Emeran A. Mayer

Basic and clinical aspects of visceral hyperalgesia

Although physiological stimuli in the healthy gastrointestinal tract are generally not associated with conscious perception, chronic abdominal discomfort and pain are the most common symptoms resulting in patient visits with gastroenterologists. Symptoms may be associated with inflammatory conditions of the gut or occur in the form of so-called functional disorders. The majority of patients with functional disorders appear to primarily have inappropriate perception of physiological events and altered reflex responses in different gut regions. Recent breakthroughs in the neurophysiology of somatic and visceral sensation are providing a series of plausible mechanisms to explain the development of chronic hyperalgesia within the human gastrointestinal tract. A central concept to all these mechanisms is the development of hyperexcitability of neurons in the dorsal horn, which can develop either in response to peripheral tissue irritation or in response to descending influences originating in the brainstem. Taking clinical characteristics and the concept of central hyperexcitability into account, a model is proposed by which abdominal pain from chronic inflammatory conditions of the gut and functional bowel disorders such as noncardiac chest pain, nonulcer dyspepsia, and irritable bowel syndrome could develop by multiple mechanisms either alone or in combination.

Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism.

Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 and, by unknown mechanisms, induce widespread inflammation. We found that a large proportion of primary spinal afferent neurons, which express proteinase-activated receptor 2, also contain the proinflammatory neuropeptides calcitonin gene-related peptide and substance P. Trypsin and tryptase directly signal to neurons to stimulate release of these neuropeptides, which mediate inflammatory edema induced by agonists of proteinase-activated receptor 2. This new mechanism of protease-induced neurogenic inflammation may contribute to the proinflammatory effects of mast cells in human disease. Thus, tryptase inhibitors and antagonists of proteinase-activated receptor 2 may be useful anti-inflammatory agents.

Irritable Bowel Syndrome

A 28-year-old woman presents with a 7-month history of recurrent, crampy pain in the left lower abdominal quadrant, bloating with abdominal distention, and frequent, loose stools. She reports having had similar but milder symptoms since childhood. She spends long times in the bathroom because she is worried about uncontrollable discomfort and fecal soiling if she does not completely empty her bowels before leaving the house. She feels anxious and fatigued and is frustrated that her previous physician did not seem to take her distress seriously. Physical examination is unremarkable except for tenderness over the left lower quadrant. How should her case be evaluated and treated?

Regional cerebral activity in normal and pathological perception of visceral pain

BACKGROUND & AIMS To characterize the cerebral processing of noxious visceral events, changes in regional cerebral blood flow associated with perception of intestinal pain were examined. METHODS The effects of rectal pressure stimuli on regional cerebral blood flow were assessed with 15O-water positron emission tomography (PET) in 12 subjects, half with irritable bowel syndrome (IBS). PET scans were obtained at baseline and during both actual and simulated delivery of anticipated stimuli. Changes in regional cerebral blood flow were interpreted using statistical parametric mapping and region of interest methods of analysis. RESULTS In healthy subjects, perception of pain during actual or simulated delivery of painful stimuli was significantly associated (P < 0.01) with activity of the anterior cingulate cortex (ACC; Brodmanns areas 24 and 32), whereas no ACC response to perception of nonpainful stimuli was observed. In patients with IBS, the ACC failed to respond to the same stimuli, whereas significant activation (P < 0.01) of the left prefrontal cortex (maximal in Brodmanns area 10) was seen. CONCLUSIONS The perception of acute rectal pain is associated with activation of the ACC in healthy subjects, and patients with IBS show an aberrant brain activation pattern both during noxious rectal distention and during the anticipation of rectal pain.

Gut feelings: the emerging biology of gut-brain communication

The concept that the gut and the brain are closely connected, and that this interaction plays an important part not only in gastrointestinal function but also in certain feeling states and in intuitive decision making, is deeply rooted in our language. Recent neurobiological insights into this gut–brain crosstalk have revealed a complex, bidirectional communication system that not only ensures the proper maintenance of gastrointestinal homeostasis and digestion but is likely to have multiple effects on affect, motivation and higher cognitive functions, including intuitive decision making. Moreover, disturbances of this system have been implicated in a wide range of disorders, including functional and inflammatory gastrointestinal disorders, obesity and eating disorders.

The neurobiology of stress and gastrointestinal disease

The role of stress in the modulation of the most common gastrointestinal disorders has traditionally been considered a domain of psychology, and has frequently been lumped together with the role of psychiatric comorbidity. Among clinicians, the term “stress” is generally taken as synonymous with psychological (“exteroceptive”) stress. Based on the deeply ingrained Cartesian view in medicine and gastroenterology, stress and psychological factors have been considered fundamentally separate and unrelated to the “real” biological changes underlying organic disease. However, recent breakthroughs in the understanding of the neurobiology of the organisms response to acute and chronic stress, and the evolving understanding of elaborate brain-gut interactions and their modulation in health and disease, are beginning to require a reassessment of chronic stress in the pathophysiology and management not only of functional but also of “organic” gastrointestinal disorders. Certain stressful life events have been associated with the onset or symptom exacerbation in some of the most common chronic disorders of the digestive system, including functional gastrointestinal disorders (FGD), inflammatory bowel disease (IBD), gastro-oesophageal reflux disease (GORD), and peptic ulcer disease (PUD). Even though methodological differences in reported studies which do and do not support such an association remain to be resolved, the association of sustained stressful life events preceding symptom exacerbation is based on several well designed surveys in patients with FGD,1-4with post-infectious irritable bowel syndrome (IBS),4 and with IBD.5-8 In addition, acute life threatening stress episodes in adult life (rape, post-traumatic stress syndrome) are an important risk factor in the development of functional gastrointestinal disorders.9 Finally, early life stress in the form of abuse plays a major role in the susceptibility of individuals to develop functional as well as IBD10-14 later in life. Thus, depending on the type of stressor, the lag time between the stressful event …

Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity

BACKGROUND & AIMS Changes in gut microbiota have been reported to alter signaling mechanisms, emotional behavior, and visceral nociceptive reflexes in rodents. However, alteration of the intestinal microbiota with antibiotics or probiotics has not been shown to produce these changes in humans. We investigated whether consumption of a fermented milk product with probiotic (FMPP) for 4 weeks by healthy women altered brain intrinsic connectivity or responses to emotional attention tasks. METHODS Healthy women with no gastrointestinal or psychiatric symptoms were randomly assigned to groups given FMPP (n = 12), a nonfermented milk product (n = 11, controls), or no intervention (n = 13) twice daily for 4 weeks. The FMPP contained Bifidobacterium animalis subsp Lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp Lactis. Participants underwent functional magnetic resonance imaging before and after the intervention to measure brain response to an emotional faces attention task and resting brain activity. Multivariate and region of interest analyses were performed. RESULTS FMPP intake was associated with reduced task-related response of a distributed functional network (49% cross-block covariance; P = .004) containing affective, viscerosensory, and somatosensory cortices. Alterations in intrinsic activity of resting brain indicated that ingestion of FMPP was associated with changes in midbrain connectivity, which could explain the observed differences in activity during the task. CONCLUSIONS Four-week intake of an FMPP by healthy women affected activity of brain regions that control central processing of emotion and sensation.

Principles and clinical implications of the brain-gut-enteric microbiota axis.

While bidirectional brain–gut interactions are well known mechanisms for the regulation of gut function in both healthy and diseased states, a role of the enteric flora—including both commensal and pathogenic organisms—in these interactions has only been recognized in the past few years. The brain can influence commensal organisms (enteric microbiota) indirectly, via changes in gastrointestinal motility and secretion, and intestinal permeability, or directly, via signaling molecules released into the gut lumen from cells in the lamina propria (enterochromaffin cells, neurons, immune cells). Communication from enteric microbiota to the host can occur via multiple mechanisms, including epithelial-cell, receptor-mediated signaling and, when intestinal permeability is increased, through direct stimulation of host cells in the lamina propria. Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system. Vagal, afferent innervation of enterochromaffin cells provides a direct pathway for enterochromaffin-cell signaling to neuronal circuits, which may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions. Disruption of the bidirectional interactions between the enteric microbiota and the nervous system may be involved in the pathophysiology of acute and chronic gastrointestinal disease states, including functional and inflammatory bowel disorders.

Evidence for two distinct perceptual alterations in irritable bowel syndrome

Background and aims—Visceral hyperalgesia has been implicated as a factor contributing to symptom generation in irritable bowel syndrome (IBS). However, previous studies using intestinal balloon distension have used psychophysical procedures which do not provide adequate and unbiased measures of visceral sensitivity. Methods—Three psychophysical tasks were examined in 45 patients with IBS (positive Rome criteria) and 14 controls using rectal balloon distension with a computerised distension device. Discomfort threshold and tolerance were assessed during an ascending series of phasic pressure stimuli and during an interactive threshold tracking procedure. In addition, stimulus response functions were generated from intensity and unpleasantness ratings of the rectal distensions. Results—Discomfort threshold and tolerance for the ascending stimuli were significantly lower for the patients with IBS compared with the controls. In contrast, discomfort thresholds during the tracking procedure and stimulus response curves for the ascending series were not different between the groups. A factor analysis of the psychophysical data was consistent with the presence of two distinct and unrelated perceptual alterations related to rectal distension: hypervigilance for visceral stimuli, manifested as lowered response criteria for using the descriptor “discomfort”; and rectal hypersensitivity, manifested as a lower discomfort threshold and left shift of the stimulus response curves. Conclusions—Patients with IBS as a group have a greater propensity to label visceral sensations negatively and show a lower tolerance for rectal balloon distension. A subgroup of patients also have baseline rectal hypersensitivity, assessed by unbiased measures of discomfort threshold and stimulus intensity judgements.

Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome.

BACKGROUND & AIMS Only a fraction of patients with irritable bowel syndrome (IBS) show hypersensitivity to rectal distention. The current study sought to determine if repetitive high-pressure stimulation of sigmoid mechanoreceptors modulates perception of rectal pain and discomfort. METHODS In 14 patients with IBS and 11 healthy controls, perception thresholds for discomfort and pain during rectal sensory tracking and verbal descriptor ratings of the perceived intensity of a rectal tonic stimulus were obtained before and after repetitive high-pressure mechanical sigmoid stimulation. Gastrointestinal and psychological symptoms were assessed by questionnaires. RESULTS Despite heterogeneity in baseline rectal sensitivity in patients with IBS, after sigmoid stimulation, 100% of patients, regardless of baseline sensitivity, developed rectal hyperalgesia manifested by at least two of the following three criteria: lowered thresholds for pain and discomfort and increased viscerosomatic referral and lower abdominal discomfort outlasting the experimental stimulation. This pattern of responses was not observed in any of the healthy controls. CONCLUSIONS In patients with IBS, repetitive stimulation of sigmoid splanchnic afferents results in the development of central sensitization manifested as hyperalgesia and increased viscerosomatic referral during rectal distention and as spontaneous rectosigmoid hyperalgesia in the absence of applied stimuli. Repetitive sigmoid contractions may induce rectosigmoid hyperalgesia in patients with IBS.