Eamonn M. M. Quigley, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Tel.: +353 21 490 1585; fax: +353 21 490 1594; e-mail: email@example.com
Abstract Probiotics, defined as live organisms that, when ingested in adequate amounts, exert a health benefit on the host, have been used for almost a century in the management of a variety of medical disorders, usually on the basis of little evidence. Advances in our understanding of the gut flora and of its relationship to the host, together with progress in microbiology, molecular biology and clinical research have identified important biological properties for probiotics and demonstrated efficacy in a number of gastrointestinal disorders. The clear delineation of a post-infective variety of irritable bowel syndrome (IBS), as well as the description, in a number of studies, of evidence of low-grade inflammation and immune activation in IBS, suggest a role for a dysfunctional relationship between the indigenous flora and the host in IBS and, accordingly, provide a clear rationale for the use of probiotics in this disorder. Other modes of action, including bacterial displacement and alterations in luminal contents, are also plausible. While clinical evidence of efficacy is now beginning to emerge, a review of available trials emphasises the importance of clear definition of strain selection, dose and viability. This is evidently an area of great potential in IBS and deserves further study at all levels.
Reflecting, perhaps, the paucity of truly disease-modifying therapies that are available to relieve the disorder, irritable bowel sufferers commonly have recourse to the use of complementary and alternative medical remedies and practices.1 Foremost among such approaches have been various dietary manipulations, including exclusion diets,2,3 and a variety of dietary supplements. In Europe, in particular, where several such products are advertised widely for their general ‘immune-boosting’ and ‘health-enhancing’ properties, probiotics have been widely used as dietary supplements by irritable bowel syndrome (IBS) patients. Recently, based on data from the experimental laboratory and some evidence from clinical trials, the concept of probiotic use in IBS has begun to wend its way into the realm of conventional medicine,4 and an assessment of the potential role of these agents in IBS is now timely. This review addresses two specific questions:
1Is there a rational basis for the use of probiotics in IBS?
2What is the evidence base for the efficacy of probiotics in IBS?
The probiotic concept
Probiotics, a word derived from the Greek and meaning ‘for life’, are defined as live organisms that, when ingested in adequate amounts, exert a health benefit on the host. Lactobacilli, bifidobacteria and non-pathogenic yeasts, such as Saccharomyces boulardii, are among the most commonly used and thoroughly evaluated probiotics. While the aforementioned definition confines the use of the term probiotic to products that contain live organisms, the probiotic concept has, of late, and perhaps inappropriately, been extended to include the use of killed organisms or even bacterial DNA. Prebiotics are defined as non-digestible but fermentable products that beneficially affect the host by selectively stimulating the growth and activity of one species, or a limited number of species, of bacteria, in the colon. Compared with probiotics, which introduce exogenous bacteria into the human colon, prebiotics stimulate the preferential growth of a limited number of health-promoting commensal flora already residing in the colon, especially, but not exclusively, lactobacilli and bifidobacteria. The potency of this stimulus is, in part, dependent both on the baseline density of the target probiotic flora (bifidobacteria and/or lactobacilli) and on the luminal pH. The oligosaccharides in human breast milk are considered the proteotypic prebiotic as they facilitate the preferential growth of bifidobacteria and lactobacilli, in the colon, in exclusively breast-fed neonates. A combination of a probiotic and a prebiotic is referred to as a synbiotic. Collectively, these substances are sometimes referred to as functional foods. For the purposes of this review, and given the paucity of data on the use of prebiotics and other functional foods in IBS, we confine our comments to probiotics.
The interpretation of the literature on probiotics, not to mind the many claims that are made in the lay press and other media, is fraught with difficulties, many related to factors intrinsic to this area. Firstly, it is not unusual for the benefits of a given species or organism to be touted based on the evidence derived from the studies involving other organisms and species, despite the fact that detailed studies have demonstrated that, in terms of a probiotic property, be it immune modulation5–8 or antibacterial activity,6,9,10 there are tremendous differences between different lactobacilli and bifidobacteria, not to mention, for example, between lactobacilli and bifidobacteria. No two probiotics are the same and extrapolations from one to another should be resisted at all times. Secondly, an individual who is about to consume a given probiotic preparation should know exactly what he or she is about to take: is it live, what is its concentration, will the organism survive as it makes contact with acid, bile and digestive enzymes while transiting the gut, and what will be the actual concentration of the organism at its desired site of action? Few probiotic preparations have been characterized and formulated with sufficient rigour to allow the manufacturer to provide answers to these critical questions. Of further concern, critical examinations of the actual constituents of commercially available probiotic preparations have revealed worrying deviations from those included in the product label.11 Finally, even fewer still have been characterized in detail in terms of their microbiological properties, immunological or physiological effects and only a handful have been subjected to clinical trial in humans.
Is there a rationale for the use of probiotics in irritable bowel syndrome?
To approach this issue, we examine current concepts of IBS pathophysiology and, in each instance, evaluate the potential for an effect for a probiotic. While the precise cause of IBS remains obscure and theories of symptom pathogenesis abound, most hypotheses centre on one or more of the following areas: an altered intraluminal milieu, immune activation, enteric neuromuscular dysfunction and brain–gut axis dysregulation.
Alterations in the intraluminal milieu
For some time, various studies have suggested the presence of qualitative changes in the colonic flora in IBS patients; a relative decrease in the population of bifidobacteria being the most consistent finding.12,13 It should be noted, however, that these findings have not always been reproduced and the methods employed have been subject to question. Nevertheless, qualitative changes in the colonic flora, be they primary or secondary, could lead to the proliferation of species that produce more gas14 and short-chain fatty acids and are more avid in the deconjugation of bile acids. The latter could, in turn, lead to clinically significant changes in water and electrolyte transport in the colon and affect colonic motility and/or sensitivity. Similarly, a repopulation of the flora with the deficient commensal could restore homeostasis. In reviewing any study of the colonic flora, whether in health or disease, it must be remembered that our understanding of the human microbiota remains far from complete; many organisms remain unculturable and unclassified.
More recently, the role of the gut flora in IBS has been taken a stage further with the suggestion that some IBS patients may harbour quantitative changes in the indigenous flora, in the small intestine, i.e. they have developed small intestinal bacterial overgrowth (SIBO).15 The occurrence of SIBO has been associated with abnormalities in small intestinal motor function16 and its eradication with symptomatic relief.17 Further evidence for a role of an altered indigenous flora in IBS is provided by a very recent study that described improvements in IBS symptomatology, in the short term, following the administration of the non-absorbable antibiotic rifaximin to a group of patients who did not have SIBO at baseline.18 In this study, breath hydrogen excretion fell significantly among those who responded to rifaximin and this fall correlated with improvements in bloating and overall symptom scores. Given reports of efficacy of probiotics in SIBO in other contexts,19 one can readily visualize opportunities for probiotic administration in this context. One could, similarly, speculate that the efficacy of some probiotics in preferentially relieving ‘gas-related’ symptoms may be related either to qualitative changes in the colonic flora, as described earlier, or through the suppression of SIBO.20–27 Manipulation of the bacterial flora may affect other aspects of the metabolic activity of the colonic microbiota.28 Clearly, this is an area deserving of further study.
Certain probiotics possess potent antibacterial and antiviral properties. Probiotic antibacterial activity may derive from the direct secretion of bacteriocins,29 the elaboration of proteases directed against bacterial toxins30 or through their ability to adhere to epithelial cells and thus exclude pathogens (Fig. 1). There is now a considerable body of evidence to support the concept of postinfectious IBS; an effective antibacterial probiotic could well play a role in preventing the 5–10% incidence of IBS that may follow an episode of confirmed bacterial gastroenteritis, especially among high-risk individuals.31 The demonstrated antiviral properties of some probiotic organisms, including the stimulation of interferon production, together with the well-documented efficacy of certain probiotics in the therapy of rotavirus diarrhoea,32 suggests the potential for a broader role for these agents in bowel dysfunction triggered by infectious agents.
Postinfectious IBS has been associated with a persistent, albeit subtle, inflammatory process in the colonic epithelium. This inflammatory process has been associated with increases in enterochromaffin cells and intraepithelial lymphocytes.33,34
Evidence now accumulates to suggest an association between IBS, in general, and immune activation. Colonic biopsies have demonstrated, in some cases, frank inflammation and, in others, more subtle evidence of immune activation;35 more recently, studies on cytokine levels in peripheral blood mononuclear cells8 and even in serum36 have revealed a pro-inflammatory state. It is also interesting to note that constipation has also been associated with a partially reversible inflammatory activation of the colonic mucosa.37 These studies have, to date, been performed in relatively small patient numbers and require confirmation. Even if, ultimately, only a subset of IBS is found to be associated with mucosal inflammation, it still provides yet another rationale for the use of probiotics. In experimental animal models of inflammatory bowel disease, various probiotics and probiotic cocktails have demonstrated potent anti-inflammatory properties, suppressing mucosal inflammation and restoring cytokine balance towards an anti-inflammatory state.5,38 In humans, the probiotic cocktail, VSL#3 (composed of Streptococcus thermophilus and several species of Lactobacillus and Bifidobacteria), has been shown to promote secretion of the anti-inflammatory cytokine, IL-10, and suppress the secretion of the pro-inflammatory cytokine, IL-12, in dendritic cells derived from the peripheral blood.7 In the same study, a detailed evaluation of the various organisms that comprise this cocktail indicated that most of the immune-modulating activity resided in bifidobacterial species.7 Similar observations have been made in other models.10 It should also be noted that some other constituents of this cocktail elicited cytokine responses which would be regarded as pro-inflammatory. The suggestion that bifidobacteria may be especially potent as immunomodulatory agents is consistent with our own observation that a symptomatic response to Bifidobacterium infantis 35624, in IBS, was associated with a normalization of a baseline abnormality in the ratio of IL-10 to IL-12 in peripheral blood mononuclear cells, which was tilted towards a pro-inflammatory state.8 The reader may ask: could these immunomodulatory effects become immunosuppressant and potentially deleterious? It needs to be stressed that there is no evidence from animal or human studies that this can occur, even in susceptible animal models. The selection of the appropriate probiotic(s) for use in this context requires further study; it is, indeed, possible that a bacterium that is highly effective as an immune suppressant may be ineffective in the face of enteric infections and vice versa.
Enteric neuromuscular dysfunction
For decades, dysmotility and visceral hypersensitivity have reigned supreme as the dominant factors in the pathophysiology of IBS.39 Of late, visceral hypersensitivity has been in the ascendancy with the description, by some, of this phenomenon as ubiquitous in IBS40 and the suggestion that many of the previously documented motor abnormalities may be non-specific and mere epiphenomena.39 This is not to deny a role for dysmotility in symptom pathogenesis but, rather, to indicate that disturbed motor function may not be the primary abnormality in IBS. Both dysmotility and visceral hypersensitivity may, indeed, be secondary to other primary etiological factors. There is, for example, an abundant literature, largely derived from animal models, to indicate that immune activation can lead to disturbed motor function and increased activity in sensory pathways from the gut.41 A recent study by Barbara et al. has extended this concept in humans. In their IBS subjects, they observed an increased density of mast cells, the consequence, perhaps of immune activation, in the colonic mucosa and further noted a close correlation between the proximity of mast cells to neural elements and pain severity.42
Probiotics have the potential to influence both motility and visceral sensation. In an animal model of postinfectious IBS, Collins an colleagues has demonstrated the ability of a probiotic to prevent and reverse dysmotility consequent upon an intestinal infestation.43 Probiotics could, in theory, reverse many of the processes involved in the initiation or perpetuation of immune-mediated hypersensitivity through antipathogenic, barrier-enhancing and immune-modulating effects.4 Experimental data, indeed, now supports an effect of probiotics on visceral hypersensitivity44–46 and has linked these benefits to anti-inflammatory,44 barrier-enhancing45 and neuromodulatory44,45 actions. The idea that probiotics may reduce access for bacteria to the gut wall and, thereby, prevent a related immune activation is supported by other studies with other organisms.47
Brain-gut axis dysregulation
The advent of functional brain imaging, and tests of autonomic function and the hypothalamic-pituitary-adrenal (HPA) axis, have permitted an exploration of the various components of the gut–brain axis in IBS. Such studies have revealed aberrant cerebral activation, exaggerated HPA responses and autonomic nervous dysfunction among some IBS subjects. There is ample evidence from experimental animal studies for the ability of pro-inflammatory cytokines, and TNF-α, in particular, to influence the HPA axis.48 Given their apparent ability to modulate cytokine balance in the periphery, could probiotics also exert an influence on these processes? In experimental animal models, orally administered probiotics have been shown to abrogate inflammatory processes far from the bowel, such as in the liver49 and synovial joints,50 raising the possibility of efficacy in such extraintestinal accompaniments of IBS as fibromyalgia and fatigue. Very recently, Dinan et al. have been able to detect elevated levels of the pro-inflammatory cytokine IL-6, in plasma, among IBS patients and documented a direct correlation between IL-6 and exaggerated ACTH and cortisol responses to corticotropin-releasing factor.36 This intriguing finding suggests a direct link, in IBS, between inflammation, presumably of intestinal origin, and brain–gut axis dysregulation. Given the aforementioned demonstration of a normalization of systemic cytokine balance by a probiotic in IBS,8 it is appropriate to speculate that some, at least, of the efficacy of probiotics in IBS may be related to this effect. Clearly, this is an area deserving of further enquiry.
What is the evidence for probiotic efficacy in ibs?
A small number of studies have evaluated the response of IBS to probiotic preparations and, while results between studies are difficult to compare because of differences in study design, probiotic dose and strain, there has been some, but by no means consistent, evidence of symptom improvement8,20–27,51–54 (Table 1). The overall impact of probiotics, in IBS, remains unclear. Hamilton-Miller, reviewing the evidence relating to the efficacy of probiotics in IBS in 2001, while drawing attention to the shortcomings of prior trials in terms of study design, concluded that there was, overall, sufficient evidence of efficacy to warrant further evaluation.55 Most studies reviewed were small in size and almost certainly underpowered to demonstrate anything other than a very striking benefit. Several did not verify bacterial transit and survival by confirmatory stool studies. Many different organisms and strains were employed and dosage varied from as little as 105 to 1013. Furthermore, some, including some more recent studies, employed probiotic ‘cocktails’ rather than single isolates, rendering it impossible to induce what, if any, were the active moieties.21,22 Nevertheless, some positive results were noted; although usually in the form of benefit to isolated symptoms rather than to global assessments. Niedzielin et al. reported resolution of abdominal pain in all 20 patients treated for 4 weeks with Lactobacillus plantarum 299V, in contrast to only 11 of 20 patients who received a placebo,51 and Halpern et al. noted a significant reduction in an IBS symptom index with a capsule containing 5 × 109 heat-killed Lactobacillus acidophilus organisms.52 O'Sullivan and O'Morain, while failing to detect an effect of Lactobacillus casei GG on overall symptomatology, did note a trend towards reduction in bloating.53 Nobaek et al., employing L. plantarum (DSM 9843)54, described a similar benefit in terms of relief of bloating as did Kim et al. in their evaluation of the probiotic ‘cocktail’ VSL#3.21
Table 1. Recent controlled clinical trials of single probiotic preparation in IBS
In our pilot study we compared, for the first time, the effects of two probiotic strains on symptoms in patients with IBS.8 We demonstrated superiority for B. infantis 35624 over both a Lactobacillus and placebo for each of the cardinal symptoms of the IBS (abdominal pain/discomfort, distension/bloating and difficult defaecation), and for a composite score. For each individual symptom, with the notable exceptions of bowel movement frequency and consistency, the group randomized to B. infantis experienced a greater reduction in symptom scores during the treatment period. These symptomatic benefits were associated with parallel trends in a quality of life measure developed specifically for IBS.8 Furthermore, this therapy was well tolerated and free of significant adverse events. As these benefits were observed independent of any change in stool frequency or form, they could not be attributed to either a laxative or an antidiarrhoeal effect. We have recently followed up this study with a larger, 4-week duration, dose-ranging study of the same bifidobacterium in over 360 community-based subjects with IBS and confirmed efficacy for this organism in a dose of 108; again all of the primary symptoms of IBS were significantly improved in the 4-week study, and a global assessment of IBS symptoms at the end of the therapy revealed a >20% therapeutic gain for the effective dose of the probiotic over placebo.56 While neither of these studies involved a comparison with any other therapeutic modality and their study design differed, in some aspects, from recent large trials of serotonergic agonists and antagonists, the therapeutic gain observed for bifidobacterium over placebo (20–25%) was certainly no less than that reported for tegaserod and alosetron (10–20%).57,58 This study with B. infantis provides, therefore, clear evidence for a benefit, in IBS, for a clearly defined single-organism probiotic preparation and, thereby, suggests that some strains, and bifidobacterium in particular, may be more effective than others for this indication. It must be emphasized that these studies were short term and given the chronicity and relapsing nature of IBS, longer term studies are required to support clinically relevant efficacy. Further, large randomized controlled trials of this bifidobacterium strain are warranted in IBS and detailed explorations of its mechanism(s) of action are indicated.
The clear delineation of a postinfective variety of IBS, and the description, in a number of studies, of evidence of low-grade inflammation and immune activation in IBS, suggest a role for a dysfunctional relationship between the indigenous flora and the host in IBS and, accordingly, provide a clear rationale for the use of probiotics in this disorder. Other modes of action, including bacterial displacement and alterations in luminal contents, are also plausible. While clinical evidence of efficacy is now beginning to emerge, a review of available trials emphasizes the importance of clear definition of strain selection, dose and viability. This is evidently an area of great potential in IBS and deserves further study at all levels.