Yehuda Ringel, MD Douglas A. Drossman, MD
Introduction: Irritable bowel syndrome (IBS) is a chronic disorder of gastrointestinal function for which no specific pathophysiologic mechanism is known. However, it is generally accepted that IBS symptoms are multidetermined, and are generated from dysregulation at multiple levels of the brain-gut axis. They are manifest by abnormal motor reactivity to various stimuli, and low sensation and pain thresholds.
The growing interest of clinicians and researchers in the pathogenesis of functional gastrointestinal disorders led to several research presentations during this year's Digestive Disease Week meeting. Although these presentations addressed various factors implicated in the pathogenesis of these disorders (ie, behavioral/psychosocial, central and peripheral contributors), this article focuses on some new insights into the possible contribution of gut infection and inflammation in the development of symptoms and other potential clinical consequences.
Infection and Inflammation: Stephen M. Collins provided a comprehensive review of the evidence suggesting the need to consider infection and inflammation in the pathogenesis of some patients with IBS. He presented data from clinical studies showing the development of IBS symptoms following acute gastroenteritis (ie, postinfectious [PI] IBS) and a higher than expected prevalence of IBS symptoms among patients with inflammatory bowel disease that was in remission. Additionally, data from animal studies demonstrated that altered gut physiology can persist even after the infection and associated inflammation have resolved. Furthermore, studies of mucosal biopsies, from both human and animal models, have shown increased inflammatory cells and inflammatory mediators in patients with IBS and in previously sensitized/stressed animals. Finally, some recent studies have shown proximity between nerve trunks and the inflammatory cells, suggesting a local neuroimmune interaction that may contribute to the pathogenesis of IBS. With respect to the latter, several key studies presented during these meeting proceedings provided some supportive evidence relating the role of infection and inflammation to IBS.
Wheatcroft and colleagues have shown a significant increase in serotonin-containing entero-endocrine cells (EC) following Trichinella spiralis infection in mice. This finding suggests that the increased EC numbers that have previously been reported in humans after Campylobacter enteritis are likely not specific to bacterial infections. These events may also occur after protozoan and other parasitic infections, and thus may contribute to postinfectious bowel dysfunction.
Dunlop and colleagues compared the numbers of rectal mucosal lymphocytes, EC, and mast cells from IBS patients (n = 76) and healthy controls (n = 40).
Although all biopsies were normal using conventional histology, immunohistochemical studies showed differences in patterns of mucosal pathology between several distinct subgroups of IBS. Patients with PI-IBS showed increased EC and CD3+ lamina propria lymphocytes (LPL),confirming previous findings. However, patients with constipation-predominant IBS were not significantly different from controls, and nonconstipated, non-PI-IBS patients showed increased CD3+, LPLs, and mast cells. These findings suggest that within the broad clinical grouping of IBS, there may be several distinct groups with different patterns of mucosal pathology. The clinical relevance of these findings needs further investigation.
The growing interest and the emerging evidence supporting the role of infection and inflammation in the pathogenesis of at least a subset of IBS patients was also manifest in some key studies presented in the American Gastroenterological Association Research Forum on the "Medical Treatment of Functional GI Disorders." As discussed below, these studies explored possible new approaches in the treatment of IBS, while focusing on modulating and reversing infections and/or inflammation.
A Role for Anti-inflammatory Agents?: Dunlop and coworkers also presented the results of an intriguing multicenter study aimed at assessing the effect of a short course of steroids on intestinal inflammatory cell counts and clinical symptoms in patients with PI-IBS. Thirty-one patients with IBS symptoms 3 or more months after initial acute gastroenteritis were randomized in a double-blind fashion to receive oral prednisolone 30 mg per day or placebo for 3 weeks. Rectal biopsies were taken and symptom questionnaires (modified Talley, Gastrointestinal Symptom Rating Scale [GSRS]-IBS, QOL-IBS & Global Health) were completed prior to and after treatment. Rectal biopsies were immunostained for ECs, lymphocytes (CD3+ lamina propria cells, crypt and surface intraepithelial lymphocytes [IELs]), and mast cells. In addition, a symptom diary was kept throughout the study and a modified GSRS score incorporating pain, diarrhea, looseness, and urgency was used as the primary end point.
Prior to treatment, the CD3 count in the lamina propria correlated with the EC counts (Spearman's coefficient 0.429, P = .036) and with the modified GSRS score (Spearman's coefficient 0.482, P = .015). Following treatment, there was a significant fall in CD3 counts. However, this fall was in both the placebo and the prednisolone groups (27, P =.05; and 20, P = .006 vs initial values, respectively) and there was no change in the EC, IEL, and mast cell counts in either group. The modified GSRS score did not change after prednisolone treatment. However, there was a surprising, and unexplained, decrease in GSRS score at the end of the treatment in the placebo group (P = .02 vs initial value).
The results of this study show that treatment with 30 mg of prednisolone started 3 or more months after the initial gastrointestinal infection is ineffective in PI-IBS. It is not yet clear if anti-inflammatory treatment started in earlier stages, and/or with higher doses, and/or for longer duration would have other outcomes. Therefore, despite preliminary evidence for an inflammatory/immune component in some patients with IBS, additional studies are needed before the use of anti-inflammatory agents can be considered in treatment.
A Role for Probiotics?: Probiotics are live microbial food supplements or components of bacteria that alter the enteric microflora and have a beneficial effect on health. The most frequently used genera are Lactobacilli and Bifidobacteria. The potential mechanisms of their action include competitive bacterial interactions, production of antimicrobial metabolites, mucosal conditioning, and immune modulation. The emerging use of probiotics in several gastrointestinal disorders (eg, inflammatory bowel disease) has led to increased interest in their use in patients with IBS.
Quigley and colleagues presented the results of a double-blind, placebo-controlled treatment study with probiotic bacteria in 77 patients (64% female) with IBS. Following a 2-week run-in period off all medication, patients were randomized to receive, once daily, either Lactobacillus spp, Bifidobacterium spp, each added to a milk drink, or the milk drink alone for 8 weeks. IBS symptoms were recorded daily throughout the entire study. In comparison to placebo, subjects randomized to Bifidobacterium experienced a significant reduction in pain, bloating, and bowel movement difficulty.
Benefit with Lactobacillus was limited to an effect on pain in weeks 2 and 7 only, and neither probiotic strain had any effect on the frequency of bowel movements. A composite score, incorporating all symptoms, showed significant improvement in response to Bifidobacterium for all weeks. The improvement in the composite score response was greater with Bifidobacterium compared with placebo and Lactobacillus (Bifidobacterium vs Lactobacillus vs placebo = 3.70 +/- 0.59 vs 5.25 +/- 0.55 vs 5.68 +/- 0.56, P < .05 for week 4). The symptomatic response with Bifidobacterium was associated with parallel improvement in quality of life as assessed by using an IBS-specific instrument.[7,8]
A follow-up 4 weeks after discontinuation of the treatment (washout period) showed that both symptoms and quality of life returned to baseline. The results showed a beneficial effect of probiotic bacteria in IBS. However, it must be kept in mind that data on the use of these agents in IBS are still very limited and not always consistent. (For example, a previous double-blind, placebo-controlled, randomized study showed beneficial effect of Lactobacillus plantarium in IBS.) In addition, as emphasized by the investigators, it seems that the beneficial effect was short-term and strain-specific. Additional information regarding the variability of strain-specific response was provided by the results of a study presented by another group from Ireland, as discussed below.
Sheil and colleagues examined cytokine production by human mononuclear cells that were incubated in vitro in various strains of Lactobacilli and Bifidobacteria. They found strain-specific alterations in cytokine gene expression and strain-specific cytokine responses for both Lactobacilli and Bifidobacteria strains. As proposed by the investigators, these results suggest that experiments on the immunomodulatory effects of one bacterium cannot be extrapolated to other bacteria. Thus, each bacterial strain that is considered for use as a probiotic may need to be validated individually.
The results of studies that have thus far been conducted with probiotics are encouraging. However, additional investigations that will better define the potential subgroup of patients, the specific strain, and the duration of treatment are required in order to establish the role of probiotics in the treatment of IBS. Until the latter is accomplished, their use will remain investigational.
A Role for Antibiotics?: Pimentel and associates tested the utility of antibiotic treatment in IBS. This study follows a recently published provocative report from the same group in which they identified an association between IBS and abnormal findings on lactulose breath test (LBT). However, this previous report had limitations due to its study design, primarily related to possible ascertainment bias, the lack of a control arm, and the unblended nature of the treatment. Thus, the results of this study and their clinical significance were uncertain. The current study was designed to test the effect of antibiotic treatment in patients with IBS in a randomized, double-blind, placebo-controlled fashion.
One hundred-one consecutive IBS subjects recruited through advertising were randomized to receive neomycin 500 mg (n = 49) or placebo (n = 52) twice daily for 10 days. All subjects underwent LBT before and 7 days after completion of treatment. The LBT was read by a blinded reviewer, and the results remained blinded throughout the study. An IBS symptom questionnaire was administered before and after treatment and a true clinical response was defined as > 50% improvement in symptoms. Abnormal LBT was found in 83% of IBS subjects who entered the study compared with 20% in sex-matched controls (P < .01). In an intention-to-treat analysis, neomycin resulted in a 39.3% improvement in an IBS composite symptom score compared with 12.3% for placebo (P < .05), and 40.1% bowel normalization compared with only 15.1% for placebo (P < .001). Of the subjects receiving neomycin, 50% had a true clinical response compared with 17% given placebo (P < .01). These results were even greater (up to 75%) in the group in which neomycin was successful in normalizing the breath test.
The investigators concluded that abnormal LBT is very common in subjects with IBS and that IBS symptoms can be significantly improved with antibiotic treatment. Important concerns raised during the discussion of this paper related to the following: (1) the unusually high positive LBT rate in this population, possibly due to false-positives likely resulting from rapid transit of lactulose in the small bowel in IBS; (2) the use of a nonstandard measure of primary efficacy (ie, composite symptom score); (3) the significant effect being driven by an unusually low treatment and placebo response rate.
The results of this study are provocative and interesting, and therefore deserve replication. They emphasize the need to consider performing LBT, when clinically indicated, as part of the evaluation of patients with IBS. In addition, the definition of IBS is a complex of symptoms that cannot be explained by other conditions. Thus, the finding of positive LBT and positive response to antibiotic treatment suggests the presence of bacterial overgrowth that may be incorrectly diagnosed as IBS.
Concluding Remarks: The above discussion seeks to bring to the fore the current state of knowledge regarding the potential role of various factors in the pathogenesis of IBS. Within this context, new insight may be gleaned with respect to the clinical and therapeutic implications for patients with this functional gastrointestinal disorder.
Ringel Y, Sperber AD, Drossman DA. Irritable bowel syndrome. Annu Rev Med. 2001;52:319-338.
Collins SM. The role of infection and inflammation. In: AGA clinical symposium – IBS: Progress at last? Program and abstracts of Digestive Disease Week 2002; May 19-22 2002; San Francisco, California. [Sp549]
Wheatcroft J, Wakelin D, Jenkins D, Spiller RC. Increased entero-endocrine cell numbers in the Trichinella spiralis infected mouse model of post-infectious bowel dysfunction. Gastroenterology. 2002;122:A-162. [Poster # S1099]
Dunlop S, Jenkins D, Spiller RC. Distinctive histological patterns of chronic inflammatory cells in rectal biopsies of patients with different clinical subtypes of IBS. Gastroenterology. 2002;122:A-316. [Poster # M1516]
Dunlop S, Jenkins D, Naesdal J, Borgaonker M, Collins S, Spiller RC.
Randomised double-blind placebo-controlled trial of prednisolone in post-infectious irritable bowel syndrome (PI-IBS). Gastroenterology. 2002;122:A-60. [Abstract #499]
Quigley E, O'Mahony L, McCarthy J, et al. Probiotics for the irritable bowel syndrome (IBS): A randomized, double-blind, placebo-controlled comparison of Lactobacillus and Bifidobacterium strains. Gastroenterology. 2002;122:A-59. [Abstract #498]
Drossman DA, Patrick DL, Whitehead WE, et al. Further validation of the IBS-QOL: A disease specific quality of life questionnaire. Am J Gastoenterol. 2000;95:999-1007.
Patrick DL, Drossman DA, Frederick IO, DiCesare J, Puder KL. Quality of life in persons with irritable bowel syndrome: Development of a new measure. Dig Dis Sci. 1998;43:400-411.
Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, randomized study on the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2001;13:1135-1136.
Sheil B, O'Mahony L, O'Callaghan L, Collins JK, Shanahan F. Variability in human cytokine responses to different Lactobacilli and Bifidobacteria.
Gastroenterology. 2002;122:A-281. [Poster #M1161]
Pimentel M, Chow E, Lin HC. Neomycin leads to a dramatic improvement in IBS symptoms that depend on lactulose breath test findings: A double blind randomized placebo controlled study. Gastroenterology. 2002;122:A. [Abstract #500]
Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503-3506.