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
Anna L Forbes IBS in the USA in 1998 were around $1.6 billion, and it is the
J O Hunter 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

A condition which arises in the nervous system?

Abstract It has long been widely believed that IBS sufferers endure gut
Irritable bowel syndrome (IBS) is characterized by a number of ­symptoms complaints as a result of mental turmoil. A strong correlation
including diarrhoea, constipation, wind and bloating. Despite many years between IBS and psychiatric disorders lead to the conclusion that
of research, IBS still has an uncertain aetiology. The Rome criteria have all patients with IBS are psychologically abnormal.3 ­Correlations
been devised to ensure recruitment consistency in studies. This contribu- between IBS and mental health are hampered, however, by the
tion looks into the possible causes of IBS and now it may be managed. 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
Keywords colonic malfermentation; constipation; diarrhoea; irritable less, adverse life events often precede its development, and these
bowel syndrome 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
Irritable bowel syndrome (IBS) is the complaint encountered are the most frequent psychiatric disorders in IBS. They exacer-
most frequently in gastroenterological clinics in the Western bate symptoms and adversely influence prognosis.5
world – and the most poorly understood. Patients suffer persis- The evidence for a cerebral cause of IBS may be summarized
tent abdominal pain with diarrhoea or constipation, wind and as follows.
bloating for which, despite intensive investigation, no cause can • Psychosocial factors may affect IBS via a central nervous
be discovered. The prognosis of IBS is benign, but its symptoms ­system (CNS) route.
may mimic those of more serious conditions, such as inflamma- • Centrally active treatments, such as psychotherapy, hypnosis
tory bowel disease or colon cancer. These must be excluded in and antidepressants, are beneficial in some cases of IBS.
every case, and certain danger signals, which may herald the pres- • Symptoms are absent during sleep when the CNS is less
ence of more serious diseases, are listed in Table 1, together with ­active.
those investigations necessary to exclude organic ­pathology. • Differences in CNS blood flow have been detected on
IBS is remarkable in that, despite many years of research, it is ­functional brain scans in IBS patients.
still unclear whether it is primarily a condition of the brain and • IBS patients have a higher prevalence of other functional and
enteric nervous system, which affects the gut, or a disorder of psychomotor disorders which could have a common cause from
the gut, which may influence the brain. This is partly because CNS malfunction.6
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 rea-
sons not only within, but also beyond the gut, such as anxiety Alarm symptoms (not present in IBS) and
and depression, or musculoskeletal problems. The Rome criteria investigations
(Table 2) devised by an international co-coordinating commit-
tee have latterly been widely applied in an attempt to ensure Alarm symptoms Suggested investigations
recruitment consistency in both surveys and pathophysiological
studies.1 Rectal bleeding Full blood count
Weight loss Urea and electrolytes
Nocturnal abdominal Liver function tests
pain or diarrhoea Thyroid function
Anaemia Serum albumin and calcium
Anna L Forbes BMedSci BMBS is a Junior Doctor at the West Suffolk
Fever C-reactive protein
Hospital in Bury St Edmunds, UK. She graduated from Nottingham
Tissue transglutaminase
University, UK. Her current research interests include irritable bowel
Stool culture and microscopy
syndrome. Competing interests: none declared.
Endoscopy or radiology of colon
in those aged >45 years.
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. Table 1

MEDICINE 35:5 267 © 2007 Elsevier Ltd. All rights reserved.

 Motility and Functional Bowel Disease
The Rome II criteria
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.
Table 2
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, particu-
larly 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 pro-
cessing 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 hypersen-
sitivity may develop it after repeated painful distensions in the
sigmoid colon, whereas normal individuals often become habitu-
ated 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 motil-
ity in animals. Intraventricular CRF antagonists can inhibit the
effect of stress on gastrointestinal motility. An abnormal stress-
CRF response might possibly underlie the marked increase in
colonic motility seen in IBS patients.10
MEDICINE 35:5
Visceral hypersensitivity in irritable bowel syndrome
100
Proportion feeling pain %
80
60
40 Normal subjects
Irritable bowel subjects
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
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 cor-
tex 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 depres-
sion, and it is possible that some of the benefits of antidepres-
sants and 5-HT agonists in IBS might be due to their effects on
these pathways.11
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 differ-
ence 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 © 2007 Elsevier Ltd. All rights reserved.
 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

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 sex-
matched controls.15 Gas excretion was measured in a purpose-
built 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 sub-
strate 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 paral-
lel symptomatic improvement was demonstrated in IBS patients
when bacterial activity was suppressed by treatment with an anti-
biotic (metronidazole) or an enteral feed containing no fibre.16
Other workers have also reported increased hydrogen excre-
tion 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
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.
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 anticho-
linergics, 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

MEDICINE 35:5 269 © 2007 Elsevier Ltd. All rights reserved.

 Motility and Functional Bowel Disease
Increased gas excretion in irritable bowel syndrome (IBS)
IBS patients in standard diet
1.0
Median rate ml/min
0.5
0 0
09:00 15:00 21:00 03:00
Time
IBS patients on exclusion diet
1.0
Median rate ml/min
0.5
0 0
09:00 15:00 21:00 03:00
Time
Median 24-hour hydrogen excretion ( ) is greater than that of methane (
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 signifi-
cantly 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 ­constipation-
predominant 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.
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 sero-
tonin reuptake inhibitors (SSRIs) appear be less effective than
TCAs when used in IBS in doses below the psychiatric therapeu-
tic range.23
MEDICINE 35:5
Controls on standard diet
1.0
Median rate ml/min
0.5
09:00 09:00 15:00 21:00 03:00 09:00
Time
Controls on exclusion diet
1.0
Median rate ml/min
0.5
09:00 09:00 15:00 21:00 03:00 09:00
Time
) on a standard diet, but is markedly reduced in IBS subjects following an
Practical approach
Faced with the variety of symptoms, the plethora of opinions
and the number of therapeutic possibilities available, the physi-
cian can be excused for feeling daunted by the management of
IBS. Some physicians take refuge in the belief that the exclu-
sion 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 unsatisfac-
tory. 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). Hypno-
sis 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
270 © 2007 Elsevier Ltd. All rights reserved.
 Motility and Functional Bowel Disease
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 accom-
panied 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 stimu-
lant 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 anti-
spasmodic, such as mebeverine, supplemented as necessary with
a non-fermentable bulking agent and low-dose antidepressants
(such as amitriptyline 25 mg).27 ◆
References
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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 non-
painful rectal distension. Gastroenterology 2000; 118: 842–48.
MEDICINE 35:5
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
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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
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26 Atkinson RJ, Hunter JO. Role of diet and bulking agents in the
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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.
271 © 2007 Elsevier Ltd. All rights reserved.