Accumulating data have strongly linked gut microbes to human health. Accordingly, manipulating intestinal microbiota holds promise as a potential treatment for restoring health. Although antibiotics have been the primary clinical choice for achieving this objective, supplementing the gastrointestinal microbiota with probiotics—or encouraging their growth with prebiotics—is now widely used as an alternative approach. Among gastrointestinal disorders, data of varying quality support the use of probiotics in preventing and treating diarrhea, inflammatory bowel disease (particularly pouchitis), irritable bowel syndrome, and liver disease. Although some data are indeed promising, the profusion of probiotic products and the fact that species, strain, and formulation all clearly influence efficacy have led to significant confusion regarding the best choice for different indications. Although sufficient evidence is not currently available to provide a clear guidance on the best probiotic for a particular clinical indication, key scientific concepts are now emerging. Building on these concepts, this review will provide practical information on the use of these products in clinical practice.
As reviewed in detail in this supplement, the intestinal microbiota and the human host have an intimate, bidirectional interaction that can have both positive and negative influences on human health. Interactions between the gut microbiota and the host have been shown to influence intestinal and systemic immunity, defense against pathogens, intestinal motility, sensation, secretion and barrier functions, liver metabolism, detoxification of xenobiotics, energy harvest, growth and development, and behavior. Moreover, the gut microbiota have been implicated in triggering or exacerbating numerous disease states, including—but not limited to—inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). As illustrated throughout this supplement, data from animal studies have shown that the intestinal microbiota have a direct effect on the host through modulation of gene expression, immunological, physiological, and psychological functions. In turn, the host is able to influence the composition and activity of its gut microbiota.
As the recognition of the importance of intestinal microbiota and their interaction with the host grew, so did the interest in targeting the intestinal microbiota as a mean to maintain and promote health. The possibility that manipulating the gastrointestinal microbiota could achieve a preventative and therapeutic effect is attractive. Indeed, more than a century ago, the Nobel laureate Elie Metchnikoff (1) postulated that supplementation of diet with lactic acid bacteria, an early probiotic intervention, had health benefits including promoting longevity. Although probiotics as a path to longevity is still not proven, considerable evidence does show that probiotics have potentially beneficial effects (2).
This review will examine the evidence for and against probiotics in the management of a broad range of gastrointestinal diseases. We focused our article on selected notable, high-quality articles published in leading journals. Rather than simply listing published results, we will provide a more annotated review. Such a review is timely, as probiotics have gained tremendous popularity in recent years among both industry and individuals searching for “natural” means to promote health. Probiotics are now both marketed alone and as an additive to numerous food products. In fact, in 2008, nearly $16 billion were spent globally for these products (3). Compared with pharmaceutical products, the size of this market makes probiotics, collectively, a “blockbuster” of greater magnitude than the top-selling drugs.
Despite the popularity of probiotics, there is little information on the advantages of many of the available probiotic preparations. In both the United States and Europe, probiotic products are considered and available only as food and dietary supplements; as such, they do not require approval of the Food and Drug Administration (FDA) for marketing. Without quality or proof of efficacy requirements mandated by regulators, probiotic products are not consistently tested for purity, viability, or effectiveness. Not surprisingly, probiotic products are only rarely sold with evidence of efficacy from well-designed, randomized, placebo-controlled trials. The consumer may select a probiotic product based on generalized marketed claim such as “promoting intestinal health” and physicians may instruct their patients to take probiotics “to restore good gut bacteria.” However, neither the consumer nor the physician may have a clear understanding if this is actually correct or important, and why. The regulatory status of probiotics may be revised in the near future in recognition of their potentially broad-ranging effects on human health.
Functions of the intestinal microbiota
In humans, the resident gut microbial population is estimated to number 100 trillion, composed of at least 500 different species, each competing and sometimes cooperating to maintain themselves within the highly competitive arena of the gut (4). As advanced molecular-based techniques come to be applied to the study of the gut microbiota, their true size and diversity is being revealed (5).
A number of lines of evidence point to an important role for intestinal microbes in maintaining normal gastrointestinal function (6,7). Although much of the evidence is based on animal studies, clinical and epidemiologic observations supporting the importance of the intestinal microbiota and growing experience with antibiotics and probiotics suggest that the concepts are likely to be applicable to humans. First, the impact of the microbiota on human health is clearly demonstrated by the harmful effects of disrupting intestinal microbiota; for example, antibiotics can disrupt the gastrointestinal microbiota, permitting colonization by Clostridium difficile and result in diarrhea or even colitis (8). Another example is the phenomenon of postinfectious IBS, in which short-term disruption of the intestinal microbiota, as a result of an acute infection, has long-lasting effects on intestinal function and symptoms (9). Second, IBD remains in remission when the gut microbiota are diverted (10) but recurs when the gut is reconnected, permitting exposure to gut microbiota again. Third, alterations in the intestinal microbiota (e.g., following infection or use of antibiotics or probiotics) can affect intestinal functions including immunologic, motility, and sensation (6).
These data suggest that the gut microbiota are important and, indeed, essential for maintaining intestinal and human health; and that disruption of the host/gut microbial interaction may be associated with a number of disease states. Thus, it is expected that manipulation of the gut microbiota could be harnessed for preventative and therapeutic effect.
Probiotics are live microorganisms that, when administered in an adequate amount, confer a health benefit on the host ( Table 1). Lactobacillus and Bifidobacterium species are the most commonly used probiotics, but Escherichia coli Nissle, enterococcus, certain Bacillus species, and certain strains of yeasts, such as Saccharomyces boulardii and Saccharomyces cerevisiae (baker's yeast), are also used in some formulations (11). Prebiotics are nondigestible food components that selectively stimulating the growth and/or activity of one or a limited number of bacteria and, thereby, improving host health (12). Examples include oligofructose, inulin, galacto-oligosaccharides, and lactulose. Synbiotics are combinations of probiotics and prebiotics intended to deliver to the gastrointestinal tract beneficial species while, at the same time, providing substrates to promote the growth and/or function of the probiotic component or resident microbes.
A broad range of probiotics are currently available in the United States and Europe (11). As shown in Table 2, these products vary widely in the microorganisms included in the formulation. Additionally, the efficacy of these agents in delivering live bacteria to the gastrointestinal tract is likely to vary widely. The importance of dosage in the formulation is illustrated by a study conducted by Whorwell et al. (13) in 2006. In this study, 330 patients with IBS were administered 3 doses of encapsulated Bifidobacterium infantis (106, 108, and 1010 colony-forming units (CFU)). Somewhat unexpectedly, only the 108 CFU dosage rather than the highest dosage (1010 CFU) was effective for the primary end point of relieving pain and discomfort at 4 weeks. Subsequent testing revealed that the 1010 CFU dosage transformed itself into a pellet that resisted dissolution. This bioavailability problem was not encountered when the same probiotic was added to a milk-based drink.
Thus, even if a particular strain or combination product has been demonstrated to be effective in an indication, no recommendations can be made regarding specific probiotic or synbiotic products unless clinically tested in its final formulation and in the dose that it will be marketed. As clinical efficacy of a probiotic product may be determined by factors such as specific microbial species, the dosage, the formulation, the viability of the probiotics both on the shelf and within the intestine, the residence time in the gut (or in various segments thereof), and the method of dosing, a report of clinical efficacy for one probiotic product or strain cannot be simply assumed for another probiotic. It is difficult to be an informed health-care provider or a consumer of probiotic products when these factors are rarely tested before a probiotic product is marketed.
Using probiotics to treat gastrointestinal diseases: scientific rationale
Probiotics have been shown to affect the intestinal mucosa in numerous ways (15,16,17,18,19). They appear to have direct effects on the epithelial barrier, including increasing mucin expression/secretion by goblet cells (thus limiting bacterial movement across the mucous layer); augmenting production of antimicrobial peptides, including β-defensin; as well as enhancing tight junction stability, thereby decreasing epithelial permeability to intraluminal pathogens and toxins. Probiotics influence mucosal immunity by increasing levels of IgA-producing cells in the lamina propria and promoting secretion of secretory IgA into the luminal mucus layers, activities that limit epithelial colonization by bacteria. In animal models of IBD, probiotics—particularly Bifidobacteria (16)—have been shown to influence cytokine expression and suppress mucosal inflammation, potentially through Toll-like receptor signaling (17,20). In general, it seems that the anti-inflammatory effects of probiotics often observed in in vitro and animal studies may not always translate to clinical beneficial effects of probiotics. This may relate to the complex immunomodulatory effects of probiotics, with the net effect not only difficult to predict but often highly specific to disease and health states and the individual probiotic strain (19,21).
Probiotics have also been shown to have a number of functional effects on the gastrointestinal tract. For example, Lactobacillus paracasei NCC2461 has been shown to attenuate postinfectious intestinal dysmotility in a mouse model (22). Additional animal studies have found that administration of probiotics appears to alleviate visceral hypersensitivity (23,24,25), an effect potentially mediated through induction of expression of cannabinoid and opioid receptors on intestinal cells (26). Finally, Collins et al. (27) have demonstrated that administration of a probiotic can prevent and reverse dysmotility associated with intestinal infection.
Probiotics have the potential to have a direct antimicrobial effect. In fact, some strains/species in probiotics have the potential to directly kill or inhibit the growth of pathogenic bacteria through production of antimicrobial factors, such as bacteriocins, proteases directed against bacterial toxins, or through exclusion of pathogens by simply adhering to epithelial cells (28,29,30).
Clinical evidence supporting the use of probiotics in gastrointestinal diseases
Prevention of acute diarrhea
The efficacy of probiotics in the prevention of acute diarrhea was assessed in a meta-analysis conducted by Sazawal et al. (31). This analysis included 34 randomized, placebo-controlled trials evaluating of the effect of probiotics in various acute diarrheal states, including antibiotic-associated diarrhea (n=19) and travelers’ diarrhea (n=6) and other acute diarrhea (n=9). The majority of the studies evaluated lactobacilli species, most commonly Lactobacillus rhamnosus GG (n=10), Lactobacillus acidophilus plus Lactobacillus bulgaricus (n=7), and S. boulardii (n=5). Twelve trials were in children (≤18 years), and 21 trials were in adults (>18 years). Overall, 28 of the 34 trials yielded protective point estimates, of which 10 attained statistical significance, and 6 trials had statistically nonsignificant nonprotective point estimates. When all studies were pooled, probiotics were associated with a 35% (95% confidence interval (CI) 22–44%; P<0.001) reduction in the risk for diarrhea, with substantial heterogeneity (χ2 P<0.001; I2=63%, 95% CI 52–75%).
Treatment of infectious diarrhea
The efficacy of probiotics in the treatment of infectious diarrhea has also been assessed in a meta-analysis. (32) A total of 63 studies (n=8,014) were included in this analysis; of these, 56 recruited infants/young children. Overall, probiotics reduced the duration of diarrhea by 24.76 h (95% CI 15.9–33.6 h), the risk for diarrhea lasting ≥4 days (risk ratio 0.41; 95% CI 0.32–0.53), and reduced stool frequency on day 2 (mean difference 0.80; 95% CI 0.45–1.14).
Prevention of c. difficile–associated diarrhea
The effect of probiotic supplementation on the incidence of C. difficile diarrhea has been prospectively examined (33). In this study, 150 consecutive inpatients were randomized to receive either a probiotic containing both L. acidophilus and Bifidobacterium bifidum or to a placebo on arrival to the hospital and monitored for the incidence of C. difficile–associated diarrhea. The incidence of fecal samples from patients who developed diarrhea during hospitalization that were positive for C. difficile–associated toxins was 2.9% in the probiotic group as compared with 7.25% in the control group. Among all patients, regardless of whether they developed diarrhea, 46% of probiotic patients were toxin positive as compared with 78% of the placebo group. This report supports the use of probiotics in reducing the likelihood of successful colonization of the gut by C. difficile.
Prevention of antibiotic-associated diarrhea
A meta-analysis of assessing the efficacy of probiotics for preventing antibiotic-associated diarrhea extends these results (34). Nine studies were reviewed, two of which were conducted in children. The odds ratio in favor of active intervention over placebo in preventing antibiotic-associated diarrhea was 0.37 (95% CI 0.26–0.53; P<0.001). The odds ratios were 0.39 (95% CI 0.25–0.62; P<0.001) for trials using the yeast S. boulardii and 0.34 (95% CI 0.19–0.61; P<0.001) for lactobacilli. Similarly, a very recent (2010) meta-analysis of 10 randomized, controlled trials on S. boulardii in antibiotic-associated diarrhea found that this yeast was associated with an odds ratio in favor of the probiotics of 0.47 (95% CI 0.35–0.62) (14).
Prophylaxis of traveler's diarrhea
Relatively limited data are available on the use of probiotics for the prophylaxis of traveler's diarrhea (35). A meta-analysis of 12 studies found that probiotic use was associated with an odds ratio in favor of treatment of 0.85 (95% CI 0.79–0.91; P<0.001). In individual studies, several probiotics, including S. boulardii and a mixture of L. acidophilus and B. bifidum, had significant efficacy. No serious adverse events were reported in any of the trials included in this meta-analysis.
On balance, the evidence supports the use of probiotics in the prevention and treatment of infectious diarrhea. However, more research is needed to guide the use of particular probiotic regimens in specific patient groups. For the prevention of infectious diarrhea, the most evidence exists for L. rhamnosus and L. acidophilus. For antibiotic-associated diarrhea, evidence exists for the efficacy of both S. boulardii and lactobacilli; a clinical report, published by Thomas and Greer (36), suggests that L. rhamnosus GG has the most substantial evidence for benefit in the prevention and treatment of acute infectious diarrhea, at least in pediatric patients. Only limited support is available for a clinical benefit of probiotics in the prophylaxis of traveler's diarrhea; however, given the absence of adverse effects in clinical studies, probiotics might be a reasonable option compared with antibiotics for this indication.
Inflammatory bowel disease
In a study by Gosselink et al. (37) of 117 ulcerative colitis patients treated with intestinal resection and ileal pouch anal anastomosis, L. rhamnosus GG significantly reduced the number of first episodes (primary prevention) of pouchitis in the 39 patients who received the probiotic daily when compared with the 78 who did not (cumulative risk at 3 years, 7% vs. 29%; P=0.011). A second study, conducted by Mimura et al. (38), evaluated the impact of VSL#3 (a mixture of eight strains, including S. thermophilus, Lactobacilus, and Bifidobacterium) on maintenance of remission of recurrent or refractory pouchitis. This study randomized 36 patients with pouchitis at least twice in the previous year or requiring antibiotics to VSL#3 (n=20) or placebo (n=16). Remission (secondary prevention) of pouchitis was maintained at 1 year in 17 patients (85%) who received VSL#3 but in only 1 patient taking placebo (P<0.0001). Finally, a meta-analysis of five studies of probiotics for the management of pouchitis in patients who underwent ileal pouch anal anastomosis yielded an odds ratio of 0.04 in favor of the treatment group (P<0.0001), suggesting that probiotics can provide considerable benefit in this patient population (39).
Five small studies, each of which evaluated a different probiotic, have evaluated the efficacy of probiotics in inducing and/or maintaining remission in patients with ulcerative colitis (40); of these, four showed significant results in favor of probiotics. A sixth study compared the efficacy of 5-aminosalicylic acid, with or without S. boulardii, as maintenance treatment in Crohn's disease in 32 patients (41). This study is notable in that clinical relapses were observed in 37.5% of patients who received mesalamine alone, compared with only 6.25% of patients who received the combination. Overall, probiotics may be beneficial in mild to moderate ulcerative colitis as adjuvant therapy. In contrast to ulcerative colitis, the evidence supporting the benefits of probiotics in patients with Crohn's disease is much weaker. Indeed, a recent review of five studies in adults and a single study in children conclude that currently the data do not support the use of probiotics in adult or children with Crohn's disease (40).
The efficacy of probiotics in IBD is discussed extensively elsewhere in this supplement. The best evidence exists for VSL#3 (a probiotic mixture ), at a dosage of 4.5 × 1011 CFU twice daily, for the maintenance of remission in patients with pouchitis (42). In ulcerative colitis, E. coli Nissle 1917 (at a dosage of 200 mg once daily) has been shown to be as effective as mesalamine 500 mg three times daily in a well-designed, double-blind, double-dummy trial (43). However, there is insufficient evidence at this time on the efficacy of other probiotic preparations and more studies are clearly needed before probiotics can be recommended as routine therapy in this patient population. As noted above, little evidence suggests that probiotics have any effect in Crohn's disease.
Irritable bowel syndrome
A meta-analysis of clinical trials of probiotics in the treatment of IBS was conducted by Moayyedi et al. (44). In this analysis, 18 randomized, controlled clinical trials, enrolling 1,650 patients with IBS, were identified examining products including Lactobacillus (6 studies), Bifidobacterium (3 studies), Streptococcus (1 study), and various combination products (9 studies) (note that 1 trial reported on both Lactobacillus and Bifidobacterium). Of these, 10 (n=918) provided outcomes as a dichotomous variable; in these studies, probiotics significantly reduced IBS symptoms (relative risk of symptoms persisting in the treatment group, 0.71; 95% CI 0.57–0.88), with a number needed to treat of 4. Fifteen trials reported outcomes as a continuous variable; when grouped for meta-analysis, these trials also found that probiotics had a statistically significant effect in improving IBS symptoms compared with placebo. This meta-analysis has shown little difference among different types of probiotics, with Lactobacillus (3 trials enrolling 140 patients), Bifidobacterium (2 trials enrolling 422 patients), Streptococcus (1 trial enrolling 54 patients), and various combination products (4 trials enrolling 302 patients) all showing a trend towards benefit (44). In terms of individual symptoms, probiotics had a statistically significant effect on improving pain scores and flatulence, as well as a trend toward improvement of bloating.
Patients with IBS, arguably, represent the largest target patient population for probiotic use, and this is reflected by the number of articles and small clinical trials assessing the efficacy of these products in IBS. A critical evaluation of the published data on this issue, including the meta-analysis of Moayyedi et al. (44) (summarized above) and other published meta-analyses and critical reviews (45), have concluded that some probiotics are beneficial in improving symptoms and reducing the risk of persistent symptoms in some patients with IBS, although the overall effect is modest. There is little evidence for harm associated with probiotics—in fact, in the meta-analysis of Moayyedi et al. 44 there was no significant difference in adverse events between probiotics and placebo (relative risk for an adverse event on probiotic, 0.93; 95% CI 0.64–1.36), suggesting that the potential benefit may outweigh any risks associated with these products (44).
Little formal information is available to guide the use of probiotics in IBS. The American Gastroenterological Society, as part of its systematic review on the management of IBS, provides limited guidance. According to these guidelines, which are based on a systematic review of the evidence, lactobacilli do not appear to be effective in the management of IBS but some efficacy is reported with bifidobacteria and certain probiotic combinations (46). Additional data have accumulated since these guidelines were published in 2009, demonstrating some efficacy with several groups of probiotics and combinations of probiotics in IBS, although the preferred probiotic strains, products, and regimen of use are not clear (45,47).
Current guidelines for the use of probiotics
The World Gastroenterology Organization has released a detailed practice guideline on probiotics and prebiotics (11). According to these guidelines, evidence exists for the use of probiotics/prebiotics in reducing the severity and duration of acute infectious diarrhea in children, preventing antibiotic-associated and C. difficile diarrhea, managing hepatic encephalopathy, preventing an initial attack of pouchitis, maintaining remission in patients with ulcerative colitis, reducing the symptoms related to lactose intolerance, and reducing the risk for necrotizing enterocolitis in preterm neonates. Refer to these guidelines for a summary of specific indications, products that have been demonstrated in these indications, and recommended dosages (11).
Based on the results of an expert panel, Floch et al. (48) have recently published an updated recommendations for probiotic use. These guidelines provide broad recommendations for the use of probiotics in a range of gastrointestinal and nongastrointestinal conditions, including treatment of infectious diarrhea in adults and children, prevention of antibiotic-associated diarrhea, treatment and prevention of C. difficile diarrhea, IBD, and IBS. Refer to these guidelines for a summary of specific recommendations.
Probiotic products vary widely, and only high-quality, properly labeled products shown in controlled human studies to be safe and effective in a specific patient population should be recommended for use. In addition, although empiric evidence suggests that there is minimal potential for harm with probiotics and prebiotics in immunocompetent individuals, because the probiotics market is at this point largely unregulated, due caution is recommended when selecting patients and products for therapeutic use, as host immunocompetency and quality, composition, and formulation among products should be expected to vary widely.
It is important to emphasize that currently all probiotic products marketed in the United States are either dietary supplements or foods, and only one product (VSL#3) is sold as a medical food. By definition, these products are targeted to the generally healthy population in contrast to drugs, which can be targeted toward people with disease conditions.
Good Manufacturing Practices were developed by the FDA so that dietary supplements (including probiotics) are processed in a consistent manner and meet quality standards (http://www.fda.gov/Food/DietarySupplements/GuidanceComplianceRegulatoryInformation/RegulationsLaws/ucm110858.htm) and the current US law requires that all products be labeled in a truthful and not misleading manner (http://www.fda.gov/Food/LabelingNutrition/LabelClaims/StructureFunctionClaims/default.htm). However, there is a need for better adherence, and possibly reinforcement, of these standards and regulations as there still appears to be probiotic products that do not conform to these regulations. In Europe, for example, the European Food Safety Authority (EFSA) has adopted a more “pharma-like” approach to the assessment of all food-related health claims (49). Furthermore, several recent articles proposed standardized guidelines for the performance of clinical trials (50,51) and assessment of safety in relation to pre- and probiotics (52).
We believe that greater adherence to standardization and regulation and better data from high-quality clinical trials assessing efficacy and safety will help direct health-care providers in making educated decisions on the proper use of probiotics in specific clinical conditions.
Clinical Implications and Conclusions
Current evidence supports the role of probiotics in a broad range of gastrointestinal conditions. Sufficient evidence exists to indicate that probiotics are effective in the prevention and treatment of diarrhea, although the precise strains (or combinations), formulations that provide the greatest efficacy, and patient groups that derive the greatest benefit remain unclear. Initial evidence is also supportive of a role for probiotics in pouchitis and, perhaps, ulcerative colitis, although the data are relatively limited for the later indication. Finally, probiotics appear to be efficacious in IBS, but again the magnitude of benefit is uncertain, available clinical data are largely derived from inadequately designed studies, and the most effective species and strains remain uncertain. Across all indications, the long-term effects and safety of probiotic use remain uncertain. Clearly, larger, well-designed, confirmatory clinical trials are needed to evaluate the efficacy of probiotics across indications.
We thank John Ferguson for editorial assistance in preparing the manuscript for publication and Mary Ellen Sanders for providing and updating Table 2.