East meets West: infection, nerves, and mast cells in the irritable bowel syndrome

The irritable bowel syndrome (IBS) is the most common gastroenterological disorder seen in Western societies where it imposes a major socioeconomic burden.¹ The economic impact of IBS arises, at least in part, from difficulties in diagnosis and treatment, which in turn reflect our limited conceptualisation of this disorder. Recent studies have identified acute bacterial gastroenteritis as a strong risk factor for the development of IBS² but evidence supporting this relationship is limited to studies performed in Western countries.^3–7

Although IBS has received less attention in non-Western countries, available data suggest that it is common in the African continent,^8–10 Malaysia,¹¹ and China¹² where the condition is significantly underdiagnosed by Western practitioners.¹³ This hesitation in diagnosing IBS in Eastern countries likely reflects uncertainty regarding the influence of culture and endemic infection on the clinical expression of IBS in these countries. Indeed, in countries where enteric parasitic infestation is common, there is controversy regarding the role of infection in the development of IBS, as eradication of the parasite may not improve IBS symptoms.¹⁴ However, studies in animal models suggest that the host response to the initial infection is a critical determinant of persistent gut dysfunction, and the continued presence of the parasite is not necessary for induction of a chronic dysfunctional state.¹⁵ Thus the role of infection in the pathogenesis of IBS in these countries may be underestimated.

It is on this background of uncertainty that the paper by Wang and colleagues,¹⁶ published in this issue of Gut, is received with considerable interest [see page 1096]. This cohort study evaluated gastrointestinal symptoms in 295 patients recovering from acute gastroenteritis in Beijing, China. During a 1–2 year follow up period, the authors found an 8.1% incidence of IBS among all patients compared with 0.8% of controls, and an incidence of 10.2% of IBS in those patients (71.4%) who had a documented Shigella infection. The authors also found that 22.4% of patients (v 7.4% of controls) exhibited functional gastrointestinal symptoms that did not meet the Rome II criteria. These results indicate that the incidence of chronic gastrointestinal symptoms following acute gastroenteritis is similar to that reported in the UK and North America.^3–7 The study by Wang and colleagues¹⁶ also provides the first positive association between Shigella infection and IBS, as pathogens reported in previous studies were Salmonella and Campylobacter. Taken together, these observations suggest that host, rather than microbial, factors influence the development of post-infective IBS (PI-IBS), although Campylobacter toxin may also contribute to the pathogenesis of PI-IBS.¹⁷ As in previous studies, the severity of the acute infection was found to be a strong risk factor for the development of PI-IBS.^4,7 In contrast with a significant predisposition of females in Western studies, the study of Wang and colleagues¹⁶ did not identify sex as a risk factor for PI-IBS, and this is in keeping with other IBS studies from Asia.¹⁸ A UK study has shown that >50% of IBS patients remain symptomatic six years post-gastroenteritis¹⁹ and it would be of interest to determine whether there is a similar prognosis in the Beijing patients.

The study by Wang and colleagues¹⁶ confirmed and extended the findings from Western studies, indicating that low grade inflammation is present in patients with PI-IBS. Increased expression of interleukin (IL)-1β mRNA in rectal biopsies of PI-IBS patients confirms the recent observations of Gwee and colleagues.²⁰ The authors also found increased IL-1β expression in the terminal ileum.¹⁶ Western studies on PI-IBS patients have been restricted to the rectosigmoid region and have not found increased mast cell numbers.^4,21 However, previous studies found increased numbers of mast cells in the caecum,²² terminal ileum,²³ and descending colon²⁴ of IBS patients although it is not known how many of those patients had a history of gastroenteritis at the onset of IBS. Spiller et al found increased numbers of intraepithelial lymphocytes and T lymphocytes, but not mast cells, in the rectosigmoid region of PI-IBS patients²¹ and suggested that these histological findings could distinguish between IBS of infective and idiopathic aetiologies.²⁵ As these studies were conducted on Western patients, it is not known whether the discrepancy in mast cell number in PI-IBS patients observed in the studies from the UK and Beijing reflect differences in patient recruitment, tissue sampling or processing, or an important biological variable related to either the infective agent or differences, for example, in microflora. Further studies are clearly necessary.

The immunohistochemical studies reported by Wang and colleagues¹⁶ were performed on a mixed group of IBS patients that met the Rome II criteria, consisting of patients with (48%) or without (52%) a history of gastroenteritis. They found an increased density of 5-hydroxytryptatimine and substance P immunoreactive nerves surrounding mast cells in the ileum and colon of IBS patients. As there was no change in the density of calcitonin gene related peptide positive nerves, the findings unlikely reflect a generalised upregulation of nerves secondary to low grade inflammation. These data confirm the recent findings of Barbara and colleagues²⁴ showing close proximity of tryptase positive mast cells and nerves along with correlation of these intimate nerve to mast cell interactions with severity of abdominal pain in IBS patients. Taken together, these two independent studies from very different regions of the globe provide strong evidence supporting a role for neuroimmune interactions in IBS. The feasibility of such interactions is provided by previous demonstrations that substance P, in low concentrations, can alter mast cell excitability²⁶ and can directly influence mast cell function when released from nerves.²⁷ These findings are in keeping with the demonstration that an increased rate of mast cell degranulation was found for mast cells located in close vicinity to nerves in the colonic mucosa of IBS patients.²⁴ Interestingly, T lymphocytes may influence expression of neurokinin (NK)-1 receptors on mast cells and this may be important in the context of IBS where there is evidence of increased lymphocyte number²¹ and activation.²⁸ A recent study has shown that the Th2 cytokine IL-4 upregulates NK-1 receptors on mast cells²⁹ and it is therefore possible that the Th polarity of intestinal immunity could influence the nature of neuroimmune interactions in IBS. As a Th2 immune response bias exists in countries where intestinal parasitic infection is endemic,³⁰ it is possible that resulting changes in neuroimmune interactions could produce differences in the pathophysiology and clinical expression of IBS between Western and Eastern societies.

There is increasing recognition of the importance of infection in the pathogenesis of IBS, and the study of Wang and colleagues¹⁶ places this relationship in a broad global context. With emerging evidence supporting a role for inflammation and immune activation in IBS, studies are encouraged to address the influence of the microbial environment on the epidemiology and clinical expression of IBS across the globe.