nature publishing group ORIGINAL CONTRIBUTIONS 34

The American Journal of GASTROENTEROLOGY Supplements VOLUME 1 | ISSUE 1 | JULY 2012 www.amjgastro.com
see related editorial on page x
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 infuences on human
health. Interactions between the gut microbiota and the host
have been shown to infuence intestinal and systemic immunity,
defense against pathogens, intestinal motility, sensation, secretion
and barrier functions, liver metabolism, detoxifcation of xeno-
biotics, energy harvest, growth and development, and behavior.
Moreover, the gut microbiota have been implicated in trigger-
ing or exacerbating numerous disease states, including but not
limited to infammatory 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 efect on the host through modulation of gene expres-
sion, immunological, physiological, and psychological functions.
In turn, the host is able to infuence 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 tar-
geting the intestinal microbiota as a mean to maintain and pro-
mote health. Te possibility that manipulating the gastrointestinal
microbiota could achieve a preventative and therapeutic efect is
attractive. Indeed, more than a century ago, the Nobel laureate Elie
Metchnikof ( 1 ) postulated that supplementation of diet with lactic
acid bacteria, an early probiotic intervention, had health benefts
including promoting longevity. Although probiotics as a path to
longevity is still not proven, considerable evidence does show that
probiotics have potentially benefcial efects ( 2 ).
Tis 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 ). Com-
pared 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 ef cacy requirements
Using Probiotics in Gastrointestinal Disorders
Yehuda Ringel , MD, FACG
1
, Eamonn M.M. Quigley , MD FACG
2
and Henry C. Lin , MD
3

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, inammatory 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 inuence efcacy have
led to signicant confusion regarding the best choice for different indications. Although sufcient evidence is not
currently available to provide a clear guidance on the best probiotic for a particular clinical indication, key scientic
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 :34 40; doi: 10.1038/ajgsup.2012.7

1
Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine , Chapel Hill, North Carolina , USA ;
2
Alimentary
Pharmabiotic Center, Department of Medicine, University College Cork, Cork , Ireland ;
3
Section 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 nonprot 501(c)(3) educational organization dedicated to increasing
awareness of the effect of gastrointestinal disorders in the United States. The foundation s goal is to provide health professionals with the most current education
and information on gastrointestinal health.
35 Probiotics in Gastrointestinal Diseases
2012 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY Supplements
mandated by regulators, probiotic products are not consistently
tested for purity, viability, or efectiveness. Not surprisingly, pro-
biotic products are only rarely sold with evidence of ef cacy from
well-designed, randomized, placebo-controlled trials. Te con-
sumer may select a probiotic product based on generalized mar-
keted 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. Te regulatory status of probiotics may be revised in the
near future in recognition of their potentially broad-ranging efects
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 diferent spe-
cies, 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 func-
tion ( 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 efects
of disrupting intestinal microbiota; for example, antibiotics can
disrupt the gastrointestinal microbiota, permitting colonization
by Clostridium dif cile 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 efects on intestinal function
and symptoms ( 9 ). Second, IBD remains in remission when the
gut microbiota are diverted ( 10 ) but recurs when the gut is recon-
nected, permitting exposure to gut microbiota again. Tird, altera-
tions in the intestinal microbiota (e.g., following infection or use of
antibiotics or probiotics) can afect intestinal functions including
immunologic, motility, and sensation ( 6 ).
Tese 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. Tus, it is expected that
manipulation of the gut microbiota could be harnessed for pre-
ventative and therapeutic efect.
Denitions
Probiotics are live microorganisms that, when administered in an
adequate amount, confer a health beneft on the host ( Table 1 ).
Lactobacillus and Bifdobacterium species are the most commonly
used probiotics, but Escherichia coli Nissle, enterococcus , certain
Bacillus species, and certain strains of yeasts, such as Saccharomy-
ces 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 activ-
ity 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 gastrointes-
tinal tract benefcial 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. Addi-
tionally, the ef cacy of these agents in delivering live bacteria to
the gastrointestinal tract is likely to vary widely. Te 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 Bifdobacterium infantis
(10
6
, 10
8
, and 10
10
colony-forming units (CFU)). Somewhat unex-
pectedly, only the 10
8
CFU dosage rather than the highest dosage
(10
10
CFU) was efective for the primary end point of relieving pain
and discomfort at 4 weeks. Subsequent testing revealed that the
10
10
CFU dosage transformed itself into a pellet that resisted dis-
solution. Tis bioavailability problem was not encountered when
the same probiotic was added to a milk-based drink.
Tus, even if a particular strain or combination product has been
demonstrated to be efective in an indication, no recommendations
can be made regarding specifc probiotic or synbiotic products
unless clinically tested in its fnal formulation and in the dose that it
will be marketed. As clinical ef cacy of a probiotic product may be
determined by factors such as specifc 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 seg-
ments thereof), and the method of dosing, a report of clinical ef -
cacy for one probiotic product or strain cannot be simply assumed
for another probiotic. It is dif cult 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: scientic
rationale
Probiotics have intestinal barrier, immunologic, antibacterial, and
motility and sensation efects that may contribute to their ef cacy
in various indications ( 14,15 ).
Table 1 . Denitions ( 11 )
Probiotics Live microorganisms that, when administered in
adequate amounts, confer a health benet on the host
Prebiotics Nondigestable substances that provide a benecial
physiological effect for the host by selectively stimulat-
ing the favorable growth or activity of a limited number
of indigenous bacteria
Synbiotics Products that contain both probiotics and prebiotics
36 Ringel et al.
The American Journal of GASTROENTEROLOGY Supplements VOLUME 1 | ISSUE 1 | JULY 2012 www.amjgastro.com
Probiotics have been shown to afect the intestinal mucosa in
numerous ways ( 15 19 ). Tey appear to have direct efects 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 infuence mucosal immunity by increasing levels
of IgA-producing cells in the lamina propria and promoting secre-
tion of secretory IgA into the luminal mucus layers, activities that
limit epithelial colonization by bacteria. In animal models of IBD,
probiotics particularly Bifdobacteria ( 16 ) have been shown to
infuence cytokine expression and suppress mucosal infammation,
potentially through Toll-like receptor signaling ( 17,20 ). In gen-
eral, it seems that the anti-infammatory efects of probiotics
ofen observed in in vitro and animal studies may not always
translate to clinical benefcial efects of probiotics. Tis may relate
to the complex immunomodulatory efects of probiotics, with the
net efect not only dif cult to predict but ofen highly specifc to dis-
ease and health states and the individual probiotic strain ( 19,21 ).
Probiotics have also been shown to have a number of functional
efects 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 25 ), an efect potentially
Table 2 . Selected probiotic strains and products available in the US and Europe
Strain
a
Commercial availability
b
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 ( Bidis regularis )
DanActive fermented milk
Activia yogurt
Danone (Paris, France)
Dannon (Tarrytown, NY)
Dannon (Tarrytown, NY)
L. johnsonii Lj-1 (NCC533; L. acidophilus La-1) Nestl (Lausanne, Switzerland)
L. plantarum 299V
L. rhamnosus 271
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 University College (Cork, Ireland)
B. longum BB536 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 Bidobacterium 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 reect a
comprehensive list of available products containing the indicated strain.
37 Probiotics in Gastrointestinal Diseases
2012 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY Supplements
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
efect. 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 patho-
gens by simply adhering to epithelial cells ( 28 30 ).
Clinical evidence supporting the use of probiotics in
gastrointestinal diseases
Prevention of acute diarrhea . Te ef cacy of probiotics in the
prevention of acute diarrhea was assessed in a meta-analysis
conducted by Sazawal et al. ( 31 ). Tis analysis included 34 ran-
domized, placebo-controlled trials evaluating of the efect of
probiotics in various acute diarrheal states, including antibiotic-
associated diarrhea ( n = 19) and travelers diarrhea ( n = 6) and
other acute diarrhea ( n = 9). Te 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 signifcance, and 6 trials had statistically nonsignifcant
nonprotective point estimates. When all studies were pooled, pro-
biotics were associated with a 35 % (95 % confdence interval (CI)
22 44 % ; P < 0.001) reduction in the risk for diarrhea, with sub-
stantial heterogeneity (
2
P < 0.001; I
2
= 63 % , 95 % CI 52 75 % ).
Treatment of infectious diarrhea . Te ef cacy 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. Over-
all, 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
diference 0.80; 95 % CI 0.45 1.14).
Prevention of c. dif cile associated diarrhea . Te efect of probi-
otic supplementation on the incidence of C. dif cile diarrhea has
been prospectively examined ( 33 ). In this study, 150 consecutive
inpatients were randomized to receive either a probiotic con-
taining both L. acidophilus and Bifdobacterium bifdum or to a
placebo on arrival to the hospital and monitored for the incidence of
C. dif cile associated diarrhea. Te incidence of fecal samples
from patients who developed diarrhea during hospitalization that
were positive for C. dif cile associated toxins was 2.9 % in the pro-
biotic 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. Tis report supports the use of probiotics in
reducing the likelihood of successful colonization of the gut by
C. dif cile .
Prevention of antibiotic-associated diarrhea . A meta-analysis of
assessing the ef cacy of probiotics for preventing antibiotic-asso-
ciated diarrhea extends these results ( 34 ). Nine studies were re-
viewed, two of which were conducted in children. Te odds ratio
in favor of active intervention over placebo in preventing antibi-
otic-associated diarrhea was 0.37 (95 % CI 0.26 0.53; P < 0.001).
Te 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-associ-
ated 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 pro-
biotics, including S. boulardii and a mixture of L. acidophilus and
B. bifdum , had signifcant ef cacy. 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 specifc 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 ef cacy of both S. boulardii and lactobacilli; a clini-
cal report, published by Tomas and Greer ( 36 ), suggests that
L. rhamnosus GG has the most substantial evidence for beneft
in the prevention and treatment of acute infectious diarrhea, at
least in pediatric patients. Only limited support is available for
a clinical beneft of probiotics in the prophylaxis of traveler s di-
arrhea; however, given the absence of adverse efects in clinical
studies, probiotics might be a reasonable option compared with
anti biotics for this indication.
Infammatory 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 signifcantly
reduced the number of frst episodes (primary prevention) of pou-
chitis in the 39 patients who received the probiotic daily when com-
pared 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, includ-
ing S. thermophilus , Lactobacilus , and Bifdobacterium ) on mainte-
nance of remission of recurrent or refractory pouchitis. Tis 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 fve studies of
probiotics for the management of pouchitis in patients who under-
went ileal pouch anal anastomosis yielded an odds ratio of 0.04 in
38 Ringel et al.
The American Journal of GASTROENTEROLOGY Supplements VOLUME 1 | ISSUE 1 | JULY 2012 www.amjgastro.com
Recommendations . Patients with IBS, arguably, represent the larg-
est target patient population for probiotic use, and this is refected
by the number of articles and small clinical trials assessing the
ef cacy of these products in IBS. A critical evaluation of the pub-
lished 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
benefcial in improving symptoms and reducing the risk of per-
sistent symptoms in some patients with IBS, although the overall
efect is modest. Tere is little evidence for harm associated with
probiotics in fact, in the meta-analysis of Moayyedi et al. (44),
there was no signifcant diference in adverse events between pro-
biotics and placebo (relative risk for an adverse event on probiotic,
0.93; 95 % CI 0.64 1.36), suggesting that the potential beneft may
outweigh any risks associated with these products ( 44 ).
Little formal information is available to guide the use of probio-
tics in IBS. Te 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 sys-
tematic review of the evidence, lactobacilli do not appear to be
efective in the management of IBS but some ef cacy is reported
with bifdobacteria and certain probiotic combinations ( 46 ). Ad-
ditional data have accumulated since these guidelines were pub-
lished in 2009, demonstrating some ef cacy 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
Te 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-asso-
ciated and C. dif cile 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 ente-
rocolitis in preterm neonates. Refer to these guidelines for a
summary of specifc indications, products that have been demon-
strated 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.
Tese 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, treat-
ment and prevention of C. dif cile diarrhea, IBD, and IBS. Refer to
these guidelines for a summary of specifc recommendations.
Probiotic products vary widely, and only high-quality, prop-
erly labeled products shown in controlled human studies to be
safe and efective in a specifc patient population should be rec-
ommended for use. In addition, although empiric evidence sug-
gests that there is minimal potential for harm with probiotics
and prebiotics in immunocompetent individuals, because the
favor of the treatment group ( P < 0.0001), suggesting that probiot-
ics can provide considerable beneft in this patient population ( 39 ).
Five small studies, each of which evaluated a diferent probi-
otic, have evaluated the ef cacy of probiotics in inducing and / or
maintaining remission in patients with ulcerative colitis ( 40 ); of
these, four showed signifcant results in favor of probiotics. A sixth
study compared the ef cacy of 5-aminosalicylic acid, with or with-
out S. boulardii , as maintenance treatment in Crohn s disease in
32 patients ( 41 ). Tis 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 combi-
nation. Overall, probiotics may be benefcial in mild to moderate
ulcerative colitis as adjuvant therapy. In contrast to ulcerative coli-
tis, the evidence supporting the benefts of probiotics in patients
with Crohn s disease is much weaker. Indeed, a recent review of
fve 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 ).
Recommendations . Te ef cacy of probiotics in IBD is discussed
extensively elsewhere in this supplement. Te best evidence exists
for VSL#3 (a probiotic mixture ), at a dosage of 4.5 10
11
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 efective as mesalamine 500 mg
three times daily in a well-designed, double-blind, double-dummy
trial ( 43 ). However, there is insuf cient evidence at this time on
the ef cacy 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 efect 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 identifed examin-
ing products including Lactobacillus (6 studies), Bifdobacterium
(3 studies), Streptococcus (1 study), and various combination prod-
ucts (9 studies) (note that 1 trial reported on both Lactobacillus
and Bifdobacterium ). Of these, 10 ( n = 918) provided outcomes as
a dichotomous variable; in these studies, probiotics signifcantly
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. Fifeen trials reported outcomes as a continuous vari-
able; when grouped for meta-analysis, these trials also found that
probiotics had a statistically signifcant efect in improving IBS
symptoms compared with placebo. Tis meta-analysis has shown
little diference among diferent types of probiotics, with Lacto-
bacillus (3 trials enrolling 140 patients), Bifdobacterium (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 beneft ( 44 ). In terms of individu-
al symptoms, probiotics had a statistically signifcant efect on
improving pain scores and fatulence, as well as a trend toward
improvement of bloating.
39 Probiotics in Gastrointestinal Diseases
2012 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY Supplements
probiotics market is at this point largely unregulated, due cau-
tion is recommended when selecting patients and products for
therapeutic use, as host immunocompetency and quality, com-
position, 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 defnition, 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/GuidanceComplianceRegulatory-
Information/RegulationsLaws/ucm110858.htm ) and the current
US law requires that all products be labeled in a truthful and not
mis leading 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 prod-
ucts 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 stand-
ardized 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 regu-
lation and better data from high-quality clinical trials assessing
ef cacy and safety will help direct health-care providers in mak-
ing educated decisions on the proper use of probiotics in specifc
clinical conditions.
Clinical Implications and Conclusions
Current evidence supports the role of probiotics in a broad range
of gastrointestinal conditions. Suf cient evidence exists to indi-
cate that probiotics are efective in the prevention and treatment
of diarrhea, although the precise strains (or combinations), for-
mulations that provide the greatest ef cacy, and patient groups
that derive the greatest beneft 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 ef cacious in IBS,
but again the magnitude of beneft is uncertain, available clinical
data are largely derived from inadequately designed studies, and
the most efective species and strains remain uncertain. Across
all indications, the long-term efects and safety of probiotic use
remain uncertain. Clearly, larger, well-designed, confrmatory
clinical trials are needed to evaluate the ef cacy 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 .
CONFLICT OF INTEREST
Guarantor of the article : Mark Pimentel, MD, FRCP(C).
Specifc author contributions : Y.R. and H.C.L. planned and
contributed to the frst draf of this article. All authors participated
in all subsequent revisions of this article and have approved the fnal
draf of the manuscript.
Financial support: Yehuda Ringel has received research grants
from Danisco, General Mills, Procter & Gamble, and Salix Pharma-
ceuticals. Eamonn M.M. Quigley has received grant support from
Merck and has patents on gut microbiota related technologies. An
independent medical educational grant from Salix Pharmaceuticals
was provided to support the development of this supplement.
Te 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 consult-
ing fees from Salix Pharmaceuticals, Procter & Gamble, Ironwood,
Danisco, General Mills, GSK, and Pfzer / Wyeth. Yehuda Ringel has
also received lecturer fees from Salix Pharmaceuticals. Eamonn
M.M. Quigley has received consulting fees from Salix Pharmaceuti-
cals, 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 Sanof. Henry C. Lin
has intellectual property rights in a related area.
REFERENCES
1 . Metchnikof E . Optimistic Studies . Putnams Sons: New York , 1908 , pp 161 83 .
2 . Dupont AW, Dupont HL . Te intestinal microbiota and chronic disorders
of the gut . Nat Rev Gastroenterol Hepatol 2011 ; 8 : 523 31 .
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-global-
market-69.html . Accessed 1 July 2011. 2009 .
4 . Eckburg PB , Bik EM , Bernstein CN et al. Diversity of the human intestinal
microbial fora . Science 2005 ; 308 : 1635 8 .
5 . Carroll MI , Ringel-Kulka T , Ringel Y. Quantifcation and identifcation of
probiotic organisms in humans . In: Floch MH, Kim AS (eds). Probiotics:
A Clinical Guide , 1st edn. SLACK: New Jersey , 2010 , pp 55 69 .
6 . Ringel Y, Carroll IM . Alterations in the intestinal microbiota and functional
bowel symptoms . Gastrointest Endosc Clin N Am 2009 ; 19 : 141 50 , vii .
7 . O Hara AM , Shanahan F. Te gut fora as a forgotten organ . EMBO Rep
2006 ; 7 : 688 93 .
8 . McFarland LV. Emerging therapies for Clostridium dif cile infections .
Expert Opin Emerg Drugs 2011 ; 16 : 425 39 .
9 . Dunlop SP, Jenkins D , Neal KR et al. Relative importance of entero-
chromaf n cell hyperplasia, anxiety, and depression in postinfectious IBS .
Gastroenterology 2003 ; 125 : 1651 9 .
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 : 1063 6 .
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 : 830S 7S .
13 . Whorwell PJ , Altringer L , Morel J et al. Ef cacy of an encapsulated
probiotic Bifdobacterium infantis 35624 in women with irritable bowel
syndrome . Am J Gastroenterol 2006 ; 101 : 1581 90 .
14 . McFarland LV. Systematic review and meta-analysis of Saccharomyces
boulardii in adult patients . World J Gastroenterol 2010 ; 16 : 2202 22 .
15 . Ohland CL , Macnaughton WK . Probiotic bacteria and intestinal
epithelial barrier function . Am J Physiol Gastrointest Liver Physiol
2010 ; 298 : G807 19 .
16 . O Mahony L , McCarthy J , Kelly P et al. Lactobacillus and bifdobacterium
in irritable bowel syndrome: symptom responses and relationship to
cytokine profles . Gastroenterology 2005 ; 128 : 541 51 .
40 Ringel et al.
The American Journal of GASTROENTEROLOGY Supplements VOLUME 1 | ISSUE 1 | JULY 2012 www.amjgastro.com
34 . D Souza AL , Rajkumar C , Cooke J et al. Probiotics in prevention of antibi-
otic 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 : 97 105 .
36 . Tomas DW, Greer FR . Probiotics and prebiotics in pediatrics . Pediatrics
2010 ; 126 : 1217 31 .
37 . Gosselink MP, Schouten WR , van Lieshout LM et al. Eradication of
pathogenic bacteria and restoration of normal pouch fora: comparison of
metronidazole and ciprofoxacin in the treatment of pouchitis . Dis Colon
Rectum 2004 ; 47 : 1519 25 .
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 : 108 14 .
39 . Elahi B , Nikfar S , Derakhshani S et al. On the beneft 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 : 1278 84 .
40 . Guandalini S . Update on the role of probiotics in the therapy of pediatric
infammatory bowel disease . Expert Rev Clin Immunol 2010 ; 6 : 47 54 .
41 . Guslandi M , Mezzi G , Sorghi M et al. Saccharomyces boulardii in
maintenance treatment of Crohns disease . Dig Dis Sci 2000 ; 45 : 1462 4 .
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 : 1202 9 .
43 . Kruis W, Fric P, Pokrotnieks J et al. Maintaining remission of ulcerative
colitis with the probiotic Escherichia coli Nissle 1917 is as efective as with
standard mesalazine . Gut 2004 ; 53 : 1617 23 .
44 . Moayyedi P, Ford AC , Talley NJ et al. Te ef cacy of probiotics in the
treatment of irritable bowel syndrome: a systematic review . Gut
2010 ; 59 : 325 32 .
45 . Ringel Y, Ringel-Kulka T . Te rationale and clinical efectiveness of
probiotics in irritable bowel syndrome . J Clin Gastroenterol 2011 ; 45 :
( Suppl): S145 S148 .
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) : S1 35 .
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 : 581 7 .
48 . Floch MH , Walker WA , Madsen K et al. Recommendations for probiotic
use-2011 update . J Clin Gastroenterol 2011 ; 45 : Suppl: S168 S171 .
49 . Guarner F, Sanders ME , Gibson G et al. Probiotic and prebiotic claims in
Europe: seeking a clear roadmap . Br J Nutr 2011 ; 106 : 1765 7 .
50 . Shane AL , Cabana MD , Vidry S et al. Guide to designing, conducting, pub-
lishing and communicating results of clinical studies involving probiotic
applications in human participants . Gut Microbes 2010 ; 1 : 243 53 .
51 . Sanders ME , Heimbach JT , Pot B et al. Health claims substantiation for
probiotic and prebiotic products . Gut Microbes 2011 ; 2 : 127 33 .
52 . Sanders ME , Akkermans LM , Haller D et al. Safety assessment of probiotics
for human use . Gut Microbes 2010 ; 1 : 164 85 .
17 . Rachmilewitz D , Katakura K , Karmeli F et al. Toll-like receptor
9 signaling mediates the anti-infammatory efects of probiotics in murine
experimental colitis . Gastroenterology 2004 ; 126 : 520 8 .
18 . Chiba Y, Shida K , Nagata S et al. Well-controlled proinfammatory
cytokine responses of Peyers patch cells to probiotic Lactobacillus casei .
Immunology 2010 ; 130 : 352 62 .
19 . de Roock S , van Elk M , van Dijk ME et al. Lactic acid bacteria difer in their
ability to induce functional regulatory T cells in humans . Clin Exp Allergy
2010 ; 40 : 103 10 .
20 . McCarthy J , O Mahony L , O Callaghan L et al. Double blind, placebo con-
trolled trial of two probiotic strains in interleukin 10 knockout mice and
mechanistic link with cytokine balance . Gut 2003 ; 52 : 975 80 .
21 . Sokol H , Pigneur B , Watterlot L et al. Faecalibacterium prausnitzii is an anti-
infammatory commensal bacterium identifed by gut microbiota analysis
of Crohn disease patients . Proc Natl Acad Sci USA 2008 ; 105 : 16731 6 .
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 : 826 37 .
23 . Verdu EF, Bercik P, Verma-Gandhu M et al. Specifc probiotic therapy
attenuates antibiotic induced visceral hypersensitivity in mice . Gut
2006 ; 55 : 182 90 .
24 . Kamiya T , Wang L , Forsythe P et al. Inhibitory efects of Lactobacillus
reuteri on visceral pain induced by colorectal distension in Sprague-Dawley
rats . Gut 2006 ; 55 : 191 6 .
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 afer colorectal distension in rats . Neurogastroenterol
Motil 2009 ; 21 : 567 73 , e18 9 .
26 . Rousseaux C , Turu X , Gelot A et al. Lactobacillus acidophilus modulates
intestinal pain and induces opioid and cannabinoid receptors . Nat Med
2007 ; 13 : 35 7 .
27 . Collins S , Verdu E , Denou E et al. Te role of pathogenic microbes and com-
mensal bacteria in irritable bowel syndrome . Dig Dis 2009 ; 27 (Suppl 1) : 85 9 .
28 . Oh S , Kim SH , Worobo RW. Characterization and purifcation of a
bacteriocin produced by a potential probiotic culture, Lactobacillus
acidophilus 30SC . J Dairy Sci 2000 ; 83 : 2747 52 .
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 : 7617 21 .
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 : 166 72 .
31 . Sazawal S , Hiremath G , Dhingra U et al. Ef cacy of probiotics in
prevention of acute diarrhoea: a meta-analysis of masked, randomised,
placebo-controlled trials . Lancet Infect Dis 2006 ; 6 : 374 82 .
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 dif cile pilot study:
efects of probiotic supplementation on the incidence of C. dif cile
diarrhoea . Int Microbiol 2004 ; 7 : 59 62 .