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ORIGINAL CONTRIBUTIONS

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Using Probiotics in Gastrointestinal Disorders


Yehuda Ringel, MD, FACG1, Eamonn M.M. Quigley, MD FACG2 and Henry C. Lin, MD3

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 probioticsor
encouraging their growth with prebioticsis 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.
Am J Gastroenterol Suppl 2012; 1:3440; doi:10.1038/ajgsup.2012.7

INTRODUCTION
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, includingbut not
limited toinflammatory 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

Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA; 2Alimentary
Pharmabiotic Center, Department of Medicine, University College Cork, Cork, Ireland; 3Section of Gastroenterology, New Mexico VA Health Care System and University of New
Mexico, Albuquerque, New Mexico, USA. Correspondence: Yehuda Ringel, MD, FACG, Division of Gastroenterology and Hepatology, Department of Medicine, University of
North Carolina School of Medicine, 4107 BioInformatics Building, 130 Mason Farm Road, Chapel Hill, North Carolina 27599-7080, USA. E-mail: ringel@med.unc.edu
This article was published as part of a supplement sponsored by the Gi Health Foundation, a nonprofit 501(c)(3) educational organization dedicated to increasing
awareness of the effect of gastrointestinal disorders in the United States. The foundations goal is to provide health professionals with the most current education
and information on gastrointestinal health.
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Probiotics in Gastrointestinal Diseases

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.
Definitions

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 (bakers yeast), are also
2012 by the American College of Gastroenterology

Table 1. Definitions (11)


Probiotics

Live microorganisms that, when administered in


adequate amounts, confer a health benefit on the host

Prebiotics

Nondigestable substances that provide a beneficial


physiological effect for the host by selectively stimulating the favorable growth or activity of a limited number
of indigenous bacteria

Synbiotics

Products that contain both probiotics and prebiotics

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, galactooligosaccharides, 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.
Current products

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 intestinal barrier, immunologic, antibacterial, and


motility and sensation effects that may contribute to their efficacy
in various indications (14,15).
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Ringel et al.

Table 2. Selected probiotic strains and products available in the US and Europe
Straina

Commercial availabilityb

Sold by

L. acidophilus NCFM
B. lactis Bi-07
B. lactis HN019 (DR10)
L. rhamnosus HN001 (DR20)

Sold as ingredient

DuPont Nutrition Biosciences ApS (Madison WI)

Saccharomyces cerevisiae boulardii

Florastor

Biocodex (Creswell OR)

B. infantis 35264

Align

Procter & Gamble (Mason OH)

L. rhamnosus R0011
L. acidophilus R0052

Sold as ingredient

Lallemand (Montreal, Canada)

B. lactis Bb-12
L. acidophilus LA5
L. paracasei CRL 431
L. fermentum VRI003 (PCC)
L. reuteri RC-14
L. rhamnosus GR-1
L. paracasei F19

Sold as ingredient

Chr. Hansen (Milwaukee WI)

L. casei Shirota
B. breve strain Yakult

Yakult

Yakult (Tokyo, Japan)

L. casei DN-114 001 (L. casei Immunitas)


B. animalis DN-173 010 (Bifidis regularis)

DanActive fermented milk


Activia yogurt

Danone (Paris, France)


Dannon (Tarrytown, NY)

Dannon (Tarrytown, NY)


L. johnsonii Lj-1 (NCC533; L. acidophilus La-1)
L. plantarum 299V
L. rhamnosus 271

Nestl (Lausanne, Switzerland)


Sold as ingredient
Good belly

Probi AB (Lund, Sweden)


NextFoods (Boulder, CO)

L. reuteri ATCC 55730 (Protectis)

BioGaia probiotic chewable tablets or drops

Biogaia (Stockholm, Sweden)

L. rhamnosus GG (LGG)

Culturelle

Valio Dairy (Helsinki, Finland)

L. rhamnosus LB21
Lactococcus lactis L1A

Sold as ingredient

Essum AB (Ume, Sweden)

L. salivarius UCC118
B. longum BB536

University College (Cork, Ireland)


Sold as ingredient

Morinaga Milk Industry Co., Ltd.


(Zama-City, Japan)

L. acidophilus LB

Sold as ingredient

Lacteol Laboratory (Houdan, France)

Bacillus coagulans BC30

Sustenex, digestive advantage;


Sold as ingredient

Ganeden Biotech Inc. (Cleveland, OH)

This table does not constitute an endorsement of any of these products, nor does it include all strains/mixtures currently available. Table developed by Sanders and used
with permission.
a
Parenthetic entries indicate alternative strain designations; B. lactis is a shorthand designation for Bifidobacterium animalis subsp lactis.
b
Strains sold as ingredients are available in numerous consumer products; contact responsible company for product list. Products listed are examples and do not reflect a
comprehensive list of available products containing the indicated strain.

Probiotics have been shown to affect the intestinal mucosa in


numerous ways (1519). 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
-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,
probioticsparticularly Bifidobacteria (16)have been shown to
influence cytokine expression and suppress mucosal inflammation,
The American Journal of GASTROENTEROLOGY Supplements

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 (2325), an effect potentially
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Probiotics in Gastrointestinal Diseases

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 (2830).
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 antibioticassociated 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)
2244%; P < 0.001) reduction in the risk for diarrhea, with substantial heterogeneity (2 P < 0.001; I2 = 63%, 95% CI 5275%).
Treatment of infectious diarrhea. The efficacy of probiotics in the
treatment of infectious diarrhea has also been assessed in a metaanalysis. (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
15.933.6 h), the risk for diarrhea lasting 4 days (risk ratio 0.41;
95% CI 0.320.53), and reduced stool frequency on day 2 (mean
difference 0.80; 95% CI 0.451.14).
Prevention of c. difficileassociated 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. difficileassociated diarrhea. The incidence of fecal samples
from patients who developed diarrhea during hospitalization that
were positive for C. difficileassociated 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.
2012 by the American College of Gastroenterology

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 0.260.53; P < 0.001).
The odds ratios were 0.39 (95% CI 0.250.62; P < 0.001) for trials
using the yeast S. boulardii and 0.34 (95% CI 0.190.61; 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 0.350.62) (14).
Prophylaxis of travelers diarrhea. Relatively limited data are
available on the use of probiotics for the prophylaxis of travelers
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 0.790.91; 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.
Recommendations. 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 travelers 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
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Ringel et al.

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 Crohns 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 Crohns 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 Crohns disease (40).
Recommendations. 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 4.51011 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 Crohns 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 0.570.88), 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.
The American Journal of GASTROENTEROLOGY Supplements

Recommendations. 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
probioticsin 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 0.641.36), 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
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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.
ACKNOWLEDGMENTS

We thank John Ferguson for editorial assistance in preparing the


manuscript for publication and Mary Ellen Sanders for providing
and updating Table 2.

2012 by the American College of Gastroenterology

CONFLICT OF INTEREST

Guarantor of the article: Mark Pimentel, MD, FRCP(C).


Specific author contributions: Y.R. and H.C.L. planned and
contributed to the first draft of this article. All authors participated
in all subsequent revisions of this article and have approved the final
draft of the manuscript.
Financial support: Yehuda Ringel has received research grants
from Danisco, General Mills, Procter & Gamble, and Salix Pharmaceuticals. Eamonn M.M. Quigley has received grant support from
Merck and has patents on gut microbiotarelated technologies. An
independent medical educational grant from Salix Pharmaceuticals
was provided to support the development of this supplement.
The grantors did not review the manuscripts before publication,
nor did they provide input into the content of the supplement.
Potential competing interests: Yehuda Ringel has received consulting fees from Salix Pharmaceuticals, Procter & Gamble, Ironwood,
Danisco, General Mills, GSK, and Pfizer/Wyeth. Yehuda Ringel has
also received lecturer fees from Salix Pharmaceuticals. Eamonn
M.M. Quigley has received consulting fees from Salix Pharmaceuticals, Norgine, Procter & Gamble, Ironwood, Almiral, Movetis, Shire,
Yakult, and Danone. Eamonn M.M. Quigley is a non-executive
director of Alimentary Health, and has received lecture fees from
Yakult, Danone, Shire, Procter & Gamble, and Sanofi. Henry C. Lin
has intellectual property rights in a related area.
REFERENCES
1. Metchnikoff E. Optimistic Studies. Putnams Sons: New York, 1908, pp 16183.
2. Dupont AW, Dupont HL. The intestinal microbiota and chronic disorders
of the gut. Nat Rev Gastroenterol Hepatol 2011;8:52331.
3. Markets and Markets. Probiotic market: advanced technologies and global
market (2009 to 2014). Available at: http://www.marketsandmarkets.
com/Market-Reports/probiotic-market-advanced-technologies-and-globalmarket-69.html. Accessed 1 July 2011. 2009.
4. Eckburg PB, Bik EM, Bernstein CN et al. Diversity of the human intestinal
microbial flora. Science 2005;308:16358.
5. Carroll MI, Ringel-Kulka T, Ringel Y. Quantification and identification of
probiotic organisms in humans. In: Floch MH, Kim AS (eds). Probiotics:
A Clinical Guide, 1st edn. SLACK: New Jersey, 2010, pp 5569.
6. Ringel Y, Carroll IM. Alterations in the intestinal microbiota and functional
bowel symptoms. Gastrointest Endosc Clin N Am 2009;19:14150, vii.
7. OHara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep
2006;7:68893.
8. McFarland LV. Emerging therapies for Clostridium difficile infections.
Expert Opin Emerg Drugs 2011;16:42539.
9. Dunlop SP, Jenkins D, Neal KR et al. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in postinfectious IBS.
Gastroenterology 2003;125:16519.
10. Edwards CM, George BD, Jewell DP et al. Role of a defunctioning stoma in
the management of large bowel Crohns disease. Br J Surg 2000;87:10636.
11. Guarner F, Khan AG, Garisch J et al. World Gastroenterology Practice
Guideline. Probiotics and prebiotics. Available at: http://www.
worldgastroenterology.org/assets/downloads/en/pdf/guidelines/
19_probiotics_prebiotics.pdf. Accessed 1 July 2011.
12. Roberfroid M. Prebiotics: the concept revisited. J Nutr 2007;137:830S7S.
13. Whorwell PJ, Altringer L, Morel J et al. Efficacy of an encapsulated
probiotic Bifidobacterium infantis 35624 in women with irritable bowel
syndrome. Am J Gastroenterol 2006;101:158190.
14. McFarland LV. Systematic review and meta-analysis of Saccharomyces
boulardii in adult patients. World J Gastroenterol 2010;16:220222.
15. Ohland CL, Macnaughton WK. Probiotic bacteria and intestinal
epithelial barrier function. Am J Physiol Gastrointest Liver Physiol
2010;298:G80719.
16. OMahony L, McCarthy J, Kelly P et al. Lactobacillus and bifidobacterium
in irritable bowel syndrome: symptom responses and relationship to
cytokine profiles. Gastroenterology 2005;128:54151.

The American Journal of GASTROENTEROLOGY Supplements

39

40

Ringel et al.

17. Rachmilewitz D, Katakura K, Karmeli F et al. Toll-like receptor


9 signaling mediates the anti-inflammatory effects of probiotics in murine
experimental colitis. Gastroenterology 2004;126:5208.
18. Chiba Y, Shida K, Nagata S et al. Well-controlled proinflammatory
cytokine responses of Peyers patch cells to probiotic Lactobacillus casei.
Immunology 2010;130:35262.
19. de Roock S, van Elk M, van Dijk ME et al. Lactic acid bacteria differ in their
ability to induce functional regulatory T cells in humans. Clin Exp Allergy
2010;40:10310.
20. McCarthy J, OMahony L, OCallaghan L et al. Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and
mechanistic link with cytokine balance. Gut 2003;52:97580.
21. Sokol H, Pigneur B, Watterlot L et al. Faecalibacterium prausnitzii is an antiinflammatory commensal bacterium identified by gut microbiota analysis
of Crohn disease patients. Proc Natl Acad Sci USA 2008;105:167316.
22. Verdu EF, Bercik P, Bergonzelli GE et al. Lactobacillus paracasei
normalizes muscle hypercontractility in a murine model of postinfective
gut dysfunction. Gastroenterology 2004;127:82637.
23. Verdu EF, Bercik P, Verma-Gandhu M et al. Specific probiotic therapy
attenuates antibiotic induced visceral hypersensitivity in mice. Gut
2006;55:18290.
24. Kamiya T, Wang L, Forsythe P et al. Inhibitory effects of Lactobacillus
reuteri on visceral pain induced by colorectal distension in Sprague-Dawley
rats. Gut 2006;55:1916.
25. Ait-Belgnaoui A, Eutamene H, Houdeau E et al. Lactobacillus farciminis
treatment attenuates stress-induced overexpression of Fos protein in spinal
and supraspinal sites after colorectal distension in rats. Neurogastroenterol
Motil 2009;21:56773 , e189.
26. Rousseaux C, Thuru X, Gelot A et al. Lactobacillus acidophilus modulates
intestinal pain and induces opioid and cannabinoid receptors. Nat Med
2007;13:357.
27. Collins S, Verdu E, Denou E et al. The role of pathogenic microbes and commensal bacteria in irritable bowel syndrome. Dig Dis 2009;27 (Suppl 1): 859.
28. Oh S, Kim SH, Worobo RW. Characterization and purification of a
bacteriocin produced by a potential probiotic culture, Lactobacillus
acidophilus 30SC. J Dairy Sci 2000;83:274752.
29. Corr SC, Li Y, Riedel CU et al. Bacteriocin production as a mechanism
for the antiinfective activity of Lactobacillus salivarius UCC118. Proc Natl
Acad Sci USA 2007;104:761721.
30. Quigley EM, Flourie B. Probiotics and irritable bowel syndrome: a rationale
for their use and an assessment of the evidence to date. Neurogastroenterol
Motil 2007;19:16672.
31. Sazawal S, Hiremath G, Dhingra U et al. Efficacy of probiotics in
prevention of acute diarrhoea: a meta-analysis of masked, randomised,
placebo-controlled trials. Lancet Infect Dis 2006;6:37482.
32. Allen SJ, Martinez EG, Gregorio GV et al. Probiotics for treating acute
infectious diarrhoea. Cochrane Database Syst Rev 2010:(11): CD003048.
33. Plummer S, Weaver MA, Harris JC et al. Clostridium difficile pilot study:
effects of probiotic supplementation on the incidence of C. difficile
diarrhoea. Int Microbiol 2004;7:5962.

The American Journal of GASTROENTEROLOGY Supplements

34. DSouza AL, Rajkumar C, Cooke J et al. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002;324:1361.
35. McFarland LV. Meta-analysis of probiotics for the prevention of travelers
diarrhea. Travel Med Infect Dis 2007;5:97105.
36. Thomas DW, Greer FR. Probiotics and prebiotics in pediatrics. Pediatrics
2010;126:121731.
37. Gosselink MP, Schouten WR, van Lieshout LM et al. Eradication of
pathogenic bacteria and restoration of normal pouch flora: comparison of
metronidazole and ciprofloxacin in the treatment of pouchitis. Dis Colon
Rectum 2004;47:151925.
38. Mimura T, Rizzello F, Helwig U et al. Once daily high dose probiotic
therapy (VSL#3) for maintaining remission in recurrent or refractory
pouchitis. Gut 2004;53:10814.
39. Elahi B, Nikfar S, Derakhshani S et al. On the benefit of probiotics in
the management of pouchitis in patients underwent ileal pouch anal
anastomosis: a meta-analysis of controlled clinical trials. Dig Dis Sci
2008;53:127884.
40. Guandalini S. Update on the role of probiotics in the therapy of pediatric
inflammatory bowel disease. Expert Rev Clin Immunol 2010;6:4754.
41. Guslandi M, Mezzi G, Sorghi M et al. Saccharomyces boulardii in
maintenance treatment of Crohns disease. Dig Dis Sci 2000;45:14624.
42. Gionchetti P, Rizzello F, Helwig U et al. Prophylaxis of pouchitis onset
with probiotic therapy: a double-blind, placebo-controlled trial.
Gastroenterology 2003;124:12029.
43. Kruis W, Fric P, Pokrotnieks J et al. Maintaining remission of ulcerative
colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with
standard mesalazine. Gut 2004;53:161723.
44. Moayyedi P, Ford AC, Talley NJ et al. The efficacy of probiotics in the
treatment of irritable bowel syndrome: a systematic review. Gut
2010;59:32532.
45. Ringel Y, Ringel-Kulka T. The rationale and clinical effectiveness of
probiotics in irritable bowel syndrome. J Clin Gastroenterol 2011;45:
(Suppl): S145S148.
46. Brandt LJ, Chey WD, Foxx-Orenstein AE et al. An evidence-based
position statement on the management of irritable bowel syndrome.
Am J Gastroenterol 2009;104 (Suppl 1): S135.
47. Whelan K. Probiotics and prebiotics in the management of irritable bowel
syndrome: a review of recent clinical trials and systematic reviews. Curr
Opin Clin Nutr Metab Care 2011;14:5817.
48. Floch MH, Walker WA, Madsen K et al. Recommendations for probiotic
use-2011 update. J Clin Gastroenterol 2011;45:Suppl: S168S171.
49. Guarner F, Sanders ME, Gibson G et al. Probiotic and prebiotic claims in
Europe: seeking a clear roadmap. Br J Nutr 2011;106:17657.
50. Shane AL, Cabana MD, Vidry S et al. Guide to designing, conducting, publishing and communicating results of clinical studies involving probiotic
applications in human participants. Gut Microbes 2010;1:24353.
51. Sanders ME, Heimbach JT, Pot B et al. Health claims substantiation for
probiotic and prebiotic products. Gut Microbes 2011;2:12733.
52. Sanders ME, Akkermans LM, Haller D et al. Safety assessment of probiotics
for human use. Gut Microbes 2010;1:16485.

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