Chapter 3.18
Irritable bowel syndrome pathogenesis
Adam D. Farmer1,2 and Qasim Aziz1
1Queen Mary University of London, London, UK
2Royal Shrewsbury Hospital, Shrewsbury, UK
Irritable bowel syndrome (IBS) is a chronic fluctuating disorder characterised by recurrent symptoms of abdominal pain or discomfort associated with a change in stool output [1]. IBS has an estimated population prevalence of 40% in Western countries, accounting for up to 60% of outpatient referral to gastroenterological clinics [2,3]. Currently, there is an absence of uniform investigational or treatment strategies for patients despite evidence suggesting that this disorder results in considerable reduction in health-related quality of life [1,4].
The aim of this chapter is to provide the reader with a succinct review of the mechanisms that have been proposed to account for the pathophysiology of IBS, namely genetic and psychological factors, visceral hypersensitivity and inflammatory changes to the milieu within the gastrointestinal (GI) tract. With respect to the latter, we also summarise current understanding of the role of GI microbiota, food hypersensitivity and probiotics.
3.18.1 Genetic factors
Epidemiological studies have suggested that there is a genetic component in the development of IBS with reports of clusters of IBS in families [5,6]. For example, Levy et al. reported that concordance for IBS was significantly greater in monozygotic (17.2%) than in dizygotic twins (8.4%) [7]. Further analysis of this evidence suggests that whilst there is a measureable genetic component to IBS, the effect is, at best, modest [8]. This effect has to be interpreted in the context of the influence of environmental and social factors. For instance, 15.2% of dizygotic twins with IBS have mothers with IBS, yet this is only 6.7% in those whose mothers do not have IBS [7].
These data provide support for the hypothesis that social learning contributes to the development of IBS as mothers share approximately the same number of genes with their children as dizygotic twins share with each other. As such, few diseases display purely Mendelian inheritance with disease phenotypes, such as IBS, actually reflecting a complex interaction between genes and the individual’s environment.
Many studies have examined a number of candidate genes in patients with IBS, with genes relating to the serotoninergic system being amongst the most extensively studied. Serotonin that is released from the presynaptic terminal is taken up from the synaptic cleft by the serotonin transporter. Thus the synaptic concentration of serotonin, and serotonin transmission per se, are determined by the expression of serotonin transporter protein. The serotonin transporter gene is located on chromosome 17.9, with its gene being located in the promoter region, known as the 5-hydroxytryptamine transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR comprises a repetitive sequence with an insertion or deletion variation. The deletion variation comprises a short (s) allele, whilst the insertion is known as the long (l) allele. The l allele produces more serotonin transporter and reuptakes serotonin more efficiently than the s allele [9].
Three studies have evaluated this polymorphism in Turkish, American and Korean patients with IBS but did not demonstrate any association with genotype and disease status [10–12]. In addition, a meta-analysis has also concluded that this polymorphism is associated with neither IBS nor its subtypes [13]. However, two studies have found that certain polymorphisms may predict response to therapy. For example, the LL genotype has been associated with a better response to alosetron, a 5-HT3 receptor antagonist, and the s allele was associated with predicting the response to tegaserod, a 5-HT4 agonist, in those with constipation-predominant IBS [14,15].
Interleukin (IL)-10 is an anti-inflammatory cytokine, where a polymorphism of its gene, 1082G/G, is associated with higher production of IL-10 [16]. Gonsalkorale et al. demonstrated that IBS patients had a reduced frequency of the G/G genotype, thus suggesting that genetically determined immune activity plays a role in the pathophysiology of IBS [17].
In summary, recent evidence does support a modest polygenetic susceptibility in IBS. However, further studies are needed to further delineate clinically important subgroups, or phenotypes, of IBS, which may lead to further insights into its pathophysiology and may facilitate utilisation of the genome-wide association study methodology.
3.18.2 Psychological factors
There has been a considerable degree of controversy in the recent past as to whether psychological factors are related to IBS per se or whether they are a sequela of the severity of symptoms. Traditional evidence of the former points to psychological factors influencing fluctuations in symptoms, which thus determines the degree of healthcare-seeking behaviour.
Drossman et al. performed a multivariate analysis of three groups: those with IBS who had sought medical attention, those with IBS who had not sought medical attention, and healthy controls [18]. They demonstrated that psychological factors were associated with healthcare seeking rather than the disorder and these factors may interact with physiological disturbances in the GI tract thus determining how the illness is experienced and acted upon. Furthermore, Whitehead et al. evaluated whether self-selection for treatment accounts for psychological abnormalities in secondary care of patients with IBS [19]. They concluded that the symptoms of psychological distress were not related to IBS status per se but did significantly influence consulting behaviour.
However, more recent evidence has begun to challenge this long accepted view. Two studies, conducted in unrelated populations, demonstrated an association between psychological factors and IBS which was unrelated to the degree of healthcare seeking [20,21]. Furthermore, a prospective study by Halder et al. evaluated the factors that may predict the development of abdominal pain, showing that psychological distress, health anxiety and fatigue levels were independent predictors of future onset rather than sequelae of symptoms [22]. Taken together, the exact relationship, and influence, of psychological factors and IBS remain to be fully elucidated although there is little doubt that there is a complex interaction between them.
3.18.3 Visceral hypersensitivity
Visceral pain is a common presenting symptom and a central defining feature of IBS. Many hypotheses have been proposed to explain the origin of this symptom in IBS, but no single factor has achieved primacy in the literature, largely due to the significant heterogeneity of these disorders. However, a common feature of IBS is that patients often display a heightened sensitivity to experimental GI stimulation, termed visceral hypersensitivity. First reported in the early 1970s, it was observed that a proportion of patients with IBS demonstrated rectal hyperalgesia to mechanical distension of their sigmoid colon using an inflatable balloon [23]. Indeed, rectal hypersensitivity to mechanical distension has been proposed to be a clinically useful discriminatory feature between IBS and other GI disorders [24,25]. Nevertheless, visceral hypersensitivity is not a sine qua non facet of IBS, with a number of studies not reproducing these initial observations. Whilst the evidence for the role of visceral hypersensitivity in IBS is often conflicting, it should be noted that the positive association between functional symptoms and rectal hypersensitivity was found in the studies with the largest numbers of patients [26,27].
The observation of visceral hypersensitivity has resulted in a considerable research effort from academia and the pharmaceutical industry alike in attempting to identify the culpable molecular mechanisms that are responsible for this epiphenomenon. Therefore, the pathophysiology of visceral hypersensitivity may be conceptualised as being due to aberrant processes that may arise at any level of the visceral nociceptive pathway. Although the pathophysiology of visceral hypersensitivity has not been completely elucidated, several mechanisms have been proposed, including psychosocial stress, nutrient, hormonal, subtle (low-grade) inflammation and changes in the sensorimotor function of the GI tract, including both peripheral and central sensitisation of the visceral afferent neuronal pathways. We will now examine each of these factors in turn.
Psychosocial stress and visceral hypersensitivity
It has been well documented that patients who experience acute severe psychosocial stress are at heightened risk of developing a multitude of functional disorders, including IBS [28]. Up to 86% of patients with IBS report traumatic life experiences [29], with 7.8% fulfilling the criteria for a diagnosis of post-traumatic stress disorder [30]. Interestingly, patients often report that their symptoms are considerably worsened by stress. This has been examined in a number of studies, most notably by Posserud et al. where pain thresholds to rectal distensions were assessed in IBS patients in comparison to healthy controls in response to mental stress [31]. They demonstrated that stress induced an exaggerated neuroendocrine response and an increase in visceral perception, suggesting that stress may exacerbate IBS symptoms.
Nutrient intake and visceral hypersensitivity
Irritable bowel syndrome patients often report a deterioration, or precipitation, in symptoms, in addition to intolerances to one or more food groups [32]. In one study 63% of IBS patients reported that their GI symptoms were exacerbated by foods rich in carbohydrates, as well as fatty food, coffee, alcohol and hot spices [33]. Whilst the role of specific dietary constituents has only been the subject of limited research to date, a number of mechanisms have been postulated to contribute to the escalation of symptoms. Experimental evidence suggests that the physiological response of the intestine to food ingestion may precipitate symptoms in predisposed individuals. For example, Simrén et al. demonstrated that intraduodenal infusion of lipids enhanced rectal sensitivity in IBS patients in comparison to healthy controls [34]. However, this enhancement in rectal sensitivity is nutrient dependent, with fatty meals having a more pronounced effect than carbohydrates [35].
Peripheral sensitisation and visceral hypersensitivity
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