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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

Irritable bowel syndrome (IBS) is a functional, multifactorial disease characterized by abdominal pain and erratic bowel habit. Changes in gastrointestinal motor function, enhanced perception of stimuli arising from the gut wall and psychosocial factors are thought to be major contributors for symptom generation. In recent years, several additional factors have been identified and postulated to interact with these classical mechanisms. Reduced ability to expel intestinal gas with consequent gas trapping and bowel distension may contribute to abdominal discomfort/pain and bloating. Abnormal activation of certain brain regions following painful stimulation of the rectum suggests altered processing of afferent signals. An acute gastrointestinal infection is now a recognized aetiological factor for symptom development in a subset of IBS patients (i.e. post-infectious IBS), who are probably unable to down-regulate the initial inflammatory stimulus efficiently. Furthermore, low-grade inflammatory infiltration and activation of mast cells in proximity to nerves in the colonic mucosa may also participate in the frequency and severity of perceived abdominal pain in post-infectious and non-specific IBS. Initial evidence suggests the existence of changes in gut microflora, serotonin metabolism and a genetic contribution in IBS pathophysiology. These novel mechanisms may aid a better understanding of the complex pathophysiology of IBS and to develop new therapies.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders seen in primary care and specialist practice characterized by abdominal pain and disturbed defecation that cannot be explained by structural or biochemical abnormalities.1 The complex and only partially understood pathogenesis of IBS symptoms has led to imprecise drug development and unsatisfactory patient management. For these reasons there is renewed interest in IBS pathophysiology and substantial efforts are being put forward for the development of more effective drugs.

Multiple factors are thought to contribute to the symptom complex experienced by IBS patients. Classical pathogenetic mechanisms include: (i) changes in gastrointestinal motility that are, however, poorly related to the patient's symptoms; (ii) increased visceral perception, seen only in a sub-group of patients; and (iii) psychosocial factors that are thought to contribute, but are unlikely the cause of symptoms. New areas of research in the field of IBS pathophysiology include functional brain imaging, infection, immunity and genetics.

Altered motor function

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

IBS has been always considered a gut motor disorder. A number of motor abnormalities have been described in the colon and small bowel of IBS patients. Exaggerated intestinal motor responses have been shown after meal ingestion, stress, mechanical stimulation, colecystokinin and corticotrophin-releasing factor infusion (for review see Camilleri and Ford2). However, the majority of studies assessing intestinal motor function in IBS were carried out in small numbers of patients using a variety of protocols and methodologies, which hamper comparative evaluations and generalizations. The relevance of motility changes for symptom generation remains elusive (i.e. only a few studies have found an association between motor events and patient's symptom perception). Furthermore, the described qualitative motility changes lack of specificity (i.e. similar motor changes could be detected in conditions other than IBS and even in healthy controls). Differences between IBS patients and healthy subjects more probably reflect a quantitative rather than qualitative abnormality (i.e. transit time is accelerated in diarrhoea and delayed in constipation-predominant IBS).3

Visceral hypersensitivity

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

Ritchie was the first investigator to describe that IBS patients had poor tolerance to balloon distension of the rectum.4 Since then, decreased sensory threshold to rectal distension in IBS patients has been confirmed by several laboratories.5–7 Increased perception of visceral stimuli also affects other regions of the gastrointestinal tract, including the sigmoid colon,8 ileum,9 duodenum10–12 and oesophagus.13 Initial studies suggested that visceral hypersensitivity could be considered as a ‘biological marker’ of IBS.5 One study showed that decreased rectal pain threshold has a good sensitivity (95%), specificity (72%) and positive predictive values (85%) to discriminate IBS patients from normal subjects and non-IBS patients.14 However, other studies showed decreased threshold to visceral sensation in roughly 60% of IBS patients. This lower sensation threshold could be a more frequent finding in the diarrhoea-predominant IBS group of patients as opposed to the constipation-predominant group, in whom discomfort may be perceived at greater distension volumes than healthy controls.15 Anticipation and hypervigilance probably play an important role in the perception of visceral sensation in IBS. As a group, patients with IBS have a greater propensity to label visceral sensations negatively and show a lower tolerance for rectal balloon distension.7

The site of altered sensory processing in IBS patients along the sensory afferent system is unknown. This may occur through alteration in neural processing at the peripheral level (i.e. sensory nerve endings in the intestinal wall), at the level of dorsal horn neurones or at the central level (i.e. higher cortical level).

Abnormal gas handling

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

Bloating and abdominal distension are frequent complaints in patients with IBS. Although there is no evidence of abnormal amount or composition of intestinal gas in IBS,16 gas may be propelled abnormally through the gut.17 In normal subjects, gas experimentally infused in the small bowel was propelled rapidly through the bowel and consequently expelled.17 Conversely, a high proportion of IBS patients retained a significant amount of the infused gas.18 Furthermore, even when IBS patients do not retain excessive gas, they report more abdominal discomfort than healthy subjects.18 IBS patients often report that gas-related symptoms are exacerbated following meal ingestion and dietary lipids are known to increase sensory perception in IBS patients.19 Serra et al. showed that the infusion of lipids in the duodenum induced delayed gas transport through the bowel and was associated with abdominal bloating.20 Taken together, these results suggest that IBS patients have a difficult expulsion of intestinal gas, which may be ascribed to abnormal intestinal motility as well as poor tolerance to intestinal gas, which is in keeping with a reduced threshold for sensory perception.

Psychosocial factors

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

After almost two centuries of research, psychological factors still represents a major field of investigation in IBS. Although these factors certainly contribute to aggravation of symptoms, it is unlikely that they are the cause of IBS. Affective disorders, including somatization, anxiety, hostility and phobia are common comorbid conditions in IBS.21–23 A history of emotional, physical and sexual abuse is frequently encountered in IBS.24–26 Psychological symptoms are more relevant in the health-care utilizing population, in whom the prevalence of psychological disorders ranges between 40% and 90%,27–30 than in individuals with IBS who do not seek medical help, in whom the prevalence has been reported to be similar to that found in the general population, or in patients with organic gastrointestinal disease.31–33 The discrepancy between psychological factors in consulters vs. non-consulters has led to the suggestion that psychological factors may influence the outcome of the disease by increasing illness behaviour of patients, fear of cancer and less coping capability.

On the other hand, psychological factors (particularly stress) affect digestive motor function and visceral perception,34, 35 although this has been demonstrated for acute stress, while the effect of chronic stress remains largely unexplored. Acute stress may also contribute to the increased activation of mucosal inflammatory cells, especially mast cells, contributing possibly to altered bowel physiology and symptom generation. Stress-induced release of corticotrophin-releasing factor (CRF) may be responsible for mast cell activation and mediator release. In support of these data, recent work in rats showed that acute stress modulates mast cell histamine content in the gastrointestinal tract via interleukin (IL)-1 and CRF release.36 These results are of particular relevance as CRF infusion in IBS patients evokes an exaggerated colonic motor response.37

Central nervous system (cns)

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

A role for abnormal CNS processing of stimuli arising from the gut in IBS patients has been postulated, although far from being fully understood. Noxious visceral stimuli originating from the periphery reach the brainstem and thalamus that relay signals to the limbic and cortical systems. Activation of the anterior cingulate cortex, a region of the prefrontal cortex,38 is thought to be crucial for the coding of suffering and related emotions.39 Functional brain imaging demonstrated an increased activation of the anterior cingulated cortex in IBS patients compared to healthy controls.40, 41 This increased brain activation occurs both during actual painful stimuli applied to the colon and anticipation of such painful stimuli.40 Significant gender differences in activation of brain regions has also been reported in IBS patients,42 thus adding further evidence indicating sex-related differences in IBS pathophysiology.43 Anti-nociceptive mechanisms are thought to reduce the cognitive sensation of physiological stimuli generated within the gut and reaching CNS centres. Although it has been suggested that this descending anti-nociceptive system is defective in IBS patients,44 further studies are needed to confirm this hypothesis.

Gastrointestinal infections

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

Acute infectious gastroenteritis is a common event in western countries, occurring on average 1.4 times per year per person. Although the vast majority of subjects recover completely following eviction of the infectious agent, a small but significant proportion of subjects go on to develop long-lasting digestive symptoms. An infectious origin has been demonstrated, or is highly presumptive, in certain forms of gastroparesis,45, 46 dyspepsia,47 chronic intestinal pseudo-obstruction,48, 49 functional bowel disorders50 and IBS.51 Chaudhary and Truelove were the first to describe that about 25% of a series of 130 IBS patients dated the onset of their symptoms to an attack of acute infectious gastroenteritis.52 This seminal observation has been confirmed subsequently by several prospective studies indicating that long-term IBS symptoms develop in 7–32% of subjects after acute enteritis.51 Risk factors for the development of post-infectious IBS include the virulence of the pathogen,53, 54 younger age, female sex, the long duration of the initial illness and the presence of psychological difficulties (including hypochondriasis and adverse life events).53, 55 The use of antibiotics during acute bacterial gastroenteritis is also thought to increase the risk of the development of long-term digestive symptoms.56 Predominant post-infectious IBS symptoms are abdominal pain, diarrhoea, urgency and bloating.53 This condition, like other non-specific forms of IBS, represents a significant burden on the health-care system, with the majority of patients consulting their family physician within 6 years of symptom onset and around 80% requiring further investigation, such as colonoscopy or barium enema.57 The prognosis of post-infectious IBS may be similar to that of non-specific IBS. One study indicates that 43% of patients that developed the symptoms post-infection recovered at 6 years compared to 31% in non-specific IBS.57 Putative mechanisms involved in the maintenance of bowel symptoms include increased mucosal serotonin-producing enterochromaffin cells, T lymphocytes, macrophages,58, 59 and pro-inflammatory cytokines.60 These factors would interact with the sensory-motor apparatus of the gut affecting bowel function and symptom perception (see below). An animal model has been developed to gain further insights into the pathophysiology of post-infectious IBS.61 This model emphasizes the importance of a long-lasting production of inflammatory mediators by resident cells in the neuro-muscular layers in the maintenance of altered bowel physiology.62

Minimal inflammation and neuro-immune interactions

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

Several lines of evidence support the hypothesis that a low-grade mucosal inflammatory process, albeit undetectable endoscopically or with conventional mucosal histology, may play a role in IBS pathogenesis. First, patients in remission from inflammatory bowel disease develop IBS-like symptoms with a higher than expected prevalence.63, 64 Secondly, IBS symptoms may develop following an acute episode of infectious gastroenteritis.51, 55 Thirdly, an increased number of inflammatory cells (e.g. mast cells, T lymphocytes, macrophages) have been detected in the colonic and ileal mucosa as well as in muscularis externa of jejunum of patients with IBS.58, 59, 65–73Table 1 provides a list of studies investigating the presence of immune activation in IBS.

Table 1.  Studies describing low-grade inflammation in irritable bowel syndrome
Clinical settingNo. of patientsDiagnostic criteriaType of inflammatory cellsIntestinal tract assessedIntestinal layer assessedRef.
  1. C-IBS, constipation-predominant irritable bowel syndrome; D-IBS, diarrhoea-predominant irritable bowel syndrome; PI-IBS, post-infectious irritable bowel syndrome.

Irritable colon4Mast cellsColonMuscularis propria69
IBS51UnspecifiedRight colonLamina propria70
D-IBS20ManningMast cellsIleumLamina propria67
PI-IBS10Rome IChronic infiltrateLeft colonLamina propria71
D-IBS14Rome IMast cellsRight colonLamina propria72
PI-IBS10Rome IT-lymphocytesRectumLamina propria58
IBS77Rome IActivated T-lymphocytesColonLamina propria65
IBS10Rome ILymphocytesProximal jejunumMyenteric plexus68
IBS75Rome IT-lymphocytes Mast cellsRectumLamina propria73
PI-IBS30Rome IT-lymphocytesRectumLamina propria59
IBS44Rome IIMast cellsLeft colonLamina propria66

Inflammatory cells in the intestinal mucosa of IBS patients are activated65, 66 and release a number of mediators, including interleukins,60 nitric oxide,74 histamine and proteases.66 These mediators are capable of affecting the function of enteric nerves with activation of abnormal secreto-motor responses within the gut, leading to altered bowel function.75, 76 Also, inflammatory mediators may act on the sensory innervation of the gut with consequent increased visceral sensory perception and generation of abdominal discomfort and pain.75 In this regard, it has been demonstrated recently that both severity and frequency of perceived abdominal painful sensations in IBS patients were correlated with the presence of activated mast cells in proximity of nerve endings in the colonic mucosa.66 However, a clear demonstration of a cause–effect relationship between minimal inflammation and IBS it is still awaited. An initial attempt to reduce intestinal inflammation with steroids in post-infectious IBS has failed to demonstrate any symptomatic improvement.77 However, these apparently disappointing results should be viewed in light of the known side-effects of steroids, including those affecting the gastrointestinal tract. It is also true that long-term changes in function and structure of nerves (i.e. neuroplasticity) within the gastrointestinal tract or in the sensory afferent system (i.e. dorsal horn of the spinal cord), that probably occur following chronic exposure to inflammatory mediators, may explain at least in part the lack of efficacy of steroids in IBS. Further studies are now awaited.

Microflora

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

It has been claimed that quantitative and/or qualitative changes in intestinal microflora may contribute to sensory-motor dysfunction of IBS. This may occur through increased fermentation of food with gas production,78 bile acid malabsorption79 and mucosal irritation and minimal inflammation.75 None the less, studies assessing intestinal microflora in IBS are as yet limited. This has to be ascribed to methodological limitations and to our incomplete knowledge of the normal human microflora. Decreased Coliforms, Lactobacilli and Bifidobacteria have been described in the faeces of IBS patients;80 however, the faecal microflora may not be representative of the resident colonic flora. A preliminary report indicates increased Anaerobes, Escherichia coli and Bacteroides in the colonic mucosa of IBS patients.81

By using the lactulose hydrogen breath test, Pimentel et al. found a high (78%) small intestinal bacterial overgrowth in IBS patients.82 These results need to be considered with caution, particularly in light of the known limits of the lactulose breath test in the diagnosis of bacterial overgrowth.83 Insights into the putative role of intestinal microflora in the pathogenesis of IBS may also be derived from responses to agents targeting the intestinal ecosystem. Probiotics influence the expression of neuronal markers in the enteric nervous system84 and introduction of conventional microflora to germ-free rats influences intestinal motility.85 Also, some beneficial effects of non-absorbable antibiotics86, 87 and probiotics88–91 have been reported in IBS in some studies. However, the precise role of these agents in the management of IBS is still a controversial issue.

Serotonin

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

The gastrointestinal tract contains the majority of serotonin (5-HT) of the human body. Although enteric nerves release a small amount of 5-HT, roughly 90% of this bioactive amine is contained in enterochromaffin (EC) cells. 5-HT plays a crucial role in the regulation of secretion, motility and sensory events in the gastrointestinal tract trough the activation of a number of receptors distributed widely on enteric nerves and sensory afferents.92 Enterocytes terminate the effects of 5-HT by removing it from the interstitial space through the action of the re-uptake serotonin transporter (SERT). Thus, changes in 5-HT content and release, expression of 5-HT receptors or changes in SERT expression/activity may contribute to sensorimotor function in IBS. Several, although contradictory, changes have been reported in intestinal 5-HT functioning in IBS, which may represent the rationale and efficacy for a 5-HT targeted drug therapy in IBS (Table 2).58, 92–98

Table 2.  Changes in enterochromaffin cells, serotonin and serotonin reuptake transporter in IBS
ConditionSiteEC cells5-HT contentSERTReference
  1. EC, enterochromaffin; C-IBS, constipation-predominant irritable bowel syndrome, D-IBS, diarrhoea-predominant irritable bowel syndrome. [UPWARDS ARROW], increase; [DOWNWARDS ARROW], decrease; ⇆, no change; –, not assessed.

IBSrectum[UPWARDS ARROW]93
D-IBSserum[UPWARDS ARROW]94
Constipationcolon[DOWNWARDS ARROW]95
PI-IBSrectum[UPWARDS ARROW]58
C-IBSrectum[UPWARDS ARROW]96
D-IBSserum[UPWARDS ARROW]97
IBSrectum⇆ (release)[DOWNWARDS ARROW] (mRNA)98

Genetic factors

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

The data suggesting that there may be a genetic component in IBS include: (i) clustering of IBS in families;99 (ii) 2-fold increased frequency of IBS in monozygotic twins compared with dyzigotic twins;100,101 (iii) polymorphysm of genes controlling down-regulation of inflammation (i.e. IL-10 and transforming growth factor-β1)102 and SERT.103 It is unlikely that genetic factors alone are the cause of IBS; they interact most probably with environmental factors for the full phenotypic expression of the disease.100 Further studies are needed to clarify the involvement of genetic factors in IBS.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References

IBS remains a complex and inadequately understood disease. However, immunological, infective and genetic factors begin to emerge as candidate mechanisms underlying disturbed sensory and motor function in this syndrome. These mechanisms may help to aid a better understanding of symptom generation and to develop novel pharmacological drugs for this common condition.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Altered motor function
  5. Visceral hypersensitivity
  6. Abnormal gas handling
  7. Psychosocial factors
  8. Central nervous system (cns)
  9. Gastrointestinal infections
  10. Minimal inflammation and neuro-immune interactions
  11. Microflora
  12. Serotonin
  13. Genetic factors
  14. Conclusions
  15. References
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