• functional gut disorders;
  • gut reflexes;
  • visceral afferents;
  • visceral sensitivity


  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References

Abstract Physiological gut stimuli during the digestive process are not normally perceived. However, gut stimuli activate a variety of afferent pathways and in some circumstances may induce conscious sensations. Experimental evidence gathered during the past decade suggests that patients with functional gut disorders and unexplained abdominal symptoms may have a sensory dysfunction of the gut, so that physiological stimuli would induce symptoms. Assessment of visceral sensitivity is still poorly developed, but in analogy to somatosensory testing, differential stimulation of visceral afferents may be achieved by a combination of stimulation techniques, which may help to characterize sensory dysfunctions. Visceral afferent input is modulated by a series of mechanisms at different levels of the brain gut axis, and conceivably, a dysfunction of these regulatory mechanisms could cause hyperalgesia. The sensory dysfunction in functional patients seems associated to altered reflex activity, and both mechanisms may interact to produce the symptoms. Evidence of a gut sensory–reflex dysfunction as a common pathophysiological mechanism in different functional gastrointestinal disorders, would suggest that they are different forms of the same process, and that the clinical manifestations depend on the specific pathways affected.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References

The digestive system can adapt to large dietary variations and implement the digestive process without symptoms. This adaptability relays on a complex net of regulatory mechanisms that, by and large, operate via reflex arcs; gut stimuli activate afferent pathways and release specific responses.1 Most afferent pathways reach reflex stations within the enteric or the autonomic nervous system, i.e. sympathetic and parasympathetic. However, under some circumstances, gut stimuli may activate afferents with cortical projection and induce conscious perception of abdominal sensations. The peripheral neurone of this viscerosensory system follows sympathetic–splanchnic pathways up to the spinal cord.1–5

Abdominal symptoms in the absence of organic cause usually reflect a digestive dysfunction. In some cases, the alteration can be clearly demonstrated, and specific syndromes have been identified. Gastroparesis is characterized by impaired contraction of the stomach and inability to empty its contents.6,7 Intestinal pseudo-obstruction, defined as chronic or recurrent symptoms of intestinal obstruction without mechanical compromise of the gut, has been shown to be caused by a motor dysfunction of the small intestine, either due to a neuropathy or to a myopathy.8–10 However, in most cases the cause of functional symptoms still remains unknown. This is a clinically relevant problem, because a considerable proportion of the patients that consult a gastroenterologist complain of abdominal symptoms, without demonstrable cause by conventional diagnostic tests.11–13 Unexplained abdominal symptoms have been classified under the category of functional gastrointestinal disorders, and several syndromes, such as functional dyspepsia and irritable bowel syndrome (IBS), have been defined.11 Functional dyspepsia applies to symptoms such as epigastric pressure, fullness and bloating, that presumably originate from the upper gastrointestinal tract, and that are frequently precipitated by meals.12 IBS is attributable to the distal gut, and is characterized by abdominal pain or discomfort associated to disordered bowel habit.13 The diagnosis of those syndromes is solely based on clinical criteria, because their underlying pathophysiology remains unestablished.14

When motility tests were initially developed, these syndromes were thought to be related to gut motor dysfunctions. Over the years, a variety of motility features have been described in patients with functional gut disorders, but unfortunately the relationship of these motor patterns to symptoms remains unclear.15–19 By the early 1990s, it became apparent that functional gastrointestinal disorders cannot be entirely explained on the basis of motility disturbances, at least using standard techniques, and furthermore, other studies found sensory gut dysfunctions in these patients. It was initially described that patients with IBS exhibited increased perception of rectal and colonic distension,20–22 and that dyspeptic patients had gastric hypersensitivity.23–25 Furthermore, increased visceral perception was found in a variety of functional thoracic, urological and gynaecological disorders. These data together suggested that patients with different visceral functional disorders could have a sensory dysfunction so that physiological stimuli that were normally unperceived could activate perception pathways and produce symptoms.26,27

Sensitivity tests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References

The concept of visceral hypersensitivity as the cause of functional symptoms attracted considerable interest in the field of visceral sensitivity, that had received relatively little attention until then.4,26 Obviously, the investigation of the mechanisms of visceral perception in healthy subjects requires probing stimuli that activate afferent pathways and induce conscious sensations.

Gut distension

The most common stimulus applied in the gut has been distension.4 Gut distension can be performed by means of a distending device, a balloon or similar, mounted onto a tube. High-compliance latex balloons made with condoms have relatively low intrinsic pressures, and compliance can be calculated with a reasonably small error. Flaccid bags with negligible intrinsic pressure require no corrections and may be preferable.28,29 However, the bag has to be oversized, because when the capacity of the bag is attained during a distension, the gut is not really being tested. Most studies use air to produce gut distension, because its resistance to flow through small tubes is relatively low. Furthermore, in contrast to liquids, air does not present the problem of hydrostatic pressure differences along the connecting line. However, air is compressible, and hence the actual distending volume depends on the pressure within the distending device. In a conventional balloon inflated with a syringe, this compression is negligible. However, when using large pumps, air compression requires careful correction before interpreting distension data. Furthermore, the compliance of the pump, specially with bellows pumps that are deformable, may require an additional correction factor.29,30

Several methods to produce distension may be used. Distensions can be produced by manual inflation using a syringe, with automated pumps, or with a barostat that applies fixed intraluminal pressures.28–31 However, these methods do not allow standardization of the distending stimuli when the compliance of the gut varies, for instance, when the gut relaxes, intraluminal pressure decreases if the volume is fixed, and if the pressure is fixed the volume enlarges.31 To overcome these problems a new instrument, the tensostat, has recently been developed.32 The tensostat is a computerized air pump that applies fixed tension levels on the gut wall. Based on intraluminal pressure and intraluminal volume, the system calculates wall tension, by applying Laplace's Law (either for the sphere or for the cylinder), and drives the pump to maintain the desired tension level on the gut wall. A study in healthy subjects using the tensostat has shown that perception of gut distension depends on stimulation of tension receptors, rather than on intraluminal volume or pressure.32 Hence, the tensostat may allow a better standardization of distending stimuli in situations in which the capacity and compliance of the gut are different.

The symptoms induced by gastrointestinal distension are similar to those reported by patients with functional gastrointestinal disorders, and include abdominal pressure and fullness, referred to the epigastrium and the paraumbilical region. The type of sensations induced by distension is rather homogeneous from the stomach down to the mid small bowel,33–36 which indicates that the expression of the gut in response to stimuli and the discriminative value of symptoms in relation to the site of origin in the gut are both relatively poor. A small proportion of distensions in the stomach and proximal duodenum induces nausea, which is rarely induced by jejunal distension. In contrast, jejunal distensions are frequently perceived as colicky or stinging sensation. The intensity of perception is stimulus-related; small stimuli are unperceived and the intensity of the conscious sensations increases from the perception threshold up to the threshold for discomfort. Interestingly, the same type of sensations are induced by barely perceptible up to uncomfortable distensions.33

Complementary stimuli

Somatic sensitivity can be evaluated by means of an array of techniques that allow a differential stimulation of afferent pathways.37,38 Some of these techniques can be also adapted for visceral stimulation (Fig. 1). Transmucosal electrical nerve stimulation has been applied to the gut via intraluminal electrodes mounted over a tube.33,34,39–43 Whereas distending stimuli activate sensory pathways and induce perception by specific stimulation of mechanoreceptors on the gut wall, transmucosal nerve stimulation induces similar perception by nonspecific stimulation of afferent pathways, that is, without relying on any specific receptor.33,34 Methods for thermal stimulation, involving both cold and warm stimuli, have been also developed to test visceral afferents.44 Thermal stimulation of the gut can be produced via intraluminal bags by recirculating water at adjusted temperatures. It has been shown that the stomach and the intestine exhibit similar stimulus-related thermal sensitivity, but gastrointestinal thermosensitivity in humans, and specifically the type of afferents activated by warm and cold stimuli, remain poorly explored. Nevertheless, thermal stimuli are potentially applicable, in conjunction with mechanical and electrical stimuli, to the evaluation of sensory dysfunctions of the gut. These combined techniques may help to identify the specific pathways affected and the level of the dysfunction.


Figure 1. Differential stimulation of afferent pathways. Stimulus-related perception of different types of stimuli applied in the jejunum in healthy subjects (data from Accarino et al.,34 Villanova et al.44).

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Measurement of sensory responses

Several methods to evaluate perception have been described in the somatic pain literature, and that may also be applicable to viscerosensory testing.30,37,38,45 Perception of gut stimuli can be evaluated by detection of sensory thresholds using various paradigms of stimuli presentation. The intensity and the quality of perception can be measured by means of rating scales, which may be analogue, numerical or descriptive. There is little experience about the affective (unpleasant) dimension of visceral sensation, which seems independent of the intensity of perception. It has been shown that visceral perception produces a parallel inhibition of a somatic flexion reflex, and the latter has been used as an objective equivalent of perception.46 Visceral sensitivity has also been evaluated using sensory-evoked potentials, by recording the responses evoked by gut stimuli at different levels of the sensory pathways.39–41,47,48 The problem with these techniques is that it cannot be ascertained whether the responses are recorded through perception or through reflex pathways. New imaging techniques, such as positron emission tomography (PET), single-photon emission computer tomography (SPECT) and functional magnetic resonance imaging (FMRI), use different tracers to detect focal changes in brain bloodflow and metabolic activity in response to different stimuli.47–52 These techniques provide images of the brain regions activated by visceral stimulation, but their application is limited by their restricted availability. Furthermore, the reproducibility between studies of brain imaging in patients with functional disorders is limited, probably due to the large number of factors, such as vigilance and anxiety, involved.

Characterization of altered sensitivity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References

Over the past decade, the initial observations of visceral hypersensitivity in functional gastrointestinal disorders have been expanded, and the sensory dysfunctions have been characterized further by extensive series of studies.

Visceral vs. somatic sensitivity

Several lines of evidence indicate that altered sensitivity in patients with functional gut syndromes exclusively affects the visceral area. Somatic sensitivity, both to the cold pressure test and to transcutaneous electrical nerve stimulation, is normal in dyspeptic patients25,53(Fig. 2). Furthermore, visceral responses to somatic pain are also normal in these patients. Specifically, somatic pain produced by cold stress induces a gastric relaxation, which is similar in dyspeptic patients and in healthy subjects.25 It has been also shown that IBS patients have normal or even increased tolerance of somatic pain34,54 (Fig. 2), and this attenuated somatosensory response has been related to the pain-reporting behaviour characteristic of painful conditions. In contrast to these data showing a selective visceral sensory dysfunction, it seems that patients with IBS have increased incidence of somatic pain disorders, such as fibromyalgia and various myofascial pain syndromes.54–57 The reason for this association is unknown. It remains to be established whether patients with IBS and concomitant fibromyalgia are different from those with IBS alone.


Figure 2. Somatic perception in functional gut disorders. Both dyspeptic and irritable bowel syndrome patients have increased tolerance to somatic stimulation. Note the similarity of results despite the different techniques and intensities of transcutaneous electrical nerve stimulation used in different studies (data from Accarino et al.,34 Coffin et al.,53).

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Pathways and territories affected

Increased sensitivity to mechanical stimuli may arise from reduced compliance of the gut wall, but this hypersensitivity mechanism has been systematically ruled out, because in most studies gut compliance has been shown to be normal.23–27,34 Hence, hypersensitivity seems related to a dysfunction of afferent perception pathways. The receptive fields of gastrointestinal afferents have not been characterized, and furthermore, in patients with functional disorders the areas affected by the gut sensory dysfunction remain controversial. Increased gastric, but normal duodenal, sensitivity has been shown in a specific subset of patients with motility-like dyspepsia predominantly complaining of postcibal bloating.53 In this study, dyspeptic patients invariably recognized that gastric distension, but not duodenal distension, reproduced their customary symptoms, whereas in healthy subjects both stimuli were perceived alike (Fig. 3). However, other studies have reported increased perception of intestinal distension in patients with functional dyspepsia.58,59 Patients with functional dyspepsia are heterogenous and the criteria for definition and selection of the patients may explain the conflicting data.


Figure 3. Sensory–reflex dysfunctions in functional dyspepsia. Dyspeptic patients exhibit reduced tolerance to gastric distension, normal duodenal sensitivity, and impaired reflex relaxation of the stomach in response to the duodenal distension (data from Coffin et al.53).

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In IBS patients, colonic hypersensitivity to distension has been well documented,20–22,26,27,60 and it has been further demonstrated that other regions of the gut, such as the jejunum and even the oesophagus also display heightened perception, suggesting a widespread sensory dysfunction.34,61,62 However, the sensory dysfunction in IBS does not affect all type of afferents, but exhibits fibre specificity. Studies using both mechanical stimuli and transmucosal nerve stimulation have shown that patients with IBS have increased perception of mechanical stimuli (distension) with normal perception of electrical stimulation34(Fig. 4). These data suggest that small bowel hypersensitivity in IBS is related to a selective alteration of mechanosensitive pathways. The level of the afferent dysfunction has not been established, but using these techniques, a response bias can be reasonably excluded. It has been postulated that patients with noncardiac chest pain tend to overinterpret oesophageal stimuli as painful.63 However, in IBS patients, transmucosal electrical nerve stimulation induces normal perception, even though electrical and mechanical stimuli produce similar, undistinguishable sensations in most tests.34


Figure 4. Jejunal hypersensitivity in irritable bowel syndrome (IBS). Patients with IBS have reduced thresholds for perception and discomfort to mechanical gut stimulation (distension), but normal responses to transmucosal electrical nerve stimulation, which directly activates afferent fibres without relaying on any specific receptor (data from Accarino et al.34).

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Visceral reflexes

Motility of the digestive tract is normally regulated by a series of reflexes, and hence, a reflex dysfunction may produce clinical symptoms. A key issue investigated in functional patients has been whether the neural dysfunction affects exclusively sensory pathways or whether reflex pathways involved in the regulation of motility are also affected. Indeed, some clinical data, such as altered bowel habit in IBS, suggest that motility regulation may also be distorted, despite the fact that gross motor abnormalities cannot be detected by manometry. Gut reflexes in humans can be investigated in the laboratory by measuring the responses to distending stimuli (Fig. 5). For that purpose, the barostat, which records changes in gut tone, has proven particularly useful. In contrast, using conventional manometry or electromyography, brief inhibitory reflexes may be missed because phasic motor activity is intermittent.17,36,64,65


Figure 5. Reflex gastric relaxation in response to duodenal distension. Gastric tone was measured as intragastric volume at constant pressure by a barostat. Note the intragastric volume increase (relaxation) after inflating a duodenal balloon (distension), and the volume recovery after balloon deflation.

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It has been shown that perception and reflex responses can be dissociated, and are probably mediated by different mechanisms.17,36 From a pathophysiological standpoint, this finding may be very important because it indicates that perception and reflex responses to gastrointestinal stimuli may be altered independently in some conditions. For instance, it has been shown that dyspeptic patients with gastric hypersensitivity also have impaired gastric reflexes.53 Physiologically, duodenal distension releases a vagal reflex that induces gastric relaxation (Fig. 5). In a group of dyspeptic patients with normal duodenal sensitivity and compliance, duodenal distension induced impaired relaxation of the stomach (Fig. 3). It has been suggested that vagal function is impaired in dyspepsia,58 and this could explain the defective duodenogastric reflex. Other data indicate that the intestinal motor responses to distension, that is, the sympathetic intestinointestinal reflexes, may also be impaired in patients with functional dyspepsia.58 Conversely, IBS patients may display exaggerated reflex responses of the gut.22 The concomitant dysfunction of sensory and reflex pathways could be due to a process that affects the gut wall, or alternatively, it may be explained on the basis of a multifocal or diffuse gut neuropathy. However, confirmatory evidence is still lacking, and this association has not been satisfactorily explained.

Potential mechanisms of sensory dysfunctions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References

Perception of visceral stimuli depends on stimulation of terminal afferents in the gut wall and transmission of the signal along the afferent neural pathway up to the brain cortex.1,5 However, final perception is determined by a net of mechanisms that modulate the afferent signal at multiple levels between the gut and the brain. A dysfunction of these control mechanisms would distort visceral perception and thus could be the cause of the sensory dysfunction observed in functional patients.

Stimulus-related mechanisms

It has been shown that the responses to gut stimuli depend on the number of receptors activated, and specifically, visceral perception in humans is substantially modified by spatial summation phenomena.66,67 The extension of the field of stimulation in the intestine determines the intensity of perception, and furthermore, summation effects are similar whether adjacent or distant fields are stimulated, at least over the proximal half of the small bowel.68 Hence, the intestine may tolerate circumscribed activation of sensory terminals by a nociceptive condition without perception, but additional recruitment of afferents at other areas, even at distant sites of the gut, may induce symptoms. This reasoning may be particularly relevant for the interpretation of a common clinical problem, such as symptoms induced by intestinal gas distension, and may help to explain the relationship between the distribution of gas pooling and symptoms.

The interaction of different types of stimuli in the gut also modifies conscious perception. For instance, unperceived stimuli, such as very low transmucosal electrical nerve stimulation or physiological loads of intestinal lipids, heighten perception of concomitant gut distension, and this effect is not explained by changes in intestinal compliance.42,68,69 However, the sensitization induced by lipids seems specifically related to mechanoreceptors because perception of transmucosal electrical stimulation of the gut, which activates gut afferents without relaying on any specific receptor, is not modified by intraluminal lipids.69 Cholecystokinin has been shown to increase the mechanoreceptors response,70 and hence could be involved in these effects. Furthermore, increased perception of gastric distension induced by intestinal lipids can be blocked by loxiglumide, a CCK-A receptor antagonist.71

Somatic pain is modulated by a complex neural circuitry that can be activated by somatic stimulation, a phenomenon known as counter-irritation or stimulation analgesia. Some data indicate that a neuronal link at the brain stem exerts control over spinal transmission via descending inhibitory pathways, as well as at higher levels of the somatic projection system.72–74 Conceivably, spinal and supraspinal circuits with specific modulatory effects may be activated depending on the type of stimulation.73 This control system of somatic pain perception also modulates visceral sensitivity. It has been shown that transcutaneous electrical nerve stimulation applied on the hand reduces the discomfort produced by gastric or by duodenal distensions.75 This viscerosensory modulation by somatic afferents is exerted without alteration of basal gut tone or visceral reflexes.75 Some forms of counter-irritation require painful stimulation,72,74,76 but visceral discomfort can be reduced by painless somatic stimuli.75 Furthermore, somatic stimuli may decrease perception of uncomfortable, but not necessarily painful, visceral sensations. These observations in humans are supported by experimental studies showing that somatic and visceral sensory input converge onto the same spinal neurones, and that these somatovisceral neurones can be modulated by both segmental and descending inhibitory mechanisms,1,5 Theoretically, impairment of such downregulation mechanisms could result in visceral hypersensitivity, and conversely, therapeutic techniques to induce visceral hyperalgesia through somatic stimulation could potentially benefit patients with abdominal symptoms.74–76 However, the pathophysiological implications of these mechanisms in functional gut disorders still remains speculative.

Central mechanisms

Visceral hypersensitivity in functional gut syndromes has been attributed to sensitization of spinal neurones, and some clinical data support this hypothesis.27 For instance, patients with IBS and functional abdominal pain have a distorted referral pattern of gut sensations and perceive intestinal distensions more diffusely over the abdomen than healthy controls.61,77,78 Visceral and somatic afferents converge onto the same sensory neurones in the spinal cord, and sensitization of these neurones by noxious visceral input produces an expansion of their somatic receptive fields.27,79 Peripheral hypersensitivity of mechanosensitive pathways could produce a secondary sensitization of spinal neurones, which could explain the expanded referral area of gut stimuli in IBS.1,27 Alternatively, central sensitization could also be produced by the autonomic nervous system. It has been shown that increased sympathetic tone magnifies perception of gut stimuli without affecting somatic perception.80 Viscerosensory neurones in the spinal cord are controlled by descending inhibitory pathways of supraspinal origin,81,82 and the sympathetic control of visceral perception could be exerted via this mechanism. Sympathetic dysregulation of visceral sensitivity may be clinically relevant. Indeed, patients with IBS display increased sympathetic activity83 and exhibit a similar sensory disturbance to that produced by sympathetic activity, namely, they manifest visceral hypersensitivity, but normal or even increased tolerance to somatic stimuli.22,34 The vagus does not seem to be involved in afferent transmission of perception signals, but may exert a central modulatory role.1,84 However, the potential role of the vagus in visceral hypersensitivity remains unexplored.

Visceral perception is also modulated at the highest level of the brain gut axis by cognitive and affective mechanisms. For instance, it has been shown that anticipatory knowledge, compared to mental distraction, increases perception and the referral area of intestinal stimuli without modifying intestinal reflexes.85 Hence, cognitive processes selectively regulate the sensitivity to gut stimuli, while visceral reflexes operate independently. These data raise the possibility that functional patients are hypervigilant and pay more attention to gut events. It has been further shown that psychological mechanisms also modulate gut perception. Symptoms of colonic distension in healthy subjects are modified by anxiety induced by mental stress and, to a lesser intent, by active relaxation.86

Studies in IBS using new imaging techniques to map the brain areas activated by rectal distension have reported conflicting results. One study using PET showed activation of different areas in IBS patients, suggesting that hypersensitivity is related to aberrant brain regulation of the afferent input.51 By contrast, another study using FMRI demonstrated a more pronounced activation pattern, but normal pathways in IBS, which suggests that increased pain perception is related to upregulation of afferent signals, and that this disregulation may take place at any level of the sensory pathways.49 Other studies have shown that oesophageal hypersensitivity in patients with noncardiac chest pain is associated to reduced cerebral-evoked responses to oesophageal stimulation, which led to the conclusion that increased visceral perception in these patients results from enhanced cerebral processing of visceral sensory input.41,48 Cognitive-affective modulation of visceral perception may also have therapeutic implications. Hypnosis, which may activate this type of mechanism, has been shown to reduce perception of rectal distension in patients with IBS and rectal hypersensitivity.87 These patients also exhibit a sustained improvement of their clinical symptoms after hypnotherapy.88,89

Relationship of sensory–reflex dysfunctions to clinical symptoms

  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References

The relationship between the sensory disturbances detected in the laboratory in patients with functional gut disorders and their clinical complaints is still unclear. Sensitivity tests do not allow a clear discrimination between patients and healthy controls, which indicates that altered perception per se may not explain the symptoms. Conceivably, real-life situations involve a larger number of stimuli than the testing conditions and may recruit a wider pool of altered responses, including both altered perception and reflexes.

Normally, ingestion of a meal induces a relaxation of the proximal stomach to accommodate the meal volume, and the magnitude of the relaxation is regulated by a complex net of reflexes.90,91 Hence, this partial relaxation prevents wall tension increments and symptoms, but the residual contraction of the proximal stomach still gently forces gastric content distally into the antrum and initiates gastric emptying. As the relaxatory input decreases, the proximal stomach regains tone and emptying progresses. A gastric hyporeactivity to relaxatory reflexes would predictably result in a defective volume accommodation of the proximal stomach and antral overload. In patients with functional dyspepsia, gastric tone and compliance are normal during fasting.25,53,92,93 However, the reactivity of the stomach to regulatory reflexes is abnormal, and the proximal stomach does not relax properly in response to reflexes arising from the antrum and the small intestine.53,94,95 Consequently, accommodation of the proximal stomach to a meal is impaired,92,93,96 which results in antral overload.97,98 Antral distension may release symptoms in these patients, because this area is hypersensitive to increases in wall tension.94 Furthermore, some experimental data indicate that increased intragastric pressure after a meal, simulating a defective gastric accommodation, produces dyspeptic-type symptoms without disturbing gastric emptying,90 a condition that resembles most patients with functional dyspepsia.17 Hence, it is plausible that the gastric hyporeflexia exacerbates the poor tolerance of dyspeptics to intragastric volumes, and thus, contributes to generation of clinical symptoms in the absence of major motor dysfunctions. Some data further suggest that specific symptoms, such as early satiety and postprandial epigastric pain, may be related to impaired accommodation.92,93

It has been reported that rectal hypersensitivity in IBS patients is associated with motor hyperactivity in response to gut stimuli.21 Again, both hypersensitivity and hyperreactivity could contribute to perception of rectal tenesmus and faecal urgency, which is a common symptom in these patients. Recent studies using a gas challenge test further substantiated the role of combined sensory–reflex disturbances in IBS. Whereas healthy subjects propulse and evacuate as much gas as infused into the jejunum, IBS patients have a poor tolerance to gas loads, and develop gas retention and abdominal symptoms.99,100 Gas transit is normally regulated by gut reflexes, and these control mechanisms are altered in IBS patients.101,102 Whether or not intestinal gas is a real problem in IBS remains unclear,103 but the important contribution of the gas challenge studies is the demonstration of abnormal control of gut motility in these patients, which, together with increased gut sensitivity, may produce their symptoms. These data together suggest that altered reflex activity and altered conscious perception of gut stimuli may combine to different degrees in patients with various functional gut syndromes, and their interaction may explain the origin of clinical symptoms.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References

Several lines of evidence indicate that patients with functional gut disorders may exhibit visceral sensitivity and perceive symptoms in response to physiological gut stimuli. However, the putative causes and the clinical implications of these disturbances still remain to be established. Furthermore, sensory dysfunctions per se do not entirely explain the clinical syndromes. Rather, it seems that these patients also have altered gut reflexes, and these mixed sensory–reflex dysfunctions may explain the development of clinical symptoms. Hence, it seems that different functional gut disorders share a common pathophysiology. Based on this disease model, symptoms in patients with functional gut disorders may depend on the neurological mechanisms and the areas affected. This model would also help to explain the clinical heterogeneity and frequent overlap of functional gut syndromes.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References

The author thanks Gloria Santaliestra for secretarial assistance. Supported in part by the Spanish Ministry of Science and Technology (BSA 2001–2584) and the National Institutes of Health, USA (Grant DK 57064).


  1. Top of page
  2. Abstract
  3. Introduction
  4. Sensitivity tests
  5. Characterization of altered sensitivity
  6. Potential mechanisms of sensory dysfunctions
  7. Relationship of sensory–reflex dysfunctions to clinical symptoms
  8. Conclusion
  9. Acknowledgments
  10. References
  • 1
    Sengupta JN, Gebhart GF. Gastrointestinal afferents and sensation. In: JohnsonLR, ed. Physiology of the Gastrointestinal Tract, Vol. 1, 3rd edn. New York: Raven, 1994: 483519.
  • 2
    Bentley FH, Smithwick RH. Visceral pain produced by balloon distension of the jejunum. Lancet 1940; 2: 38991.
  • 3
    Ray BS, Neill CL. Abdominal visceral sensation in man. Ann Surg 1947; 126: 70924.
  • 4
    Ness TJ, Gebhart GF. Visceral pain: a review of experimental studies. Pain 1990; 41: 167386.
  • 5
    Cerveró F. Visceral pain: what's in the gut and what's in the brain. In: TachéY, WingateD, eds. Brain–Gut Interactions Boca Raton, FL: CRC Press, 1991: 33946.
  • 6
    Azpiroz F, Malagelada J-R. Gastric tone measured by an electronic barostat in health and postsurgical gastroparesis. Gastroenterology 1987; 92: 93443.
  • 7
    Janssens J, Peeters TL, Vantrappen G et al. Improvement of gastric emptying in diabetic gastroparesis by erythromycin. N Engl J Med 1990; 322: 102831.
  • 8
    Krishnamurthy S, Schuffler MD. Pathology of neuromuscular disorders of the small intestine and colon. Gastroenterology 1987; 93: 61039.
  • 9
    Stanghellini V, Camilleri M, Malagelada J-R. Chronic idiopathic intestinal pseudo-obstruction: clinical and intestinal manometric findings. Gut 1987; 28: 512.
  • 10
    Annuras S. Intestinal pseudo-obstruction syndrome. Ann Rev Med 1988; 39: 115.
  • 11
    Mitchell CM, Drossman DA. Survey of the AGA membership relating to patients with functional gastrointestinal disorders. Gastroenterology 1987; 92: 12824.
  • 12
    Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada JR, Tytgat GNJ. Functional gastroduocenal disorders. Gut 1999; 45 (Suppl. II): 37–42.
  • 13
    Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Müller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut 1999; 45 (Suppl. II): 437.
  • 14
    Kellow JE, Delvaux M, Azpiroz F, Camilleri M, Quigley EMM, Thompson DG. Principles of applied neurogastroenterology physiology/motility-sensation. Gut 1999; 45 (Suppl. II): 1724.
  • 15
    Camilleri M, Malagelada J-R, Kao PC, Zinsmeister AR. Gastric and autonomic responses to stress in functional dyspepsia. Dig Dis Sci 1986; 31: 116977.
  • 16
    Stanghellini V, Ghidini C, Maccarini MR, Paparo GF, Corinaldesi R, Barbara L. Fasting and postprandial gastrointestinal motility in ulcer and non-ulcer dyspepsia. Gut 1992; 33: 18490.
  • 17
    Tucci A, Corinaldesi R, Stanghellini V et al. Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Gastroenterology 1992; 103: 76874.
  • 18
    Kumar D, Wingate DL. The irritable bowel syndrome: a paroxysmal motor disorder. Lancet 1985; 2: 9737.
  • 19
    Kellow JE, Phillips SP. Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 1987; 92: 188593.
  • 20
    Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the irritable bowel syndrome. Gut 1973; 14: 12332.
  • 21
    Whitehead WE, Engel BT, Schuster MM. Irritable bowel syndrome: physiological and psychological differences between diarrhea-predominant and constipation-predominant patients. Dig Dis Sci 1980; 25: 40413.
  • 22
    Whitehead WE, Holtkotter B, Enck P et al. Tolerance for rectosigmoid distension in irritable bowel syndrome. Gastroenterology 1990; 98: 118792.
  • 23
    Bradette M, Pare P, Douville P, Morin A. Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone. Dig Dis Sci 1991; 36: 528.
  • 24
    Lémann M, Dederding JP, Flourie B, Franchisseur C, Rambaud J, Jian R. Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia. The irritable stomach. Dig Dis Sci 1991; 36: 124954.
  • 25
    Mearin F, Cucala M, Azpiroz F, Malagelada J-R. The origin of symptoms on the brain gut axis in functional dyspepsia. Gastroenterology 1991; 101: 9991006.
  • 26
    Mayer EA, Raybould HE. Role of visceral afferent mechanisms in functional bowel disorders. Gastroenterology 1990; 99: 1688704.
  • 27
    Mayer EA, Gebhart GF. Basic and clinical aspects of visceral hyperalgesia. Gastroenterology 1994; 107: 27193.
  • 28
    Azpiroz F, Malagelada J-R. Pressure activity pattern in the canine proximal stomach: response to distension. Am J Physiol 1984; 247: G265G72.
  • 29
    Azpiroz F, Malagelada J-R. Physiological variations in canine gastric tone measured by an electronic barostat. Am J Physiol 1985; 248: G229G37.
  • 30
    Whitehead WE, Delvaux M, The Working Team. Standardization of barostat procedures for testing smooth muscle tone and sensory thresholds in the gastrointestinal tract. Dig Dis Sci 1997; 42: 22341.
  • 31
    Notivol R, Coffin B, Azpiroz F, Mearin F, Serra J, Malagelada J-R. Gastric tone determines the sensitivity of the stomach to distension. Gastroenterology 1995; 108: 3306.
  • 32
    Distrutti E, Azpiroz F, Soldevilla A, Malagelada J-R. Gastric wall tension determines perception of gastric distension. Gastroenterology 1999; 116: 103542.
  • 33
    Accarino AM, Azpiroz F, Malagelada J-R. Symptomatic responses to stimulation of sensory pathways in the jejunum. Am J Physiol 1992; 263: G6737.
  • 34
    Accarino AM, Azpiroz F, Malagelada J-R. Selective dysfunction of mechanosensitive intestinal afferents in the irritable bowel syndrome. Gastroenterology 1995; 108: 63643.
  • 35
    Azpiroz F, Malagelada J-R. Perception and reflex relaxation of the stomach in response to gut distention. Gastroenterology 1990; 98: 11938.
  • 36
    Rouillon JM, Azpiroz F, Malagelada J-R. Reflex changes in intestinal tone: relationship to perception. Am J Physiol 1991; 261: G2806.
  • 37
    Price DD, Long S, Huitt C. Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy. Pain 1992; 49: 16373.
  • 38
    Gracely RH. Studies of pain in normal man. In: WallPD, MelzackR, eds. Textbook of Pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994: 31536.
  • 39
    Meunier P, Collet L, Duclaux R, Chéry-Croze S. Endorectal cerebral evoked potentials in human. Int J Neurosci 1987; 37: 1936.
  • 40
    Frieling T, Enck P, Wienbeck M. Cerebral responses evoked by electrical stimulation of the rectosigmoid in normal subjects. Dig Dis Sci 1989; 34: 2025.
  • 41
    Smout AJPM, De Vore MS, Dalton CB, Castell DO. Cerebral potentials evoked by esophageal distension in patients with non-cardiac chest pain. Gut 1992; 33: 298302.
  • 42
    Accarino AM, Azpiroz F, Malagelada J-R. Gut perception in humans is modulated by interacting gut stimuli. Am J Physiol in press .
  • 43
    Kamm MA, Lennard-Jones JE, Nicholls RJ. Evaluation of the intrinsic innervation of the internal anal sphincter using electrical stimulation. Gut 1989; 30: 9358.
  • 44
    Villanova N, Azpiroz F, Malagelada J-R. Perception and gut reflexes induced by stimulation of gastrointestinal thermoreceptors in humans. J Physiol (Lond) 1997; 502 (1): 21522.
  • 45
    Chapman CR, Casey KL, Dubner R, Foley KM, Gracely RH, Reading AE. Pain measurements: an overview. Pain 1985; 22: 131.
  • 46
    Bouhassira D, Chollet R, Coffin B et al. Inhibition of a somatic nociceptive reflex by gastric distension in humans. Gastroenterology 1994; 107: 98592.
  • 47
    Aziz Q, Thompson DG. Brain-gut axis in health and disease. Gastroenterology 1998; 114: 55978.
  • 48
    Hollerbach S, Bulat R, May A et al. Abnormal cerebral processing of oesophageal stimuli in patients with noncardiac chest pain (NCCP). Neurogastroenterol Motil 2000; 12: 55565.DOI: 10.1046/j.1365-2982.2000.00230.x
  • 49
    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: 8428.
  • 50
    Bouras EP, O'Brien TJ, Camilleri M, O'Connor MK, Mullan BP. Cerebral topography of rectal stimulation using single photon emission computed tomography. Am J Physiol 1999; 277: G68794.
  • 51
    Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA. Regional cerebral activity in normal and pathological perception of visceral pain. Gastroenterology 1997; 112: 6472.
  • 52
    Rothstein RD, Stecker M, Reivich M et al. Use of positron emission tomography and evoked potentials in the detection of cortical afferents from the gastrointestinal tract. Am J Gastroenterol 1996; 91: 23726.
  • 53
    Coffin B, Azpiroz F, Guarner F, Malagelada J-R. Selective gastric hypersensitivity and reflex hyporeactivity in functional dyspepsia. Gastroenterology 1994; 107: 134551.
  • 54
    Veale D, Kavanagh G, Fielding JF, Fitzgerald O. Primary fibromyalgia and the irritable bowel syndrome different expressions of a common pathogenetic process. Br J Rheumatol 1991; 30: 2202.
  • 55
    Barton A, Whorwell PJ, Marshall D. Increased prevalence of sicca complex and fibromyalgia in patients with irritable bowel syndrome. Am J Gastroenterol 1999; 94: 1898– 901.
    Direct Link:
  • 56
    Pace P, Manzionna G, Bollani S, Sarzi-Puttini P, Bianchi-Porro G. Visceral sensitivity in patients with fibromyalgia and in normal controls. Gastroenterology 1997; 112: A802.
  • 57
    Chang L, Mayer EA, Johnson T, Fitzgerald LZ, Naliboff B. Differences in somatic perception in female patients with irritable bowel syndrome with and without fibromyalgia. Pain 2000; 84 (2–3): 297307.
  • 58
    Greydanus MP, Vassallo M, Camilleri M, Nelson DK, Hanson RB, Thomforde GM. Neurohormonal factors in functional dyspepsia: insights on pathophysiological mechanisms. Gastroenterology 1991; 100: 13118.
  • 59
    Holtmann G, Goebell H, Jockenhoevel F, Talley NJ. Altered vagal and intestinal mechanosensory function in chronic unexplained dyspepsia. Gut 1998; 42: 5016.
  • 60
    Mertz H, Naliboff B, Munakata J, Niazi N. Altered rectal perception is a biological marker of patients with irritable bowel syndrome. Gastroenterology 1995; 109: 4052.
  • 61
    Moriarty KJ, Dawson AM. Functional abdominal pain: further evidence that the whole gut is affected. Br Med J 1982; 284: 16702.
  • 62
    Trimble KC, Farouk R, Pryde A, Douglas S, Heading RC. Heightened visceral sensations in functional gastrointestinal disease is not site-specific. Evidence for a generalized disorder of gut sensitivity. Dig Dis Sci 1995; 40: 160711.
  • 63
    Richter JE, Bradley LA. The irritable esophagus. In: MayerEA, RaybouldHE, eds. Pain Research and Clinical Management. Vol. 9: Basic and Clinical Aspects of Chronic Abdominal Pain. Amsterdam: Elsevier, 1993: 4554.
  • 64
    Azpiroz F, Malagelada J-R. Isobaric intestinal distension in humans: sensorial relay and reflex gastric relaxation. Am J Physiol 1990; 258: G2027.
  • 65
    Rouillon JM, Azpiroz F, Malagelada J-R. Reflex changes in intestinal tone: relationship to perception.Am J Physiol1991; 258: G202–7.
  • 66
    Serra J, Azpiroz F, Malagelada J-R. Perception and reflex responses to intestinal distension are modified by simultaneous or previous stimulation. Gastroenterology 1995; 109: 1742– 9.
  • 67
    Serra J, Azpiroz F, Malagelada J-R. Modulation of gut perception by spatial summation phenomena. J Physiol (Lond) 1998; 506: 57987.
  • 68
    Feinle C, Rades T, Otto B, Fried M. Fat digestion modulates gastrointestinal sensations induced by gastric distention and duodenal lipid in humans. Gastroenterology 2001; 120: 11007.
  • 69
    Accarino AM, Azpiroz F, Malagelada J-R. Modification of small bowel mechanosensitivity by intestinal fat. Gut 2001; 48: 6905.DOI: 10.1136/gut.48.5.690
  • 70
    Davison JS, Clarke GD. Mechanical properties and sensitivity to CCK of vagal gastric slowly adapting mechanoreceptors. Am J Physiol 1988; 255: G5561.
  • 71
    Feinle C, D'Amato M, Read NW. Cholecystokinin-A receptors modulate gastric sensory and motor responses to gastric distension and duodenal lipid. Gastroenterology 1996; 110: 137985.
  • 72
    De Broucker T, Cesaro P, Willer JC, Le Bars D. Diffuse noxious inhibitory controls in man. Involvement of the spino-reticular tract. Brain 1990; 113: 12234.
  • 73
    Ness TJ, Gebhart GF. Interactions between visceral and cutaneous nociception in the rat. I. Noxious cutaneous stimuli inhibit visceral nociceptive neurons and reflexes. J Neurophysiol 1991; 66: 208.
  • 74
    Melzack R. Folk medicine and the sensory modulation of pain. In: WallPD, MelzackR, eds. Textbook of Pain, 3rd edn. Edimburgh: Churchill Livingstone, 1994: 120917.
  • 75
    Coffin B, Azpiroz F, Malagelada J-R. Somatic stimulation reduces perception of gut distension. Gastroenterology 1994; 107: 163642.
  • 76
    Woolf CJ, Thompson JW. Stimulation fibre-induced analgesia: transcutaneous electrical nerve stimulation (TENS) and vibration. In: WallPD, MelzackR, eds. Textbook of Pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994: 1191208.
  • 77
    Swarbrick ET, Hegarty JE, Bat L, Williams CB, Dawson AM. Site of pain from the irritable bowel. Lancet 1980; 2: 4436.
  • 78
    Kingham JCG, Dawson AM. Origin of chronic right upper quadrant pain. Gut 1985; 26: 7838.
  • 79
    Cerveró F, Laird JMA, Pozo MA. Selective changes of receptive field properties of spinal nociceptive neurones induced by noxious visceral stimulation in the cat. Pain 1992; 51: 33542.
  • 80
    Iovino P, Azpiroz F, Domingo E, Malagelada J-R. The sympathetic nervous system modulates perception and reflex responses to gut distension in humans. Gastroenterology 1995; 108: 6806.
  • 81
    Tattersall JEH, Cerveró F, Lumb BM. Viscero-somatic neurons in the lower thoracic spinal cord of the cat: excitations and inhibitions evoked by splanchnic and somatic nerve volleys and by stimulation of brain stem nuclei. J Neurophysiol 1986; 56: 141123.
  • 82
    Cerveró F, Lumb BM. Bilateral inputs and supraspinal control of viscerosomatic neurons in the lower thoracic cord of the cat. J Physiol (Lond) 1988; 403: 22137.
  • 83
    Agarwal A, Cutts TF, Abell TL et al. Predominant symptoms in irritable bowel syndrome correlate with specific autonomic nervous system abnormalities. Gastroenterology 1994; 106: 94550.
  • 84
    Ren K, Randich A, Gebhart GF. Effects of electrical stimulation of vagal afferents on spinothalamic tract cells in the rat. Pain 1991; 44: 3119.
  • 85
    Accarino AM, Azpiroz F, Malagelada J-R. Attention and distraction: effects on gut perception. Gastroenterology 1997; 113: 41522.
  • 86
    Ford MJ, Camilleri M, Zinsmeister AR, Hanson RB. Psychosensory modulation of colonic sensation in the human transverse and sigmoid colon. Gastroenterology 1995; 109: 1772– 80.
  • 87
    Prior A, Colgan JM, Whorwell PJ. Changes in rectal sensitivity after hypnotheraphy in patients with irritable bowel syndrome. Gut 1990; 31: 8968.
  • 88
    Whorwell PJ, Prior A, Faragher EB. Controlled trial of hyphotherapy in the treatment of severe refractory irritable bowel syndrome. Lancet 1984; 2: 12324.
  • 89
    Whorwell PJ, Prior A, Colgan JM. Hypnotheraphy in severe irritable bowel syndrome: further experience. Gut 1987; 28: 4235.
  • 90
    Moragas G, Azpiroz F, Pavía J, Malagelada J-R. Relations among intragastric pressure, postcibal perception and gastric emptying. Am J Physiol 1993; 264: G11127.
  • 91
    Mayer EA. The physiology of gastric storage and emptying. In: JohnsonLR, ed. Physiology of the Gastrointestinal Tract, Vol. 1, 3rd edn. New York: Raven, 1994: 92976.
  • 92
    Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998; 115: 134652.
  • 93
    Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J. Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001; 121: 52635.
  • 94
    Caldarella MP, Azpiroz F, Malagelada J-R. The distal stomach is responsible for symptomatic gastric accommodation in functional dyspepsia. Gastroenterology 2000; 118: A670.
  • 95
    Feinle C, Meier O, Otto B, D'Amato M, Fried M. Symptomatic and plasma CCK responses to increasing doses of duodenal lipid in patients with functional dyspepsia (FD) and the role of CCK-A receptors. Gut 2001; 48: 34755.
  • 96
    Salet GAM, Samsom MJMM, Roelofs Van Berge Henegouwen GP, Smout AJPM, Akkermans LMA. Responses to gastric distension in functional dyspepsia. Gut 1998; 42: 8239.
  • 97
    Hausken T, Thune N, Matre K, Gilja OH, Odegaard S, Berstad A. Volume estimation of the gastric antrum and the gallbladder in patients with non-ulcer dyspepsia and erosive prepyloric, changes, using three-dimensional ultrasonography. Neurogastroenterol Motil 1994; 6: 26370.
  • 98
    Troncon LEA, Bennett RJM, Akhluwalia NK, Thompson DG. Abnormal intragastric distribution of food during gastric emptying in functional dyspepsia patients. Gut 1994; 35: 32732.
  • 99
    Serra J, Azpiroz F, Malagelada J-R. Intestinal gas dynamics and tolerance in humans. Gastroenterology 1998; 115: 54250.
  • 100
    Serra J, Azpiroz F, Malagelada J-R. Impaired transit of intestinal gas in the irritable bowel syndrome. Gut 2001; 48: 149.
  • 101
    Harder H, Serra J, Azpiroz F, Malagelada J-R. Reflex control of intestinal gas dynamics and tolerance. Gastroenterology 2000; 118: A689.
  • 102
    Caldarella MP, Serra J, Azpiroz F, Malagelada J-R. Stimulation of intestinal gas propulsion is the key to treat gas retention in functional patients. Gastroenterology 2000; 118: A138.
  • 103
    Maxton DG, Martin DF, Whorwell P, Godfrey M. Abdominal distension in female patients with irritable bowel syndrome: exploration of possible mechanisms. Gut 1991; 32: 6624.