increased cerebral activity on painful stimulation in irritable bowel syndrome (IBS) Control

IBS PFC

ACC IC THAL

The regions of interest, with green borders, are the anterior cingulated cortex (ACC), the insular cortex (IC), the prefrontal cortex (PFC) and the thalamus (THAL). Increased activity is shown in red-yellow, and is greater in the ACC of the IBS patient. Reproduced with kind permission of the American Gastroenterological Association from Mertz H, et al. Gastroenterology 2000; 118: 842–48.11

Figure 2

Thus, the relative importance of the nervous system and the gut in the pathogenesis of IBS remains to be resolved. Hydrogen is unlikely to be the only substance produced by abnormal fermentation. It is probable that a range of other compounds are involved which may affect colonic function, leading to spasm and diarrhoea, and possibly increased visceral ­hypersensitivity.

Colonic malfermentation Colonic bacteria have many roles in the large intestine, including the fermentation of food residues entering the caecum and colon to produce short-chain fatty acids and gases such as hydrogen and methane. King and colleagues compared fermentation in 6 IBS patients fulfilling the Rome criteria with 6 age- and sexmatched controls.15 Gas excretion was measured in a purposebuilt whole-body calorimeter. The maximum rate of hydrogen excretion was high in IBS both on a standard diet and after 20 g of oral lactulose, a non-absorbable sugar which acts as a substrate for colonic bacterial fermentation. After 2 weeks on an exclusion diet matched with the standard diet for fibre content, there was a dramatic fall in maximal hydrogen excretion in the patients, together with a significant improvement in symptoms (Figure 3).15 Similarly, reduced hydrogen excretion and a parallel symptomatic improvement was demonstrated in IBS patients when bacterial activity was suppressed by treatment with an antibiotic (metronidazole) or an enteral feed containing no fibre.16 Other workers have also reported increased hydrogen excretion on the breath in IBS, with symptomatic improvement follow­ ing antibiotics.17 They suggested that IBS arises because of small intestinal bacterial overgrowth (SIBO) but to date, such bacterial overgrowth has not been confirmed by culture, and it seems likely that the most important site for gas production is the colon. Malfermentation thus provides a mechanism to explain the occurrence of food intolerance in IBS.18 A number of studies have confirmed improvement in approximately 50% of IBS patients’ symptoms when they avoid certain foods, particularly grains, dairy products, citrus, caffeinated drinks, yeast, ­ potatoes and onions. Such intolerances provide the rationale for the use of low fibre and exclusion diets in the management of IBS. There is no evidence for classical IgE-­mediated allergy as a basis for food intolerances,19 although it has recently been suggested that IgG antibodies may be involved. This seems unlikely as IgG food antibodies are present in healthy blood donors, and the ­success rates with diets based on these (number needed to treat [NNT] 3–4) is less than that with straightforward exclusion diets (NNT 1–2).20

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Pharmacological management The range of possible pharmacological treatments for IBS is wide. These patients are unusually susceptible to drug side effects, and treatment should begin at low dosage and be adjusted according to response. Antispasmodics Antispasmodics are used to relax intestinal smooth muscle and thereby relieve abdominal cramps and pain. Antispasmodic drugs belong to a range of pharmaceutical families, including anticholinergics, calcium-channel blockers (including peppermint oil thought to inhibit gut motility), and opioid receptor agonists. In practice, mebeverine is most widely used for this purpose in the UK. It is cheap and safe, but its NNT is 4.5.2 Opiates Opiates act as analgesics by stimulating descending anti-­nociceptive pathways and inhibiting pain pathways at the level of the spinal cord, modulating gut motility and sensory function. They inhibit intestinal secretions and propulsive motor patterns and hence reduce diarrhoea. Codeine is a highly effective anti-­diarrhoeal whose side effects (nausea and sedation) reduce its tolerance. Loperamide does not cross the blood–brain barrier and is therefore less sedative, but, whilst improving diarrhoea, it lacks effectiveness for pain relief. Serotonin (5-HT) antagonists and agonists Recent studies of a novel 5-HT3 agonist have demonstrated reduction of small bowel transit time and increased frequency of 269

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Motility and Functional Bowel Disease

Increased gas excretion in irritable bowel syndrome (IBS) IBS patients in standard diet

Controls on standard diet 1.0

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Controls on exclusion diet 1.0

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Median 24-hour hydrogen excretion ( ) is greater than that of methane ( ) on a standard diet, but is markedly reduced in IBS subjects following an exclusion diet, although not in healthy controls. Reproduced with kind permission of Elsevier from King TS, et al. Lancet 1998; 352: 1187–89.15

Figure 3

migrating motor complexes. This may explain the action of 5- HT3 antagonists used for chemotherapy-induced vomiting, such as granisetron, which inhibit the colonic response to feeding in IBS and delay colonic transit.7 Alosetron, a new and more specific 5- HT3 antagonist, also improves stool consistency and significantly reduces the symptoms of diarrhoea-predominant IBS.21 Alosetron has been reported to cause intestinal ischaemia, and its use in the USA is now restricted. It is not available in the UK. 5-HT4 agonists show potential for the treatment of ­constipationpredominant IBS. Tegaserod is a partial 5-HT4 agonist. In vivo, tegaserod has been shown to enhance motility at all levels of the gastrointestinal tract by a mechanism likely to involve 5- HT4 receptors on enteric cholinergic neurones. In addition, the drug has demonstrated inhibition of rectal afferents following rectal distension, without altering rectal compliance. This implies an inhibitory effect on nociceptive afferents, again suggesting an agonist effect on 5- HT4 receptors. 22 Other studies employing full 5-HT4 agonists are in progress.

Practical approach Faced with the variety of symptoms, the plethora of opinions and the number of therapeutic possibilities available, the physician can be excused for feeling daunted by the management of IBS. Some physicians take refuge in the belief that the exclusion of organic disease will relieve the patient’s anxiety that she must inevitably improve, and therefore make little, if any, attempt themselves to control her symptoms. The large numbers of patients who seek help for IBS from alternative practitioners suggests however, that this approach is frequently unsatisfactory. Although there is at present no simple single treatment for IBS, consideration and correction of the underlying pathophysio­ logy often provides considerable benefit and there can be no ­justification for therapeutic nihilism. It is essential first to exclude organic disease (Table 1) and ­reassure the patient. It is then necessary to seek evidence of ­anxiety. Several validated questionnaires are available for this purpose. Anxiety may produce air-swallowing, bloating and wind, and may be treated with relaxation, breathing retraining, anxiolytic drugs or cognitive–behavioural therapy (CBT). Hypnosis is valuable in the management of anxiety, especially in patients with underlying phobias, but it is rarely available on the NHS and is unnecessary for the majority of cases of IBS. Evidence of colonic malfermentation should be sought from the history; such patients suffer bouts of urgent loose stools at least 2 or 3 times a week. These usually respond to a low-fibre

Antidepressants Antidepressants are known to improve IBS symptoms, but their role in its management can be limited by side effects. Tricyclic antidepressants (TCAs), in particular, have demonstrated distinct benefits for abdominal pain in low dose regimens. Selective serotonin reuptake inhibitors (SSRIs) appear be less effective than TCAs when used in IBS in doses below the psychiatric therapeutic range.23

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diet (which is less demanding) or a full exclusion diet.24 If the low-fibre diet leads to constipation, this can be relieved by a non-fermentable bulk laxative such as methyl cellulose, sterculia or cracked linseed, which are less likely than fermentable agents such as bran or ispaghula to lead to painful gas formation. Constipation is not always apparent, especially when accompanied by occasional episodes of overflow diarrhoea,25 but should be suspected when the patient frequently passes small hard stools with straining and feelings of incomplete evacuation. The loaded colon is frequently palpable per abdomen. Treatment is again with non-fermentable bulking agents, but these work better if the colon is initially emptied using a powerful laxative such as sodium picosulphate or polyethylene glycol. Occasional doses of a stimulant laxative such as senna may be necessary from time to time if the bowel again becomes loaded. If flatulence remains a problem, a low-fibre diet may be recommended. High fibre diets generally make malfermentation, and thus symptoms of IBS, worse.26 Those patients who do not respond to the above measures may be helped by a time-honoured regimen consisting of an antispasmodic, such as mebeverine, supplemented as necessary with a non-fermentable bulking agent and low-dose antidepressants (such as amitriptyline 25 mg).27 ◆

12 Madden JAJ, Hunter JO. A review of the gut microflora in irritable bowel syndrome and the effects of probiotics. Br J Nutrition 2002; 88(suppl 1): S67–S72. 13 Balsari A, Ceccarelli A, Dubin F, Fosce E, Poli G. The faecal microbial population in the irritable bowel syndrome. Microbiologica 1982; 5: 189–94. 14 Middleton SJ, Coley A, Hunter JO. The role of faecal Candida albicans in the pathogenesis of food-intolerant irritable bowel syndrome. Postgraduate Med J 1995; 68: 453–54. 15 King TS, Elia M, Hunter JO. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 1998; 352: 1187–89. 16 Dear KLE, Elia M, Hunter JO. Do interventions which reduce colonic bacterial fermentation improve symptoms of irritable bowel syndrome? Digestive Dis Sci 2005; 50: 758–66. 17 Pimentel M, Chow EJ, Lin HC. Normalisation of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized, placebo-controlled study. Am J Gastroenterology 2003; 98: 412–19. 18 Nanda R, James R, Smith H, et al. Food intolerance and the irritable bowel syndrome. Gut 1989; 30: 1099–104. 19 Alun Jones V, McLaughlin P, Shorthouse M, Workman EM, Hunter JO. Food intolerance: a major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982; 2: 1115–17. 20 Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in irritable bowel syndrome; a randomized controlled trial. Gut 2004; 53: 1459–64. 21 Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 2000; 355: 1035–40. 22 Nguyen A, Camilleri M, Kost LJ, et al. SDZ HTF 919 stimulates colonic motility and transit in vivo. J Pharmacol Experiment Ther 1997; 280: 1270–76. 23 Clouse RE, Lustman PJ. Antidepressants for IBS. In: Camilleri M, Spiller RC, eds. Irritable bowel syndrome: diagnosis and treatment. Edinburgh: WB Saunders, 2002. 24 Parker TJ, Naylor SJ, Riordan AM, et al. Management of patients with food intolerance in irritable bowel syndrome: the development and use of an exclusion diet. J Human Nutr Dietetics 1995; 8: 159–66. 25 Ragnarsson G, Bodemar G. Division of the irritable bowel syndrome into subgroups on the basis of daily recorded symptoms in two outpatient samples. Scand J Gastroenterol 1999; 34: 993–1000. 26 Atkinson RJ, Hunter JO. Role of diet and bulking agents in the treatment of IBS. In: Camilleri M, Spiller RC, eds. Irritable bowel syndrome: diagnosis and treatment. Edinburgh: WB Saunders, 2002. 27 Truelove SC. Treatment of IBS. In: Jewell DP, Gibson PR, eds. Topics in Gastroenterology 12. Oxford: Blackwell Scientific Press, 1985.

References 1 Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999; 45(suppl II): 1143–47. 2 Spiller RC. Irritable bowel syndrome. In: Weinstein WM, Hawkey CJ, Bosch J, eds. Clinical gastroenterology and hepatology. Philadelphia: Elsevier Mosby, 2005. 3 Creed FH, Guthrie E. Psychological treatment of the irritable bowel syndrome: a review. Gut 1989; 30: 1601–09. 4 Koloski NA, Talley NJ, Boyce PM. Predictors of health care seeking for irritable bowel syndrome and nonulcer dyspepsia: a critical review of the literature on symptom and psychosocial factors. Am J Gastroenterol 2001; 96: 13404–09. 5 Fowlie S, Eastwood MA, Prescott R. Irritable bowel syndrome: the influence of psychological factors on the symptom complex. J Psychosomatic Res 1992; 36: 175–80. 6 Bennett EJ, Tennant CC, Piesse C, et al. Level of chronic life stress predicts clinical outcome in irritable bowel syndrome. Gut 1998; 43: 256–61. 7 Gershon MD. Importance of serotonergic mechanisms in gastrointestinal motility and sensation. In: Camilleri M, Spiller RC, eds. Irritable bowel syndrome: diagnosis and treatment. Edinburgh: WB Saunders, 2002. 8 Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 1973; 14: 125–32. 9 Silverman D, Munakata J, Ennes H, et al. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997; 112: 64–72. 10 Saito K, Kasai T, Nagura Y, Ito H, Kanazawa M, Fukudo S. Corticotropin-releasing hormone receptor 1 antagonist blocks brain-gut activation induced by colonic distension in rats. Gastroenterology 2005; 129: 1533–43. 11 Mertz H, Morgan V, Tanner G, et al. Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distension. Gastroenterology 2000; 118: 842–48.

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Further reading Camilleri M, Spiller RC. Irritable bowel syndrome: diagnosis and treatment. Edinburgh: WB Saunders, 2002. Weinstein WM, Hawkey CJ, Bosch J. Clinical gastroenterology and hepatology. Philadelphia: Elsevier Mosby, 2005. Chudleigh VA, Hunter JO. Diseases of the gastrointestinal tract. In: Geissler C, Powers H, eds. Human nutrition, 11th edn. Edinburgh: Elsevier Churchill Livingstone, 2005. Hunter JO, Woolner JJ, Workman EM. Solve your food intolerances, 5th edn. London: Vermilion, 2005.

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