Irritable Bowel Syndrome: New and Emerging Therapies

Lucinda A. Harris; Lin Chang

Disclosures

Curr Opin Gastroenterol. 2006;22(2):128-135. 

In This Article

Pathophysiologic Mechanisms

Recent evidence strongly suggests that the primary pathophysiologic mechanism of IBS involves a dysregulation in brain-gut interactions.[3] Many central and peripheral factors (genetic predisposition, environmental factors, chronic stress, inflammation or infection) may contribute to an altered brain-gut axis.[2] Those alterations may eventually cause disorders of mucosal immune response, intestinal motility and permeability, and visceral sensitivity that produce abdominal pain or discomfort and compromised bowel function.[4]

Altered Gastrointestinal Motility and Visceral Sensitivity

The pathogenesis of IBS, like that of most functional disorders of the gut, is controversial and evolving. Alterations in gastrointestinal motility and visceral hypersensitivity are not universally present in all individuals with IBS.[5,6] Mechanisms associated with visceral hypersensitivity in IBS involve hypervigilance to expected aversive visceral events and hyperalgesia induced by sustained noxious visceral stimulation.[7] Using various paradigms of balloon distention, studies have shown that, overall, IBS patients demonstrate lowered visceral perceptual thresholds, increased viscerosomatic referral areas, and increased sensory ratings when compared with healthy individuals.[5,7,8,9,10]

Modulation of the Central Nervous System

Neuroimaging studies including positron emission tomography[11] and functional magnetic resonance imaging[12] of the brain have reported that several regions which are part of a central pain processing circuitry ('central pain matrix'), including the insula and the anterior cingulate cortex, as well as other regions belonging to corticopontine pain modulation have altered activation in response to rectosigmoid stimuli in IBS patients compared with healthy controls.[13] In patients with IBS, the central nervous system may fail to activate pain inhibitory mechanisms or increase activation of pain facilitatory pathways in response to incoming or anticipated visceral pain.[14]

Role of Stress

The role of stress may be particularly important in altering brain-gut interactions, resulting in the development or exacerbation of IBS symptoms.[15,16] Rectal distention studies in IBS patients have shown altered visceral perception and neuro-endocrine responses to a stressor compared with healthy controls.[17,18] Although stress affects the gut in both healthy individuals and IBS patients, new evidence suggests there may be greater reactivity in the major mediator of stress in the brain-gut axis, corticotrophin-releasing factor (CRF). Therapeutic agents targeted at CRF receptors are currently under development for IBS (see below).

Infection and Inflammation

Postinfectious IBS has been identified in 7-30% of patients with a recent history of established bacterial gastroenteritis.[19] A variety of mechanisms on the mucosal and cellular level are currently being investigated for their potential role in postinfectious IBS. Decreased ability to downregulate the inflammatory response to infection may result in such defects as increased inflammatory cytokines or mucosal cells, like enterochromaffin cells or proinflammatory cytokines.[20] Researchers are also exploring the use of probiotics as possible immune modulators[21**] and small bowel intestinal overgrowth as a potentially pathogenetic mechanism of IBS.[22]

Serotonin

Serotonin (5-hydroxytryptamine, 5-HT) is a key potentiator of gut motility (e.g. stimulates peristalsis), sensation, and secretion. Ninety-five percent of serotonin is found in the gut, where 90% is localized within the enterochromaffin cells and 10% is found within the enteric neurons.[23] Altered serotonin signaling mechanisms have recently been reported in IBS, including a decreased level of the serotonin reuptake transporter protein. This transporter protein is the chief mechanism by which the body regulates the amount of serotonin in the extracellular space and is genetically predetermined in each individual by the presence of long, short or heterozygous polymorphisms.[24] The serotonin reuptake transporter gene polymorphism may influence the response to serotonergic agents.[25] Various serotonergic agents have been found to be efficacious in the treatment of IBS and are discussed below. One should note that while serotonin is a key modulator of gut function, there are other neurotransmitters and hormones involved in gut motility, sensation and secretion that are potentially important targets for current and future drug development.

Genetic Factors

Familial clustering and twin studies have both supported a role for genetic predisposition in the pathophysiology of IBS.[26,27] While these studies demonstrate the importance of genetic factors, environmental factors may have even more of an impact on the development of IBS.[27]

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