Probiotics and inflammatory bowel disease: a natural fit?

The human gut is host to an enormous quantity of diverse organisms, with which we live in symbiosis. Alterations of the critical balances and interactions between the host and this flora may contribute to various conditions, likely to include disease states such as inflammatory bowel disease (IBD). Modification of this flora and modulation of altered host–flora interactions may prove key factors in managing disease states as diverse as allergy and cirrhosis. Probiotics appear to be the new player that may permit us to regain control of errant flora and host responses in the gut. Probiotics, generally considered safe agents, clearly have beneficial roles in several disease states, such as antibiotic-associated diarrhea and acute viral enteritis. There is theoretic potential for these agents to be efficacious in a number of additional conditions, including the management of IBD. The current evidence supporting the use of probiotics in IBD is discussed and future possibilities are outlined.

The IBDs are chronic gastrointestinal conditions without known medical cure [1]. Although the precise factors leading to the development of IBD are not defined, many lines of evidence suggest a key pathogenetic role for the intestinal microflora. It is likely that dysregulated immune interactions between the gut epithelium (especially innate responses) and bacteria (or bacterial products) in a genetically predisposed individual are essentially important in the development of IBD [2].

As our understanding of the pathogenesis of IBD evolves, we have been able to understand more about these key processes. A prime example of this is the NOD2 protein. Earlier this decade, it was established that mutations in the CARD15/NOD2 gene were present more frequently in individuals with Crohn’s disease (CD) than in those with ulcerative colitis (UC) or normal controls [3]. It is now evident that the NOD2 protein is a key element in the gut innate defense system: NOD2 is an intracellular sensor for a bacterial protein, muramyl dipeptide [4]. This finding has helped to confirm the importance of all three elements believed to be crucial in the pathogenesis of IBD: bacteria, host immune responses and genetics.

Strong evidence supporting the key role of bacteria in IBD comes from studies of murine models of colitis with severe genetically engineered immune dysregulation, and this is reinforced by a range of clinical observations. For example, in murine colitis models of mucosal inflammation, mice housed under specific pathogen-free or conventional conditions develop disease, while those housed in germ-free conditions remain disease free [5]. Furthermore, treatment of interleukin (IL)-10-deficient mice with antibiotics, which eradicate particular groups of bacteria from the gastrointestinal tract, is shown to attenuate colitis [6]. Clinically, therapies that are known to modify flora (e.g., antibiotics [2]) and enteral nutrition [7] can also have benefits in some individuals with CD. Moreover, diversion of colonic flow (and hence diversion of flora) leads to improvements in disease [2].

Given these features, therefore, it is not surprising that probiotics have been considered in the management of IBD. Probiotics are best defined as viable microorganisms that, when taken orally, exert beneficial effects upon the host [8]. Many organisms used as probiotics belong to the Lactobacilli group of lactase-producing bacteria (e.g., Lactobacillus acidophilus). Other organisms, including Bifidobacterium and nonpathogenic Escherichia coli, as well as yeasts such as Saccharomyces boulardii, have probiotic effects. Probiotics may be employed alone or combined with prebiotics (inactive food components that stimulate growth of beneficial bacteria in the gut) as synbiotics. There are now some data supporting a limited role for probiotics in the management of IBD.

Probiotics

The concept of probiotics was developed approximately 100 years ago [8]. However, a mechanistic and functional understanding of these agents has only developed much more recently. A number of possible different mechanisms of action have now been defined for different agents. These include the production of antimicrobial agents, immunologic and cytoprotective activities [9], competition for nutrients, inhibition of mucosal binding, alteration in production of mucins and immunomodulatory effects [10].

Despite a lack of clear scientific data, probiotics, now advertized regularly on television, are increasingly popular and widely used by many lay people in the community. These patterns of elevated use include the increasingly frequent administration of agents to children of varying ages [11]. Usage is even greater in children with chronic gastrointestinal [12] or other problems [13]. This widespread acceptance of the benefits of probiotics has tended to exceed or precede scientific support. At present, there are convincing data for the benefits of probiotics in only a few specific conditions.

Various probiotic agents, including Lactobacillus acidophilus, Lactobacillus GG and Lactobacillus reuteri are useful in the prevention and treatment of acute viral enteritis in children [14]. These agents can prevent the acquisition of viral enteritis and assist in a more rapid resolution of symptoms. They may also be useful in the prevention or treatment of traveler’s diarrhea [15]. Antibiotic-associated diarrhea, estimated to occur in up to 40% of individuals receiving oral antibiotics, can lead to significant morbidity, mortality and additional costs to health services [16,17]. Probiotic agents, especially Lactobacilli and the yeast S. boulardii, both have preventative and therapeutic roles in antibiotic-associated diarrhea [17].

Probiotics now appear to also have roles in various atopic conditions. A 50% reduction of eczema in children at enhanced risk of eczema was demonstrated in a Finnish study where mothers and babies were given L. GG for 6 months [18]. In a recent Australian study, the extent and severity of eczema in children improved with the use of a single probiotic agent [19]. Other roles suggested for probiotics include, amongst others, reduction of recurrent urogenital tract infections and lowering of serum lipids.

Established roles for probiotics in inflammatory bowel disease

Evidence supporting the view that probiotics may be helpful in IBD comes from both animal models of IBD and clinical studies. For example, in IL-10 knockout mice, administration of probiotic bacteria attenuates the development of inflammation on exposure to normal environmental bacteria [20]. Similar benefits have also been shown in chemical models of colitis in animals [21,22]. Interestingly, probiotic bacteria, including use of VSL#3, a probiotic mixture that includes eight probiotic bacteria in high titer, also have therapeutic effects in established colitis in IL-10 knockout mice, resulting in decreased inflammation [23].

A number of human studies have also shown that probiotic bacteria, either as single agents or in combination, may be beneficial in IBD, most particularly in pouchitis. Several probiotic agents are efficacious in either the prevention or treatment of pouchitis. VSL#3 reduced the frequency of relapse of pouchitis in a group of adults [24]. The same combination of bacteria, when used prophylactically, prevents the development of pouchitis in newly created pouches [25]. In addition, the single probiotic L. GG combined with fructo-oligosaccharide (prebiotic) was helpful in a small group of ten patients with active pouchitis [26].

In CD, several probiotic agents (S. boulardii, E. coli Nissle, L. GG and VSL#3) have been employed in open or blinded studies. For example, in a double-blinded study of 28 adult patients with CD, treatment with E. coli Nissle reduced the frequency of relapse (30%) in a treated group as compared with 70% in a placebo group [27]. An open-label study of L. GG led to improved clinical features and intestinal barrier function [28]. A reduction in the recurrence of active disease following resection has also been demonstrated in adults with CD following treatment with VSL#3 [29]. In this study, four of 20 patients receiving VSL#3 developed endoscopic relapse after resection, whereas relapse was present in 40% of a similar-sized group of patients treated with mesalazine. On the other hand, a recent study involving pediatric patients with CD showed that use of L. GG did not prevent relapses of disease over a 2-year follow-up period [30].

E. coli Nissle [30] and VSL#3 [32] also appear to have benefits for maintenance of remission in ulcerative colitis. Interestingly, a recent report shows that VSL#3 may also have a role in the treatment of mild-to-moderate active colitis [33]. Three-quarters of a group of 32 adults had remission or response after a 6-week course of VSL#3.

Probiotics may be beneficial in IBD through a number of potential mechanisms, directed at either the intestinal microflora or the host. The former mechanisms include modification of the microbial balance within the gut and competition for nutrients and binding sites. In terms of the host, probiotics may have immunomodulatory effects, such as stimulation of anti-inflammatory mediators (especially IL-10) with reduced proinflammatory cytokine production, and alteration of intestinal barrier function (permeability). Thus, experiments ascertaining the possible clinical benefits of probiotics must also consider aspects of these direct and indirect effects.

Although there are a number of clinical studies demonstrating the benefits of probiotics in IBD, it is notable that a number of agents have been utilized, that not every agent provides the same benefits and that the same agent may not be helpful in different settings. For instance, L. GG is shown to have effects in active disease but is not helpful in preventing disease relapse. Overall, it is likely that probiotics will have defined roles in UC and/or CD, but that these roles will be agent-specific and perhaps disease-phenotype specific.

Nonetheless, it remains crucially important to ensure that high quality clinical studies are undertaken in children and adults, and that these endeavors are supported by mechanistic studies. Such experiments focusing on the functional aspects of these agents, and not just upon clinical outcomes, may also provide further clues to the pathogenesis of IBD. By demonstrating how the process can be fixed we may learn how the process went wrong in the first instance.

Potential roles for probiotics in inflammatory bowel disorder in the future

Based on our current knowledge and understanding of the importance of bacterial interactions with the gut epithelium in IBD, it is reasonable to argue that agents which modulate these interactions may indeed modify the consequent host responses. The great difficulty is in understanding these events in the complex milieu of the gut, especially within the context of inflammation with potential secondary modification of permeability and host defenses.

It would be reasonable to expect that certain types of probiotics may exert benefits in certain individuals. These benefits will likely be enhanced by a combination of organisms (with complementary mechanisms). However, clinical benefits may also depend upon a myriad of host factors, some of which cannot yet be defined. Examples include host genetic factors, individual variations in the composition and balance of the intestinal flora population (reflecting place of birth, diet and environment). Until these aspects and their interactions are better understood, the roles of probiotics will remain difficult to clearly define.

Furthermore, probiotics may be best regarded as adjuncts to traditional or standard therapies, rather than as independent therapies. For instance, there is not yet extensive study of the additive benefits of probiotics in combination with standard therapy used to induce remission in the setting of active gut inflammation.

Conclusions

In conclusion, there is much to support the contention that probiotics could play roles in the management of IBD. The evidence to support these roles has, however, lagged behind popular usage patterns. At present, there are strong data to recommend probiotics for the prevention and treatment of pouchitis. There is not yet conclusive data to support the use of probiotics in other roles in IBD. However, there is developing evidence to suggest that they may have a role in the treatment of active colitis. There is a suggestion that not all probiotics are alike: different agents may have varying roles in certain circumstances or disease phenotypes. Further comprehensive and convincing data are now required prior to the widespread use of probiotic therapies so as to ensure that appropriate therapies are used for the management of individuals with IBD.