Mechanism Of Irritable Bowel Syndrome Research Articles

Post-inflammatory colonic afferent sensitisation: different subtypes, different pathways and different time courses

Objective:Intestinal infection evokes hypersensitivity in a subgroup of patients with irritable bowel syndrome (IBS) long after healing of the initial injury. Trinitrobenzene sulfonic acid (TNBS)-induced colitis in rodents likewise results...

Prevalence, Characteristics, and Impact of Bloating Symptoms in Patients With Irritable Bowel Syndrome

Bloating symptoms are common in patients with irritable bowel syndrome (IBS) seen in primary care and gastrointestinal clinics. However, the underlying mechanisms of IBS are poorly understood, and there are few data available about the epidemiology of this syndrome or the impact of its symptoms. We investigated the prevalence, characteristics, and impact of bloating symptoms in patients with IBS. IBS patients were identified by Rome II criteria in a U.S. population representative web-based survey. Patients were asked about the quality, frequency, and severity of their gastrointestinal symptoms. The impact of these symptoms was investigated by assessing patients' health-related quality of life, utilization of health care, and use of medications. Of the 337 IBS patients in this study, 82.5% (n = 278) reported bloating symptoms, the second most bothersome symptom after abdominal cramping. The symptoms were more prevalent in female patients, 87.4% (n = 209), than in male patients, 70.4% (n = 69) (P < .0001), and in patients with constipation, 88.7% (n = 47), and mixed symptoms, 88.8% (n = 135), than in patients with diarrhea, 72.3% (n = 96), (P = .02 and P < .01, respectively). Bloating symptoms were the third (of 14) most important reason to seek medical care, and more than half of the patients reported regular use of anti-gas medications. Bloating symptoms were associated with decreased energy levels (P = .04), food intake (P < .01), and physical functioning (P = .06). Bloating symptoms are common in patients with IBS, and their prevalence and relative severity differ on the basis of sex and IBS subtype. Bloating symptoms are associated with a decrease in the quality of life and increases in health care utilization and use of medications.

Transient Receptor Potential Vanilloid-4 Has a Major Role in Visceral Hypersensitivity Symptoms

The transient receptor potential vanilloid-4 (TRPV4) is an osmosensitive channel that responds to mechanical stimulation. We hypothesized that TRPV4 could be important in visceral nociception and in the development of hypersensitivity. TRPV4 expression was investigated by immunohistochemistry and reverse transcription-polymerase chain reaction. Calcium signaling and patch-clamp studies were performed in dorsal root ganglia (DRG) neurons validating the use of 4alphaPDD as a selective TRPV4 agonist. The effects of TRPV4 activation on visceral nociception were evaluated in mice that received intracolonically TRPV4 agonist (4 alpha-phorbol 12,13-didecanoate [4alphaPDD]) and in TRPV4-deficient mice in which abdominal muscle contractions in response to colorectal distention (CRD) were recorded. Intervertebral injections of TRPV4 or mismatch small interfering RNA (siRNA) were used to specifically down-regulate TRPV4 expression in sensory neurons and to investigate the role of TRPV4 in basal visceral nociception or in protease-activated receptor 2 (PAR(2)) activation-induced visceral hypersensitivity. TRPV4 agonist 4alphaPDD specifically activated a cationic current and calcium influx in colonic projections of DRG neurons and caused dose-dependent visceral hypersensitivity. TRPV4-targeted but not mismatched siRNA intervertebral treatments were effective at reducing basal visceral nociception, as well as 4alphaPDD or PAR(2) agonist-induced hypersensitivity. Effects of the TRPV4 ligand were lost in TRPV4-deficient mice. 4alphaPDD selectively activates TRPV4 in sensory neurons projecting from the colon, and TRPV4 activation causes visceral hypersensitivity. TRPV4 activation is implicated in the nociceptive response to CRD in basal conditions and in PAR(2) agonist-induced hypersensitivity. These results suggest a pivotal role for TRPV4 in visceral nociception and hypersensitivity.

This Month in Gastroenterology

Irritable bowel syndrome (IBS) is the most frequently seen disorder in Western gastroenterology practice. Although the disorder is extremely prevalent, the pathogenesis remains unclear. Whether the origin of IBS is central, in the mind, or peripheral, in the gastrointestinal tract, is the subject of a long-standing controversy. Beside changes in signaling molecules and their receptors, changes in the commensal bacterial flora are considered a major candidate peripheral pathogenic mechanism in IBS.

Alosetron: An Effective Treatment for Diarrhea-Predominant Irritable Bowel Syndrome

Serotonin (5-HT) is one of the key mediators of gut motility, secretion and sensation. Most 5-HT is localized in the gastrointestinal tract. Particularly important for gut function and regulation are the 5-HT(1P), 5-HT(3) and 5-HT(4) receptors. These receptors have been the focus of research evaluating the pathophysiologic mechanisms of irritable bowel syndrome (IBS) as well as targets for the development of novel agents to treat irritable bowel syndrome. Alosetron is one of three 5-HT(3) antagonists currently available. The other two, ondansetron and granisetron, are primarily used in the treatment of chemotherapy-induced nausea and vomiting. Alosetron, which slows gut transit, has been approved for the treatment of severe diarrhea-predominant IBS (IBS-D) in women. This review will examine the common, yet therapeutically challenging, disorder IBS, as well as the role of alosetron in the treatment of IBS-D.

Selective Processing of Gastrointestinal Symptom-related Stimuli in Irritable Bowel Syndrome

We sought to determine whether irritable bowel syndrome (IBS) was associated with attentional bias toward symptom-related cues in IBS patients versus healthy controls, using a modified Stroop task to measure selective processing of gastrointestinal symptom-related cues. Fifteen patients with a clinical diagnosis of IBS and 15 healthy controls were recruited into the study. All participants attended a single testing session, during which they completed a modified Stroop task using gastrointestinal symptom-related and neutral control words. Results indicated a significant main effect of word type (p = .013), with slower color-naming times for IBS-related compared with neutral words, and a significant main effect of exposure (p = .001), with slower color-naming times in the unmasked condition compared with the masked condition. The group x word type x exposure interaction was significant (p = .048). A series of post hoc tests indicated that among patients there was significant interference of symptom-related words in the masked condition but not in the unmasked condition, whereas among controls, the reverse was true. These results indicate that IBS patients selectively process gastrointestinal symptom-related words compared with neutral words when they are presented subliminally but not when they are presented supraliminally. In contrast, healthy controls demonstrate the opposite pattern. Implications for the cognitive mechanisms in IBS, and future research directions, are discussed.

Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome

Visceral hypersensitivity is considered an important pathophysiological mechanism in irritable bowel syndrome, yet its relationship to symptoms is unclear. To detect possible associations between symptoms and the presence of hypersensitivity to rectal distension in patients with irritable bowel syndrome. Ninety-two irritable bowel syndrome patients and 17 healthy volunteers underwent a rectal barostat study. The association between specific irritable bowel syndrome symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic curves. Irritable bowel syndrome patients had significantly lower thresholds for discomfort/pain than healthy volunteers: 24 (18-30) and 30 (27-45) mmHg above minimal distending pressure, respectively. Forty-one patients (45%) showed hypersensitivity to rectal distension. Proportions of patients with different predominant bowel habits were similar in hypersensitive and normosensitive subgroups (diarrhoea predominant: 39 and 41%, respectively; alternating type: 27 and 28%, respectively; constipation predominant: 34 and 31%, respectively). Severe abdominal pain was more frequent in hypersensitive, compared with normosensitive patients (88% vs. 67%, P = 0.02), but none of the individual irritable bowel syndrome symptoms could accurately predict the presence of hypersensitivity, as assessed by Area under the Receiver Operating Characteristic curve analysis. Hypersensitive and normosensitive irritable bowel syndrome patients present with comparable, heterogeneous symptomatology. Therefore, selection based on clinical parameters is unlikely to discriminate individual irritable bowel syndrome patients with visceral hypersensitivity from those with normal visceral sensitivity.

Treatments targeting putative mechanisms in irritable bowel syndrome

The pathophysiology of irritable bowel syndrome (IBS) is heterogeneous; it is possible for several mechanisms to be disturbed in the same patient. Isolating a single target for pharmacological manipulation is also difficult because of the complexity and overlap of the neural circuitry in the enteric and central nervous system. This review summarizes the rationale and efficacy of current and future therapies for IBS, on the basis of putative pathophysiological models. The modulation of gastrointestinal sensorimotor function, intestinal gas handling, the gastrocolonic reflex, neurohormonal stress responses, central processing of afferent information, and microbial flora are the current frontiers for experimental therapeutics for IBS. Patients presumed to have POSTINFECTIOUS IBS have also been targeted as a distinct group. In the very near future, it is unlikely that a single drug will come to the fore as a suitable and successful treatment for everyone with IBS, but new data on potential therapeutic targets lend hope for the improved long-term management of IBS. Disease modification rather than just symptom-based treatments must remain the goal.

New pathophysiological mechanisms in irritable bowel syndrome.

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.

Visceral perception thresholds after rectal thermal and pressure stimuli in irritable bowel syndrome patients.

Visceral hypersensitivity has been shown to be present in irritable bowel syndrome (IBS). The current study sought to compare the characteristics of visceral perception thresholds after rectal thermal and pressure stimuli between IBS patients and healthy subjects. A total of 46 patients with IBS were diagnosed using Rome II criteria. Thirteen healthy individuals participated in the study. Rectal visceral perception thresholds were examined in patients with IBS and in normal controls after thermal and pressure stimuli. Subjects were asked to report the sensation type, location, and spread. Compared with healthy subjects, IBS patients demonstrated significantly initially lower perception thresholds and defecation thresholds to rectal thermal and pressure stimuli, particularly in patients with diarrhea-predominant IBS. Ice stimuli on the abdominal wall had varied effects on symptoms in patients with IBS and did not affect perception thresholds. Visceral perception thresholds were decreased significantly after rectal thermal and pressure stimuli in patients with IBS. Visceral hypersensitivity may be one of the important pathogenic mechanisms in IBS.

Exaggerated motility of the descending colon with repetitive distention of the sigmoid colon in patients with irritable bowel syndrome

Visceral hypersensitivity is one of the mechanisms of irritable bowel syndrome (IBS), but it does not explain the entire symptomatology, i.e., altered bowel habit with abdominal pain relieved by defecation. We tested our hypothesis that an abnormal link between luminal stimulation and mural response may have some role in the pathophysiology of IBS. Patients with IBS (n = 10, median 21 years old, 5 male patients, 5 female patients) and healthy control subjects (n = 10, median 21 years old, 5 men, 5 women) were studied. A manometric catheter with three transducers was inserted to the descending colon and a balloon was placed in the distal sigmoid colon. Another catheter with three transducers was inserted to the duodenum. After baseline for 30min, the sigmoid colon was stimulated by balloon distention for 30min followed by recovery for 30min. Balloon distention was repeated 100 times, and each stimulation consisted of a 5-s inflation and a 10-s deflation, with a volume of 50ml maximum. The sensory threshold of balloon inflation was then examined, and plasma adrenocorticotropic hormone (ACTH) was measured with radioimmunoassay. Repetitive colonic distention induced a significant increase in motility indices (mmHg s/s%) of the descending colon in the IBS patients (from 118 +/- 25 to 333 +/- 108, P < 0.05) but not of those in controls (from 90 +/- 16 to 89 +/- 19). A significant group difference (P < 0.05), period effect (P < 0.02), and group x period interactions (P < 0.01) were detected with two-way ANOVA. Duodenal motility indices in controls were significantly reduced by colonic distention (from 169 +/- 25 to 104 +/- 14, P < 0.01), but those in the IBS patients were not (from 156 +/- 17 to 124 +/- 20). The sensory threshold of balloon inflation in the IBS patients (74 +/- 10ml) was significantly lower than that in controls (125 +/- 6ml, P < 0.001). There was no significant difference in plasma ACTH levels between the IBS patients and controls. Repetitive distention of the distal sigmoid colon below the sensory threshold induced orad exaggerated motility of the colon in IBS patients. The distention inhibited motility of the small intestine in healthy subjects, but this inhibition was blunted in IBS patients. These results suggest that IBS patients may have not only visceral hypersensitivity, but also an abnormal intestinal reflex.

Visceral afferent hypersensitivity in irritable bowel syndrome—evaluation by cerebral evoked potential after rectal stimulation

OBJECTIVES: Gut hypersensitivity has been shown to be present in irritable bowel syndrome. The current study sought to determine the involvement or hypersensitivity of the gut afferents, objectively, by recording cerebral evoked potential after rectal stimulation. METHODS: In 13 patients with irritable bowel syndrome and nine healthy controls, rectal perception thresholds to electrical stimulation were measured, and cerebral evoked potentials were recorded from 2 cm behind vertex (Cz′) after rectal stimulation electrically (frequency 1 Hz, duration 0.5 ms) at an intensity 50% above perception threshold and with filter setting 1–250 Hz. RESULTS: Perception thresholds to rectal electrical stimuli in patients with irritable bowel syndrome were lower than controls ( p < 0.05). Rectal stimulation led to recognizable and reproducible cerebral evoked potentials. P1, N1, P2 latencies in patients with irritable bowel syndrome were shorter than that in controls ( p < 0.05). P1/N1 amplitude was greater in patients with irritable bowel syndrome than in controls ( p < 0.05). CONCLUSIONS: The shorter latency and increased amplitude of cerebral evoked potential after rectal stimulation in patients with irritable bowel syndrome compared to controls provide objective evidence supporting visceral afferent hypersensitivity as the underlying mechanism in irritable bowel syndrome.

Perceptual responses in patients with inflammatory and functional bowel disease

BACKGROUND AND AIMSEnhanced visceral sensitivity following a transient inflammatory process in the gut has been postulated as an aetiological mechanism of irritable bowel syndrome (IBS). In this study we compared...

Insights into the pathophysiology and mechanisms of constipation, irritable bowel syndrome, and diverticulosis in older people.

To review the epidemiology, pathophysiology and mechanisms of irritable bowel syndrome (IBS), constipation, and diverticulosis, for the purpose of addressing these three common conditions in older adults (>65 years of age). Using a MEDLINE search, we identified original English language journal articles and reviews from 1965 to December 1998. We also selected articles published before 1965 or after 1998 that were cross-referenced or pertinent to the topics researched. The prevalence of constipation and diverticulosis is higher in older than in younger adults. Significant risk factors for constipation in older women are failure of the anorectal angle to open or excessive perineal descent, which represent disturbances of pelvic floor function and rectal evacuation. In contrast, the prevalence of IBS is no greater than in younger adults. Nevertheless, these syndromes impact on the patient's functional status and quality of life. The mechanisms resulting in these gastrointestinal syndromes are unclear. Uncoordinated colonic activity and colonic segmentation may lead to IBS and diverticulosis, respectively, and these pathophysiological findings suggest disorders of inhibitory control of neuromuscular function. The total number of neurons in the myenteric plexus is decreased, and collagen deposited in the distal colon is increased with aging in humans. Animal studies suggest that senescent colonic muscle responds less to excitatory factors in vitro, and neural injury in older animals may result from apoptosis, defects of mitochondrial metabolism, and inadequate levels or response to neurotrophins. Future investigations will reveal whether similar mechanisms underlie human disease. Currently, treatment is aimed at relief of symptoms of IBS or constipation or dealing with the complications of diverticulosis. Constipation, IBS, and diverticulosis are common problems of aging. There is a need for further systematic research of the basic mechanisms in neuromuscular dysfunction with aging, including the studies of physical characteristics of the colonic wall, pelvic floor function (particularly in women with excessive perineal descent), and neurohormonal control of motility and sensation. Insights on the pathophysiology and mechanisms of neural injury may lead to more specific treatments in the future, e.g., serotonergic agents and neurotrophins. Meanwhile, collaborations between primary care physicians, geriatricians, and gastroenterologists can optimize management of these three common conditions that significantly impact the quality of life of older adults.

A Study of Intestinal Dysfunction Induced by Restraint Stress in Rats

Background: The pathogenesis of intestinal dysfunction induced by stress has not been established. We tried to clarify possible causal mechanisms of irritable bowel syndrome. Methods: An experimental model of intestinal dysfunction was designed using loading restraint stress in rats. A cannula was inserted into the origin of the duodenum or colon, with the other end leading to the skin. To provide intestinal content, a semi-solid colored marker was used for monitoring intestinal transit. After 1 week the marker was injected into the intestine through the cannula under unanesthetized wakefulness. Results: Under restraint stress, transit in the small intestine was suppressed, but actual suppression took place only in the upper half, where the contents normally moved fast. Transit time in the colon was reduced by restraint stress. This reduction was attributed to the disappearance of the stagnant region, which was present under normal conditions. Conclusions: These results suggested that restraint stress affects the function of the pacemaker site of the intestine.