Brain-gut axis: from basic understanding to treatment of IBS and related disorders.

The objectives of this review are to describe advances in understanding the mechanisms, and provide an update of current and promising therapy directed at the gut or the brain in the treatment of irritable bowel syndrome (IBS). The diagnosis of IBS is typically based on identification of symptoms, such as the Rome III criteria for IBS in adults and children (1,2). The criteria are similar in children and adults (Table 1). The focus of this review is the bowel dysfunction associated with IBS. Therefore, readers interested in treatment of functional abdominal pain (FAP) syndrome are referred to a recent review (3); there are no recently approved drugs for the treatment of FAP. Table 1 Symptom Criteria for IBS in Adults [A (ref. #1)] and Children [B (ref. #2)] Pathophysiology There are three main pathophysiological mechanisms associated with IBS (4): psychosocial factors, altered motility and altered sensation. In addition, research in the last decade has identified other factors that contribute to the development of the syndrome, including prior gastroenteritis, genetics, luminal irritants, changes in the microbial flora, mucosal inflammation or local immune activation, disorders of evacuation of stool or gas, and certain transmitters and transporters, such as serotonin. These mechanisms are reviewed extensively elsewhere (4–7). The bidirectional communication and neuroanatomical regions involved between the brain and the gut are illustrated in Figure 1 from a recent review by Mayer and Tillisch (7), to which the reader is referred for in depth analysis of the brain-gut axis in abdominal pain syndromes. Figure 1 Cortical modulation of homeostatic afferent input to the central nervous system. Prefrontal regions modulate activity in limbic and paralimbic regions, subregions of the anterior cingulate cortex, and hypothalamus, which in turn regulate activity of descending ... Whereas visceral hypersensitivity was considered a potential biological marker of IBS (8), results from several centers (9–13) have not replicated the 95% prevalence of rectal hypersensitivity or hyperalgesia in the original report, and the range is as low as 21%, and rectal hyposensitivity has even been reported in adults. In addition, the interpretation of original reports that suggested activation of the prefrontal cortex and the anterior cingulate cortex in IBS (14) and visceral pain is complex, since several other centers of activation and deactivation are described (15) and because of appreciation that differences in regional gray matter density in the brain may reflect anxiety or depression (e.g. prefrontal cortex) and that the cognitive/evaluative centers are apparently more specific for IBS (16). Rectal hypersensitivity in children with IBS has been reported by at least 4 centers (17–20). It was noted that a rectal sensory threshold for pain of 30mmHg had a sensitivity rate of 89% and a specificity rate of 83% for diagnosis of IBS and that children with IBS had abnormal pain referral after rectal distension (19). However, Vlieger et al. observed only 23% with rectal hypersensitivity among children with functional abdominal pain or IBS, and there were no significant differences in sensation thresholds in IBS and FAP (21). It has also been reported that “emotional instability”, a highly prevalent personality characteristic of children with IBS, seems to modulate the perception response to visceral stimulations (20). Brain imaging studies are still in their infancy in pediatrics, and no information is currently available about central nervous system activation in children with IBS. Altered motor function of the colon and the pelvic floor is increasingly recognized in patients with IBS and related symptoms. For example, 48% of adults with diarrhea-predominant IBD (IBS-D) and about 20% of those with constipation-predominant IBS (IBS-C) had accelerated or slow colonic transit respectively (13), and there are increased numbers of postprandial colonic high amplitude colonic contractions that are associated with colonic mass movements in patients with IBS-D (22,23). Children with IBS were found to have a disturbed rectal contractile response to a meal (17). A valid noninvasive transit test goes a long way in identifying these disturbances of colonic motility. One such test is the radiopaque marker transit Metcalf method (24); using this protocol, about one-third of adults with unexplained chronic constipation or chronic diarrhea had demonstrably abnormal transit (25). Among children, the method of Bouchoucha et al. is often preferred (26). A single abdominal radiograph is taken following six successive daily ingestions of the same number of identical radiopaque markers (26). Such a simple, noninvasive, inexpensive test has the potential to guide treatment by selecting for pharmacotherapy those patients who have abnormal transit. Even among children with constipation, 50% have colonic transit time within the normal range (27). Colonic transit measurement may also identify the predominant bowel dysfunction (13) in adult patients with alternating bowel function (IBS-M); in one study, colonic transit by scintigraphy demonstrated that patients presenting with IBS-M had significantly accelerated transit at 48 hours, relative to healthy controls.