CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10:960 –968
PERSPECTIVES IN CLINICAL
GASTROENTEROLOGY AND HEPATOLOGY
A Gastroenterologist’s Guide to Probiotics
MATTHEW A. CIORBA
Department of Medicine, Division of Gastroenterology, Washington University, St Louis School of Medicine, St Louis, Missouri
Podcast interview: www.gastro.org/cghpodcast.
Also available on iTunes.
The enteric microbiota contribute to gastrointestinal
health, and their disruption has been associated with many
disease states. Some patients consume probiotic products
in attempts to manipulate the intestinal microbiota for
health benefit. It is important for gastroenterologists to
improve their understanding of the mechanisms of probi-
otics and the evidence that support their use in practice.
Clinical trials have assessed the therapeutic effects of pro-
biotic agents for several disorders, including antibiotic- or
Clostridium difficile–associated diarrhea, irritable bowel syn-
drome, and the inflammatory bowel diseases. Although
probiotic research is a rapidly evolving field, there are suf-
ficient data to justify a trial of probiotics for treatment or
prevention of some of these conditions. However, the ca-
pacity of probiotics to modify disease symptoms is likely to
be modest and varies among probiotic strains—not all pro-
biotics are right for all diseases. The current review pro-
vides condition-specific rationale for using probiotic ther-
apy and literature-based recommendations.
Keywords: Clostridium difficile; IBD; IBS; Crohn’s Disease and
Colitis; Yogurt; Pouchitis.
F or more than a hundred years it has been recognized that
certain microorganisms may impart health benefits to the
host when administered in adequate amounts. These microor-
ganisms, termed probiotics, have recently become a topic of
significant focus in basic and clinical investigation. Relevant to
the practice of gastroenterology, probiotics are commonly used
by patients with gastrointestinal (GI) complaints or diseases.
Increasingly, probiotics are also being recommended by the
clinicians who treat these conditions.1
The goal of this review is to provide clinicians with an
overview of the rationale and data which support or refute the
role of probiotics for treating commonly encountered GI dis-
orders. The information provided is based on review of primary
literature from randomized controlled trials (RCTs), meta-anal-
yses, expert consensus panel recommendations, and society-
based practice recommendations. References are provided for
more in-depth reading and tables or figures summarize key
information.
The Human Microbiome and Probiotic
Mechanisms
To understand the role that probiotics may have in
influencing health, it is important to have an appreciation of
the roles of the normal intestinal microbiome (commensal
microbiota). The human GI tract is host to over 500 bacterial
species as well as a less well-described virome. These microbiota
form a virtual bioreactor facilitating digestion, nutrient provi-
sion, and the shaping of our immune system.2 Our intestinal
bacteria weigh up to 1 kg and bacterial cells outnumber human
cells by 10:1. The bacterial genome may outnumber the human
genome by 100:1. Nutritional factors including several B vita-
mins, vitamin K, folate, and short-chain fatty acids are pro-
duced by these bacteria. Up to 10% of an individual’s daily
energy needs can be derived from the by-products of bacterial
fermentation. Gastrointestinal microbiota are also critical for
normal immune system development.3 The physiologic impact
mediated by our resident microbes is substantial enough to
have earned the label of “other organ” from some.4
Beyond contributing to or modifying the metabolic and
nutritional functions of the commensal microbiota, probiotic
bacteria have several putative mechanisms by which they may
confer specific beneficial effects. General categories include
modulation of immune or sensory-motor function, enhance-
ment of mucosal barrier function, and antipathogen effects
(Figure 1).5–7 Some of these mechanisms have been worked out
in animal models and/or in vitro systems only.
Soluble products secreted or shed by probiotics also mediate
important physiologic benefits; thus, viable bacteria are not
necessarily required for all benefits.8,9 The mechanisms by
which probiotics exert benefit varies by specific probiotic strain
and likely depends on the clinical indication.10,11 Therefore, as
with antibiotic prescribing, clinical use of probiotics should
focus on matching the probiotic strain and dosage to the
condition for which it has shown benefit in clinical trials. In the
future, greater understanding of probiotic-specific mechanisms
Abbreviations used in this paper: AAD, antibiotic-associated diar-
rhea; CD, Crohn’s disease; CDAD, Clostridium difficile–associated di-
arrhea; ECN, Escherichia coli Nissle 1917; GI, gastrointestinal; IBS,
irritable bowel syndrome; LGG, Lactobacillus rhamnosus GG; NNT,
number needed-to-treat; RCT, randomized controlled trial; UC, ulcer-
ative colitis.
© 2012 by the AGA Institute
1542-3565/$36.00
http://dx.doi.org/10.1016/j.cgh.2012.03.024
September 2012
Figure 1. Mechanisms of action of probiotics in the gastrointestinal tract.
could allow for precise selection of a particular probiotic strain
to target a patient’s specific pathogenic defect and clinical
problem.
Probiotic Concepts for Practice
What Makes a Probiotic a Probiotic?
Definitions of the terms probiotic, prebiotic, and syn-
biotic are provided in Table 1. This review focuses on probi-
otics, though some probiotics have been tested as part of a
PROBIOTICS IN PRACTICE 961
synbiotic product. Lactobacillus and Bifidobacterium species are
the most commonly used probiotics. However, 1 of the first
probiotics, which is still in use, is the nonpathogenic Esche-
richia coli Nissle 1917 (ECN). Most probiotics were initially
cultured from humans and resemble known commensal gut
bacteria. However, the commensal population they resemble
typically represents only a fraction of the total luminal
bacteria. Saccharomyces boulardii is a probiotic yeast strain
with the potential advantage of having resistance to most
antibiotics.
962 MATTHEW A. CIORBA
Table 1. Definitions
Probiotics Live microorganisms that confer a health benefit
on the host when administered in adequate
amounts
Prebiotic Dietary substances that nurture specific changes
in the composition and/or activity of the GI
microbiota (favoring beneficial bacteria), thus
conferring benefit(s) upon host health
Synbiotics Products that contain both probiotics and
prebiotics
NOTE. Adapted from Guarner F, Khan AG, Garisch J, et al. Probiotics
and prebiotics: world gastroenterology organisation global guidelines,
2011. Available at: http://www.worldgastroenterology.org/probiotics-
prebiotics.html.48
According to current definitions, probiotics should survive
both gastric acid and bile to reach the small intestine and colon
where they exert their effects. Clinical and basic investigations
on probiotics have used a multitude of probiotic species, both
as single strains and multispecies products. Many of these
probiotics are available in a lyophilized (freeze-dried) pill form,
though some are available in yogurt or as packets (sachets)
which can be mixed into noncarbonated drinks. Whether syn-
ergism or antagonism exists between probiotic species when
offered together has not been examined in clinical studies,
though both scenarios are theoretically possible. Though not
exhaustive, Table 2 lists several of the more commonly available
probiotic preparations which have shown benefit in human
trials. Probiotics are considered dietary supplements; thus, they
are not covered by medical insurance and their production is
not regulated by the Food and Drug Administration. As such,
product quality, purity, and viability have been reported to be
variable.12 However, several clinically tested probiotic products
with quality-controlled production are now marketed by repu-
table companies.
Does Any Yogurt Work Just Like a Probiotic?
Lactic acid–producing bacteria have been used for cen-
turies in food fermentation. Many yogurts contain live-active
lactobacillus cultures and are considered functional food prod-
ucts; however, most are not considered probiotics per se. This
term is reserved for products with an adequate number of
microorganisms at time of consumption specifically shown to
confer health benefits in controlled human trials. Yogurts for-
tified with an adequate number of viable bacteria shown to
exert benefit in controlled trials are classified as probiotics.
Given this information, and the knowledge that probiotic ben-
efits appear species-specific, expected clinical end points may
not be achieved by generically recommending yogurt to patients
in whom a purported probiotic benefit is desired. It should be
noted, however, that yogurt consumption has other benefits
including improved lactose tolerance and the provision of pro-
tein, vitamin D, and calcium.
How Long Does One Have to Take a
Probiotic?
As viable microorganisms, probiotics can survive in the
human gut and impact microbes which colonize the gut. Pro-
biotics are often detectable in the stool by culture or gene-based
assays during periods of consumption. However, many probi-
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 9
otic strains do not colonize the gut and are no longer recover-
able in stool 1 to 4 weeks after stopping consumption.13 For
example, McNulty and colleagues recently evaluated a fer-
mented milk product with probiotic strains matching the com-
mercially available Activia (Dannon, White Plains, New York).
The investigators showed that the probiotic product did not
change the gut’s overall bacterial composition, but instead
altered gene expression patterns relevant to carbohydrate me-
tabolism in the host’s resident gut microbes.14 These changes in
the human fecal “metatranscriptome” were transient, confined
only to the time of the probiotic consumption. Thus, if sus-
tained benefit from a probiotic is desired, continued consump-
tion is likely required.
Where Can Probiotics Fit Into a Therapeutic
Algorithm?
Data for probiotic use in several GI disorders are re-
viewed in the following section. For AAD and viral gastroen-
teritis, supporting data are strong and probiotics are among the
only treatment modalities available. However, the duration of
symptoms in these conditions is typically short regardless of
probiotic use. In ulcerative colitis (UC), pouchitis, and irritable
bowel syndrome (IBS), adequate data exist for clinicians to
consider recommending a therapeutic trial of specific probiotic
strains or preparations in selected patients. In these conditions
probiotics are usually administered as adjunctive therapy,
rather than primary or first-line therapy. The decision to rec-
ommend probiotic therapy ultimately depends on the clinical
scenario, patient interest, and clinician preference. In hepatic
encephalopathy, Crohn’s disease (CD), and Clostridium difficile–
associated diarrhea (CDAD), conventional medical therapies
remain the gold standard. Practice relevant probiotic concepts
are summarized in Table 3.
Probiotic Therapy for Gastrointestinal
Conditions
Acute Onset Infectious Diarrhea
Several RCTs have evaluated the use of probiotics in
acute infectious diarrhea. The data are largely from pediatric
studies where both prevention and treatment were examined.
Trials were conducted across the world with durations of up to
1 year. In the pediatric population, rotavirus has been the most
common cause of infectious diarrhea. Data suggest that the
benefit of probiotics in preventing acute infectious diarrhea is
modest.15,16 Lactobacillus rhamnosus GG (LGG), Lactobacillus reu-
teri and Lactobacillus casei all have shown benefit, with an ap-
proximate number needed-to-treat (NNT) of 7 children to pre-
vent 1 case of rotavirus in the child care center setting.17–19 With
the currently available rotavirus vaccine in consideration, the
American Academy of Pediatrics states that probiotics for pre-
venting acute infectious diarrhea are not universally endorsed,
but acknowledges that they may have a role in special circum-
stances.15 According to the US Center for Disease Control, data
are not sufficient to support the use of probiotics such as LGG
to prevent traveler’s diarrhea of bacterial origin.
The data supporting treatment of acute infectious diarrhea
with probiotics are stronger. LGG is the most effective probiotic
reported to date, reducing both severity and duration of diar-
rhea by approximately 1 day.20,21 The American Academy of
Pediatrics supports the recommendation of LGG early in the
 September 2012
Table 2. Available Probiotic Products Specifically Tested for Gastrointestinal Disorders

Practice
Brand name (Company) Bacterial species Clinical condition Effectiveness32,42,a guidelines15,48,84,b Bacteria count/dosing Cost/quantity

Activia (Dannon, White B lactis DN-173010 (plus IBS C 1bc 4 oz/cup, 1–4 qd $10–$18/24
Plains, NY) yogurt starters L bulgaricus, count
L lactis, and Streptococcus
thermophilus)
Align (Proctor and Gamble, B infantis 35624 IBS B 1bc 1 Billion/1 qd $29.99/28
Cincinnati, OH) count
BioGaia (Everidis Health L reuteri Protectis Infectious diarrhea treatment A 1ad 100 Million qd $22–$30/5 mL
Sciences, St Louis, MO) SD2112 (ATCC 55730) IBS C 1bd (29 servings)
Bio-K⫹ (Bio-K Plus L acidophilus CL1285 and L AAD prevention 1bc 50 Billion/capsule bid $29.99/15
International, Inc, Laval, casei LBC80R CDAD prevention 1bc count
QC, Canada)
Culturelle (Valio, Helsinki, LGG (LGG also included in AAD prevention A AAP, 1bc, 1bd 10 Billion/1 qd $18–$25/30
Finland/i-Health, Inc, Danimals yogurt; Dannon) Infectious diarrhea treatment A AAP, 1ad, 2bc count
Cromwell, CT) Infectious diarrhea prevention B 1bc, 1bd
CDAD prevention B/C
CDAD prevention of recurrence B/C
Crohn’s disease C
IBS B/C (children) 1ad,1bc,e

Danactive (Dannon) L casei DN-114001 AAD prevention A 1bc 3.1 oz/cup; 10 $5.00/8 count
Infectious diarrhea prevention 1bd billion/cup
CDAD prevention 1bc
Florastor (Biocodex, Inc, Saccharomyces boulardii AAD prevention A AAP, 1ad, 1bc 250 mg/1 bid $19.99/20
Creswell, OR) (yeast) Infectious diarrhea treatment A 1ad, 1bc count
Infectious diarrhea prevention B
CDAD prevention B/C
CDAD prevention of recurrence B/C 1bc
Crohn’s disease C
Mutaflor (Ardeypharm, ECN UC induction B 100 mg/capsule bid $62–$81/60
Herdecke, Germany) UC maintenance A 1bc, BSG “A” Canadaf
VSL*3 (Sigma-Tau Combination probiotic product IBS B/C 122.5 Billion/capsule; $86/30
Pharmaceuticals, Inc, (Streptococcus UC induction B 1bc 450 billion/sachet; sachets
Towson, MA) thermophilus, B breve, B UC maintenance A IBS: ½–1 sachet/d; $52/60 count
longum, B infantis, L Pouchitis: prevention and A 1bc, BSG “B” Pouchitis: 2–4
acidophilus, L plantarum, L maintaining remission sachets/d; UC: 1–8
paracasei, L delbreuckii/ sachets/d

PROBIOTICS IN PRACTICE
bulgaricus)

aEffectiveness based on expert panel recommendations where: A ⫽ strong, positive, well-conducted, controlled studies in the primary literature; B ⫽ some positive, controlled studies but presence

of some negative studies or inadequate amount of work to establish the certainty; C ⫽ some positive studies but clearly inadequate amount of work to establish the certainty.
bPractice guidelines include those of (1) World Gastroenterology Organisation’s global guidelines evidence level assignment48 where 1a ⫽ systematic review with homogeneity of RCTs; 1b ⫽

individual RCT with narrow confidence interval; and 2b ⫽ individual cohort study (including low quality RCT)85; (2) American Academy of Pediatrics recommended (AAP)15; (3) British Society of
Gastroenterology guidelines Grade of Evidence (BSG)84: grade A indicates consistent results among RCTs, grade B indicates consistent cohort studies or smaller RCTs.
cAdult.
dPediatric.
eAs part of a multispecies probiotic product.

963
fECN is currently removed from the US market respecting the FDA’s decision on the classification of the product as a “biologic” instead of its former status as a “medical food.”
964 MATTHEW A. CIORBA
Table 3. Practical Considerations Relevant to Probiotics in
Practice
Common side effects of probiotics are typically transient but
include gas and bloating
Different probiotic strains possess unique properties for benefiting
host physiology
One probiotic does not fit all GI illnesses; probiotic selection should
be based on the clinical indication and take into consideration
the strain and dosage used in clinical trials
Symptomatic benefits offered by probiotics are likely to be modest;
thus, probiotic therapies may best be used to supplement rather
than replace conventional therapies
Continuous consumption throughout the period of desired effect
appears required for probiotics
Avoid probiotics in the critically ill and those with severe immune
compromise
course of acute infectious diarrhea to reduce symptom dura-
tion.15
Antibiotic Associated Diarrhea
Antibiotic use is common in children, and diarrhea
develops in approximately 20% of those taking antibiotics.
Prevention of non–C difficile-related antibiotic-associated diar-
rhea (AAD) with probiotics has been assessed in RCTs. A 2011
Cochrane Review evaluating more than 3400 patients from 16
studies concluded that the overall evidence suggests a protective
effect of probiotics in preventing AAD.22 Studies using LGG
and S boulardii produced the most convincing results.23 The
NNT to prevent 1 case of AAD was approximately 7 in the
Cochrane Review. The American Academy of Pediatrics sup-
ports the recommendation of probiotics for prevention of, but
not treatment of, AAD.15
In the adult population probiotics also appear effective in
limiting AAD. A meta-analysis evaluating studies on various
probiotics and antibiotic regimens published between 1977 and
2005 found that both LGG and S boulardii offered a reduction
in risk of AAD development (combined RR 0.31 and 0.37,
respectively).24 Two recent placebo-controlled RCTs evaluated
combination probiotic products for the prevention of AAD as
their primary end point. Hickson et al used the probiotic
mixture currently marketed as DanActive (Dannon) in the
United States and found that it significantly reduced AAD (12%
vs 34%) in an older cohort of hospitalized patients.25 A second
study evaluated a combination probiotic containing both L casei
and Lactobacillus acidophilus (Bio-K⫹; Bio-K Plus International,
Laval, Quebec, Canada) in 255 patients. Patients given the
higher dose of probiotic concurrent with antibiotics (and for 5
days afterward) had fewer occurrences of AAD (15.5% vs
44.1%).26 As a secondary end point, both of these studies also
showed a reduction in development of CDAD (discussed be-
low).
C Difficile–Associated Diarrhea
C difficile–associated diarrhea is a common nosocomial
and community-based medical condition. Typically linked to
antibiotic-induced disturbance of the intestinal microbiota,
CDAD is now increasingly identified in patients without recent
antibiotic exposure.27 Antibiotic therapy with metronidazole,
oral vancomycin, and now fidaxomicin make up the current
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 9
treatment paradigm.28 Recurrence of CDAD remains a clinical
problem. In 1994, a trial reported that S boulardii (500 mg twice
a day) offered for 4 weeks after antibiotic therapy reduced
overall CDAD recurrence rates.29 However, the finding was only
significant for those with a history of recurrent CDAD. A
follow-up study, designed to be confirmatory, did not find S
boulardii to significantly reduce CDAD recurrence after standard
therapy.30 Though a favorable trend was found in patients
treated with high-dose vancomycin (2 g/d) in the latter study,
the clinical significance of this is less clear. Lactobacillus pro-
biotics have been tested as single species and as combination
probiotic products for preventing CDAD recurrence. While
some results have been promising, most studies are underpow-
ered, have methodological flaws, or have not been reproduced.31
Probiotic-based primary prevention still may be an approach
to the current scourge of C difficile. The 2 recent probiotic trials
discussed previously in the AAD section suggest that this may
be feasible. The Hickson study reported that DanActive (Dan-
non) supplementation in older hospitalized adults reduced
AAD, but also CDAD (0% vs 17% placebo).25 The study evalu-
ating the combination probiotic Bio-K⫹ (Bio-K Plus Interna-
tional) also showed a reduction in CDAD in the treated cohort
(1.2% vs 23.8% placebo).26 The high incidence rate of C difficile
positivity in the placebo groups (17% and 23.8%) is a criticism
for both of these studies. Nonetheless, if confirmatory studies
show similar results, these intriguing findings may lead to a
paradigm shift in managing older adults requiring antibiotic
therapy.
While controversy exists, current society guidelines and ex-
pert opinion panels state that existing data are not sufficient to
justify recommending available probiotics for preventing pri-
mary or recurrent CDAD.31–33
Irritable Bowel Syndrome
Irritable bowel syndrome is characterized by symptoms
of abdominal pain and altered bowel habits which occur over at
least 3 months. This common disorder is managed with varying
clinical styles as no dominant therapeutic strategy has
emerged.34 The pathophysiology of IBS remains unknown, but
several lines of evidence link symptomatic expression of this
disorder with the intestinal microbiota. IBS patients may have
subtle differences in their luminal and mucosal-associated in-
testinal microbiota compared with controls.35,36 New-onset IBS
symptoms can develop in up to a third of individuals after
recovery from a self-limited episode of infectious gastroenteri-
tis.37,38 Small-bowel bacterial overgrowth has been reported in a
proportion of IBS patients, and antibiotics offer relief of IBS
symptoms in some individuals.39,40 Although controversy exists,
bacteria likely contribute to at least some symptoms of IBS.41
Several clinical trials have investigated the potential for pro-
biotics as therapy in IBS. These trials are the subject of several
single-topic reviews.42– 44 Systematic summarization of these
results is complicated by the inclusion of several probiotic
strains/species, single or combination preparations, dosing reg-
imens, and unique study designs. Several studies included end
points which were not clinically applicable, or demonstrated
improvement over baseline, but not compared with placebo.42
Most studies were short-term only; data on long-term efficacy
are still lacking.
A meta-analysis of 3 RCTs suggests that LGG moderately
improves pain symptoms in children with IBS (NNT ⫽ 4).45
September 2012
Traditional IBS treatment end points have not been adequately
met in studies of other single strain lactobacillus species in
adults.42 A Bifidobacterium infantis strain (B infantis 35624; Align,
Proctor and Gamble, Cincinnati, Ohio) was evaluated in 2
clinical trials. One study found significant reductions in pain,
bloating, bowel movement difficulty, and composite symptom
score vs placebo and a lactobacillus species.46 In a larger follow-up
study, reduction in pain and global relief of IBS symptoms were
significantly greater in the B infantis–treated group compared
with placebo.47
General recommendations from the American College of
Gastroenterology as well as expert consensus panels from both
the United States and in Europe are similar.32,34,48 There is
reasonable rationale for why probiotics may work as treatment
for IBS. There are at least some positive controlled studies
showing that probiotic supplementation reduces IBS symptoms
in some patients. The evidence of benefit is not sufficiently
strong to support the general recommendation of probiotics
for IBS; however, the benefit appears greatest for bifidobacteria
species and certain combinations of probiotics which include
bifidobacteria species rather than single species lactobacillus pro-
biotics.
With probiotics, patients might experience a global im-
provement in symptomatology rather than specific improve-
ment in bowel function. Because treatment options for IBS
remain limited in both number and efficacy, a therapeutic
trial of probiotics is reasonable for patients interested in this
approach.
Inflammatory Bowel Diseases
Evidence points to the intestinal microbiome being a
key player in the development and perpetuation of the inflam-
matory bowel diseases.49 Defects in the innate immune re-
sponse to commensal intestinal bacteria resulting in an exag-
gerated adaptive immune response to these organisms are
implicated in the pathogenesis of CD.50 Several key CD risk
genes have functions related to bacterial killing, and antibiotics
have therapeutic efficacy in CD and pouchitis.51,52 Compared
with CD, a central role for gut bacteria is less strongly impli-
cated in the pathogenesis of UC.53 However, the evidence sup-
porting probiotics in patient management is better for UC and
pouchitis than for CD.
Several limitations exist with trials which have evaluated
probiotic therapy in the inflammatory bowel diseases. These
include small cohort sizes, use of different probiotic doses and
strains, varied treatment durations, and differences in concur-
rent conventional treatments. Regardless, patients with inflam-
matory bowel disease often take or consider taking probiotics
and appreciate their clinician having knowledge of the topic.
Crohn’s Disease
Probiotic use in the management of CD is not sup-
ported by currently available RCT data. Trials have found LGG
and other lactobacilli not superior to placebo as an additive to
standard care for inducing or maintaining remission in CD or
for preventing postoperative relapse.54 –56 There are also no solid
data to support the use of ECN or S boulardii in CD.57
Ulcerative Colitis
Several published RCTs have shown benefit of probiot-
ics in the management of UC. These studies have examined
PROBIOTICS IN PRACTICE 965
induction of remission and maintenance of remission typically by
comparing the probiotic with oral mesalamine or adding the
probiotic to standard therapy. ECN at 200 mg/d was similar in
efficacy to 1500 mg of mesalamine for maintaining UC in
remission.58
High dose VSL#3 (3.6 trillion colony-forming units per day;
Sigma-Tau Pharmaceuticals, Inc, Towson, MA) has shown ther-
apeutic efficacy in 2 RCTs evaluating patients with mild-to-
moderately active UC. When offered to UC patients having a
flare while taking mesalamine or an immunomodulator, the
probiotic cohort demonstrated improved symptom-based dis-
ease activity indexes and rectal bleeding, but not endoscopic
scores, compared with the placebo group.59 A study conducted
in India included 144 adults with relapsing UC and showed the
VSL#3 group to have significantly higher remission rates (42.9%
vs 15.9%) and endoscopic healing (32% vs 14.7%).60 Most pa-
tients in both groups remained taking a stable dose of mesala-
mine therapy. A high dropout rate in both groups (29% VSL#3,
59% placebo) was a limitation of the latter study. VSL#3 was
also shown to improve rates of induction and maintenance of
remission in children with UC (n ⫽ 29 total).61 Recent Co-
chrane reviews conclude that there are insufficient data to
demonstrate that probiotics have efficacy in maintaining remis-
sion in UC; however, they have not recently addressed induction
of remission in UC.62 Single strain Lactobacillus and Bifidobacte-
rium (infantis 35624, Align, Proctor and Gamble) probiotics did
not show efficacy for maintaining UC remission in clinical
trials.63,64
In summary, the overall evidence suggests that ECN and
VSL#3 have modest efficacy, similar to and perhaps comple-
mentary to mesalamine, in inducing and maintaining remission
for mild-to-moderately active UC.
Pouchitis
Chronic or recurrent pouchitis is an important compli-
cation occurring in approximately 10% to 20% of UC patients
after ileal anal pouch formation surgery. VSL#3 (Sigma-Tau
Pharmaceuticals, Inc) was shown beneficial in prophylaxis
against pouchitis onset after surgical take-down65 and in main-
taining clinical remission after antibiotic induction.66,67 These
trials were conducted in Europe and included approximately 20
patients per group. A practice-based report from the Cleveland
Clinic found only 19% of patients (6 of 31) who started taking
VSL#3 after treatment with antibiotics to still be taking the
probiotic at 8 months.68 A single study from the Netherlands
found that compared with a historical cohort, patients taking
LGG had a delayed onset of pouchitis at 3 years (7% vs 29%).69
Clinical expert-generated guidelines concur that probiot-
ics (VSL#3) can be effective for preventing recurrence of
pouchitis.32,70,71
Complications of Chronic Liver
Disease/Hepatic Encephalopathy
Luminal microbiota play an important role in the
pathogenesis of both spontaneous bacterial peritonitis and he-
patic encephalopathy. Ammonia produced by gut bacteria is
believed to play a key role in hepatic encephalopathy. Antibiot-
ics are employed in clinical practice to reduce severity or fre-
quency of both these chronic liver disease complications. Lac-
tulose, a mainstay of therapy, is a prebiotic for lactobacilli which
can limit bacterial ureases.
966 MATTHEW A. CIORBA
The role for probiotics in these disorders is an area of
ongoing investigation.72 Treatment of hepatic encephalopathy
with L acidophilus was studied as early as 1965.73 More recently,
Liu and colleagues offered a probiotic and prebiotic mixture to
97 patients with minimal hepatic encephalopathy and observed
a reduction in ammonia levels and improvement in encepha-
lopathy.74 Another group found that a yogurt-based probiotic
supplement significantly improved quantitative measurements
of minimal hepatic encephalopathy in patients with nonalco-
holic cirrhosis.75 The latter group is now completing a more
comprehensive trial using the probiotic LGG in a similar pa-
tient cohort.76
Society guidelines and expert consensus panels do not cur-
rently support a recommendation of probiotic use for any
chronic liver disease–associated condition.
Safety of Probiotics
For most populations, probiotic consumption is con-
sidered safe and complications rare. A review on the safety of
probiotics by Snydman points out that although case reports of
bacteremia and endocarditis (LGG) as well as cases of fungemia
(S boulardii) exist, epidemiologic evidence suggests that there is
no overall increase in population risk based on usage data.77
This position is substantiated by a recent US government com-
missioned review panel report.78 As a caveat, however, a high
profile multicenter placebo controlled Dutch RCT examining
probiotic supplementation in severe acute pancreatitis found a
higher incidence of mesenteric ischemia and death in the treat-
ment group.79 This is the only trial to date to infer such a
relationship, but supports the concept that probiotics should
be avoided in critically ill patients. Indwelling central vein
catheters and perhaps cardiac valvular disease may be relative
contraindications.80
What Lies Ahead for Probiotics in
Digestive Diseases
Inspired investigators and technical advances in genom-
ics are facilitating in-depth scientific investigation of the hu-
man microbiome and the functional capacities of probiotics.
These advances are sure to bring paradigmatic changes to our
fundamental understanding of how microbiota influence
health and how they can be manipulated to combat disease and
improve quality of life. Future indications and therapeutic
directions for probiotics may include conditions as diverse as
mood disorders, obesity, autism, and diabetes. Recent clinical
trials and translational studies suggest that lactobacillus pro-
biotics may offer epithelial cytoprotection to limit symptoms of
radiation enteritis, a dose-limiting side effect for patients re-
ceiving abdominal radiation therapy for malignancy.8,81,82
Promise is held for confirmative testing of helminth-based
therapy and “turbo-probiotics” designed to secrete human cy-
tokines. Gene-based bacterial profiling studies from disease
affected humans have identified what may be novel “probiotics”
such as Faecalibacterium prausnitizii and Clostridium species IV
and XIVa. Finally, the identification, purification, and repack-
aging of probiotic-derived soluble factors possessing proven
capacity to modify biological function may allow us to harness
the power of probiotics while averting the potential risks asso-
ciated with live bacteria. As these advances progress to the
clinic, the term pharmabiotic has been proposed by some inves-
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 9
tigators in an effort to encompass both beneficial microbes and
their products.83
Conclusions
Evidence supports a role for considering the recommen-
dation of conventional probiotics for some clinical conditions.
Probiotic strain selection should focus on quality-tested prod-
ucts with clinically demonstrated benefit for the given disorder.
Patients and physicians should expect modest effects and con-
sider using probiotics as a supplement to, rather than a replace-
ment for, conventional therapy. Though challenges exist, ongo-
ing investigations offer great promise for the future. Perhaps
one day clinicians will have the opportunity to use directed
selection of a probiotic or probiotic-derived product to specif-
ically address a patient’s unique disease-causing physiologic or
genetic defect.
Supplementary Material
Note: To access the supplementary material accompa-
nying this article, visit the online version of Clinical Gastroenter-
ology and Hepatology at www.cghjournal.org, and at http://dx.
doi.org/10.1016/j.cgh.2012.03.024.
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Reprint requests
Address requests for reprints to: Matthew A. Ciorba, MD, Depart-
ment of Medicine, Division of Gastroenterology, Washington Univer-
sity, St Louis School of Medicine, 660 South Euclid Avenue, Box 8124,
St Louis, Missouri 63110. e-mail: mciorba@dom.wustl.edu; fax: (314)
362-8959.
Acknowledgments
The author thanks colleagues at Washington University for their
critical assessment of this review, and for the knowledge shared by
participants of FASEB’s Probiotics, Intestinal Microbiota and the Host:
Physiological and Clinical Implications 2011 Summer Research Con-
ference.
Conflicts of interest
The author discloses the following: M.A.C. has received grant sup-
port for laboratory research from VSL Pharmaceuticals, Inc.
Funding
This work is partially supported by NIH grant DK089016.