Jurnal

Disease-a-Month 61 (2015) 259290
Contents lists available at ScienceDirect
Disease-a-Month
journal homepage: www.elsevier.com/locate/disamonth
Probiotics
Barry A. Mizock, MD, FACP, FCCM
Denitions
Commensal bacteria (indigenous microbiota)
These are the microorganisms that are present on body surfaces that are covered by epithelial
cells and are exposed to the external environment (gastrointestinal and respiratory tract, vagina,
skin, etc.). Commensal bacteria are considered as self by the hosts immune system.
Pathobiont
These are the bacteria that are normally symbiotic but have the potential to be pathologic
under certain conditions.
Intestinal dysbiosis
An unnatural shift in the composition of the gut microbiota that may result from diet (e.g.,
high fat), psychological or physical stress, antibiotics, or radiation that is associated with an
imbalance between protective and harmful bacteria.
Human microbiota (microora)
Refers to the 10100 trillion microbial cells harbored by each person, primarily in the gut.
Human microbiome
The entire collection of genes found in all the microbes associated with a particular host.
Human metagenome
A metagenome is comprised of all the genetic elements of the host and all those of all the
microorganisms (microbiome) that live in or on that host.
http://dx.doi.org/10.1016/j.disamonth.2015.03.011
0011-5029/& 2015 Mosby, Inc. All rights reserved.
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B.A. Mizock / Disease-a-Month 61 (2015) 259290
Metagenomics
Metagenomics is the study of the collective genomes of the members of a microbial
community. It involves cloning and analyzing the genomes without culturing the organisms in
the community, thereby offering the opportunity to describe the hosts diverse microbial
inhabitants, many of which cannot yet be cultured.
Functional metagenomics
A technique directed toward connecting specic microbial phyla to specic functions in the
environment.
Prebiotic (functional ber)
A selectively fermented ingredient that allows specic changes both in the composition and
activity in the gastrointestinal microora that confers benets upon host well-being and health.
Probiotic
Live microorganisms that when administered in adequate amounts confer a health benet on
the host.
Synbiotic
Nutritional supplements combining probiotics and prebiotics in a form of synergism.
Medical food
A food administered under the supervision of a physician and intended for the specic
dietary management of a disease for which distinctive nutritional requirements are established.
Live cultures
Microbes associated with foods as food fermentation agents or starter cultures.
History of probiotics
Recognition of the relationship between gut health and human disease may be traced back to
Hippocrates (460370 BC) who stated: All diseases begin in the gut. The Old Testament
provided some of the earliest evidence suggesting that ingested bacteria could have a benecial
effect on health; it was stated that Abraham owed his longevity to the consumption of sour milk.
Research in the modern era began with Theodor Escherich, who in 1886 described the
relationship of intestinal bacteria to the physiology of digestion in the infant. In 1892, Ludwig
Doderlein proposed that microorganisms (lactobacilli) could be used to treat vaginal infections.
Eli Metchnikoff is considered the father of the probiotic concept. In his 1907 bookThe
Prolongation of lifehe proposed that colonic bacteria played a role in aging and adverse health
in adults (death begins in the colon). This theory grew of the observation that Bulgarian
peasants who consumed fermented milk foods had remarkable longevity; they had an average
life span of 87 years, with four of every 1000 living past 100 years. He postulated that the body
was slowly poisoned (autointoxicated) by toxins produced by proteolytic microbes in the
intestine that were responsible for aging. He further hypothesized that aging could be prevented
by modifying the gut ora with useful microbes obtained by consumption of sour milk and
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lactic acid-producing bacteria. Metchnikoffs experiments led him to believe that this bacterial
strain (which he called the Bulgarian bacillus) could successfully establish itself in the gut and
decrease the number of putrefactive bacteria, thereby delaying the aging process. To test this
hypothesis, he drank sour milk every day until his death at the age of 71 years. The organism
investigated by Metchnikoff was previously isolated by Stamen Grigoroff who demonstrated
how healthy bacteria in yogurt helped digestion and improved the immune system. This
organism was subsequently renamed Lactobacillus delbrueckii, subspecies bulgaricus. Unfortunately, there is little evidence that the probiotic concept was received with any enthusiasm in
the Western world. In 1908, Henry Tissier, a pediatrician working at the Pasteur Institute in Paris,
rst reported the isolation of Y-shaped bacteria (which he named Bidus) from the stool of a
breast-fed infant. He observed that Bidus was found in signicant numbers in the stool of
healthy infants, whereas children with diarrhea had low concentrations of this organism. Tissier
proposed that this organism could be used to treat infant diarrhea by displacing proteolytic
bacteria from the gut. Bidus was subsequently renamed Bacillus acidophilus because of its acid
tolerance.
In 1917, during World War I, Alfred Nissle isolated a nonpathogenic strain of Escherichia coli
from the stool of a soldier, who was one of a few who did not develop enterocolitis during a
severe outbreak of Shigellosis. This strain was named E. coli Nissle 1917 and was subsequently
used to treat gastrointestinal salmonellosis and shigellosis.
Minoru Shirota recognized the therapeutic potential of using bacteria to modulate
gastrointestinal microora. In 1930, he succeeded in isolating and culturing a Lactobacillus
strain capable of surviving the passage through the gastrointestinal tract. This bacterium was
named Lactobacillus casei strain shirota.
Several individuals have been credited with proposing the term probiotic. Werner Kollath in
1953 used the term Probiotika to describe active substances that are essential for a healthy
development of life. In 1964, Lilly and Stillwell used the term probiotic (for life) to describe
substances secreted by one microorganism that stimulate the growth of another. In 1989, Roy
Fuller proposed a denition that removed the term substances, which could have included
antibiotics. His denition of probiotic: a live microbial feed supplement that benecially affects
the host animal by improving its intestinal microbial balance, emphasized that probiotics must
be viable organisms. The most current denition of probiotic was proposed by the joint Food and
Agriculture Organization/World Health Organization Working Group in 2002. Their denition of
probiotic: live microorganisms that when administered in adequate amounts confer a health
benet on the host is currently favored. The term functional food was rst used in Japan in the
1980s, where there is a government approval process called Foods for Specied Health Use.
Functional foods can be considered as those, which are given a function beyond basic nutrition,
often related to health promotion or disease prevention, by adding new ingredients or more of
existing ingredients. Yogurt and other fermented milks containing probiotics (e.g., ker) may be
considered among the rst functional foods.
The term prebiotic is credited to Gibson and Roberfroid who dened a prebiotic as a nondigestible food ingredient that benecially affects the host by selectively stimulating the growth
and/or activity of one of a limited number of bacteria in the colon. This denition shares
characteristics with that of dietary ber. The term synbiotic is used when the functional food
contains both probiotics and prebiotics.
Ecology of gut microbiota

The healthy human intestinal microbiota is estimated at 1014 organisms, which collectively
encode 34 million genes, or approximately 150 times more than the human genome. This
microbial genome enables the microbiota to perform diverse metabolic activities that are not
encoded in the human genome and that are of benet to the host. These include extracting
energy and nutrients from food, vitamin biosynthesis, bile salt transformation, developing
innate and adaptive immunity, maintaining gut epithelial integrity, functioning as a barrier to
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colonization by microbial pathogens, and metabolism of drugs. Food degradation products that
humans cannot digest (e.g., cellulose or oligosaccharides) can be fermented into short-chain
fatty acids by enteric organisms, where they may be used as an energy source or have other
benecial effects. Fermentation is therefore a process that offers symbiotic benet to the host by
enabling utilization of a wider variety of foodstuffs. Alterations in composition of the gut
microbiota that are unfavorable to the host (dysbiosis) have been linked to a number of diseases
including inammatory bowel disease, Clostridium difcile infections, diabetes and obesity.
These will be discussed in further detail in a subsequent section.
The ecology of the gut microbiota changes with age. At birth in vaginally delivered infants,
the gut becomes colonized with organisms similar to its mothers vaginal ora. In contrast,
infants delivered by Cesarean section harbor bacterial communities that resemble those of the
skin such as Staphylococcus, Corynebacterium, and Propionibacterium species. The bacterial
inoculum provided by passage through the mothers vagina during delivery helps to colonize
the infants gut and establishes a microbiome that promotes the development of innate and
adaptive immunity. The lack of initial acquisition of this natural inoculum in babies delivered by
Cesarean section might account for observations of subsequent alterations in immunity in this
population that places them at higher risk for infection or atopic diseases. Benecial bacteria
such as Bidobacterium are also transferred to the infant from the mother during breast-feeding
and serve to colonize the infant gut. During the rst few years of life, diversity of the gut
microbiome increases rapidly in response to diet and illness. Administration of antibiotics in
infants appears to diminish the diversity of gut ora that in turn could have negative effects on
long-term health such as increasing the risk of developing asthma, allergy, and obesity.2 In
adulthood, the microbiome may continue to change, albeit at a slower rate than in childhood.
The microbiome of healthy elderly individuals is similar to younger persons; however, that of
frail elderly may be substantially different.1,3
The distribution of bacteria in the gut varies based on location. Bacterial density is low in the
stomach and duodenum, due to the presence of gastric acid and pancreatic enzymes. The density
increases in the distal small intestine (a mix of aerobes and anaerobes) and is greatest in the
large intestine where bacterial concentration rises to estimated 10111013 bacteria per gram of
colonic content, of which 99.99% are anaerobes.
It had been previously thought that the human intestinal microbiome contained
approximately 5000 species based on stool culture results. However, determining this
population using culture has signicant limitations. Development of molecular proling
techniques such as 16S rRNA gene sequence analysis indicated that approximately 6080% of
sequences did not conform to known cultured species of bacteria.4 Thus, a signicant proportion
of the numerically most abundant bacteria within the gut remain unstudied or unnamed. In
addition, stool analysis does not provide information about localized changes in the small bowel
and colon and is also not representative of organisms in the mucosal layer adjacent to the
intestinal epithelium. Although 16S rRNA gene sequence analysis is useful in identifying
bacterial species, it provides no information about bacterial physiology or metabolism. Newer
techniques involving genome sequencing of community DNA may be useful in this regard,
because they enable identication of certain bacterial genes that code for metabolic function.
This has given rise to the analytic technique called functional metagenomics.5
The presence of a core microbiota has been proposed by Arumagam et al.6 in which the
human gut microbiome falls into three distinct types or enterotypes. Each of the three
enterotypes is identiable by variation in the levels of one of the three main genera: Bacteroides,
(enterotype 1), Prevotella (enterotype 2), and Ruminococcus (enterotype 3). It was subsequently
proposed that fecotypes might be a more accurate descriptor than enterotypes due to variation
in the population and abundance throughout the gastrointestinal tract. In 2011, Wu et al.7
concluded that only enterotypes 1 and 2 were strongly supported by the data and that the
evidence for the Ruminococcus enterotype was lacking. They also observed that these two
enterotypes were associated with long-term diets; enterotype 1 (Bacteroides) with diets rich in
protein and animal fat, and Prevotella with simple carbohydrates. However, the existence and
biological signicance of distinct enterotypes has been the subject of much debate with some
263
investigators, favoring the concept of a continuum of species functionality rather than discrete
types.8 Studies in humans have demonstrated that gut microbial communities are highly
variable over time. A longitudinal study of four body sites in two individuals indicated marked
variability across months, weeks, and even days.9 This suggested that no core temporal
microbiome existed at high abundance. Rather than categorizing the intestinal microbiome
based on morphologic or culture criteria, it may be more informative to link microbial
composition to function. Therefore, although the population of individual bacterial species may
exhibit temporal variation, it is possible that groups of bacteria sharing a common metabolic
function (metabolome) are more consistently maintained.10 Thus, the functional attributes of a
bacterial community could be preserved despite changes in constituent species.
A healthy diet encourages the growth of microbes that are benecial to the host. One of the
essential ingredients of a gut healthy diet is that it is rich in certain substances that feed
desirable microbes in the colon. Important members of this food class include those containing
ber and resistant starch such as found in fruits, vegetables, legumes, or garlic. These foods resist
multiple digestive enzymes that are produced in salivary, gastric, and pancreatic secretions.
Consequently, they are not digested in the small bowel but undergo fermentation and further
metabolism in the cecum and proximal colon. Fermentable substances such as fructooligosaccharides or inulin are also available as dietary supplements or added to enteral feeding
formulas.
Metabolic cross-feeding is a phenomenon in which one species lives off the products of
another species in a synbiotic relationship.11 Soluble (e.g., oligosaccharides) and non-soluble
ber (e.g., cellulose) and resistant starch escape digestion in the small intestinal but are
fermented by saccharolytic bacteria such as Lactobacillus or Bidobacterium in the colon to form
pyruvate and lactate (Fig. 1). Butyrate and other short-chain fatty acids (SCFA) are synthesized
from pyruvate by anaerobic bacteria, with the major butyrate producers being Clostridium
clusters XIVa and IV (e.g., Roseburia and Faecalibacterium prausnitzii).12 Thus, direct stimulation
of fermentation by certain foods and prebiotic supplements may lead indirectly to increased
butyrate formation. In humans, butyrate is the preferred energy source for colonic epithelial
cells. Butyrate also inuences gene expression and inhibits the activation of NFkB, leading to
decreased expression of proinammatory cytokines and a consequent anti-inammatory
effect.13 Butyrate enemas have been used therapeutically in patients with predominately distal
ulcerative colitis.14
Intestinal dysbiosis, obesity, and diabetes

Intestinal dysbiosis can be dened as an unnatural shift in the composition of the gut
microbiota that is associated with an imbalance between protective and harmful bacteria. A
number of factors can promote intestinal dysbiosis including diet, underlying illness, antibiotics,
or radiation. Recent evidence suggests that alterations in the intestinal microbiota could play an
important role in the pathogenesis of obesity and its related diseases such as the metabolic
syndrome, type 2 diabetes, and non-alcoholic fatty liver disease.
Analysis of the gut microbiota in obese mice has revealed differences at the phylum level
when compared to lean animals, with greater numbers of Firmicutes than Bacteroidetes and less
diversity overall.15 Similar observations have been noted in obese humans.16 However, these
associations have not been found consistently, resulting in some uncertainty as to their
signicance. An important question is whether the microbiota common to the obese phenotype
actually contributes to the development or maintenance of obesity. Turnbaugh et al.17
investigated the effect of diet on intestinal microbiome of humanized mice in which fecal
microbiota from healthy adult humans was transplanted into germ-free animals. The mice were
initially fed a low-fat plant polysaccharide-rich diet and then switched to a Western diet high in
sugar and fat. The Western diet induced changes in the gut microbiome within a single day that
was characterized by an overgrowth of bacteria within the Firmicutes phylum as well as a
signicant reduction in several Bacterioidetes species. In addition, mice that were fed by the
264
Fig. 1. Intestinal bacterial fermentation and butyrate production.
Western diet had a signicant increase in adiposity within 2 weeks of feeding, compared to ageand gender-matched mice, consuming the low-fat polysaccharide-rich diet.
Although alterations in the gut microbiota have been implicated as a cause of obesity and the
metabolic syndrome, a high-fat diet may alter the intestinal microbiota independent of
obesity.18 In addition, the specic type of dietary fatty acid may be more important than total
calories from fat. Studies in mice have indicated that diets rich in omega-6 polyunsaturated fatty
acids (PUFAs) promote growth of pathobionts (resident microbes with pathogenic potential),
whereas diets supplemented with omega-3 PUFA can reverse such alterations.19
Various mechanisms have been proposed to explain the ability of the gut microbiome to
inuence obesity. They include (1) alterations of intestinal permeability with increased
translocation of bacterial products such as lipopolysaccharide (LPS), resulting in a low level of
chronic systemic inammation; (2) the ability of SCFA such as acetate and propionate to signal
via intestinal epithelial receptors; and (3) caloric salvage by some microbiota being more
efcient at making calories available from food.
In 2007, Cani et al.20 proposed that the gut microbiota plays a key role in the onset of lowgrade inammation associated with obesity and insulin resistance. Consumption of a high-fat
diet promotes translocation of lipopolysaccharide (via chylomicrons), originating from enteric
265
gram-negative bacteria to target tissues. This in turn triggers the secretion of proinammatory
cytokines (e.g., tumor necrosis factor, interleukin 1, and interleukin 6) from immune cells that
cause insulin resistance, hyperinsulinemia, and excessive hepatic and adipose tissue lipid
storage. This process was termed metabolic endotoxemia. With overfeeding or obese
conditions, a constant stimulus from nutrient intake results in a more consistently active
inammatory response. As the consequence of progressive activation of the systemic immune
response, insulin resistance becomes more prominent, and frank diabetes may result. In contrast
to the classical systemic inammatory response that is triggered by infection, this low-grade
chronic inammation occurs in the absence of infection. The term metainammation (i.e.,
metabolically triggered infection) has been proposed to describe this process.21
There are relatively few studies that couple changes in microbiota composition upon
probiotic supplementation with anti-obesity functions. In healthy overweight subjects,
administration of Lactobacillus gasseri SBT2055 resulted in reduction of abdominal visceral
and subcutatneous fat.22 The concept of using probiotics to treat obesity is intriguing, but
requires further conrmation.
Types of probiotics
Probiotics must be identied by their genus, species, and strain level. The majority of
probiotics in clinical use are species from three genera: Lactobacillus, Bidobacterium, and
Saccharomyces. Both Lactobacilli and Bidobacteria are saccharolytic bacteria that can ferment
carbohydrates to lactic acid that inhibits growth of pathogenic bacteria. In addition, pyruvate
produced from fermentation can be utilized by certain colonic anaerobes to produce benecial
SCFA. Lactobacilli are normally found in healthy gut but are present in relatively low numbers
even in individuals consuming probiotics. Lactobacilli are also found in the vaginal secretions of
healthy women. Some of the Lactobacilli commonly found in yogurt and probiotic supplements
include L. acidophilus, L. acidophilus DDS-1, L. bulgaricus, L. rhamnosus GG, L. plantarum, L. reuteri,
L. salivarius, L. casei, L. johnsonii, and L. gasseri. Bidobacteria are the constituents of normal gut
ora and can also be found in the vagina and oral cavity. Bidobacteria that are used as probiotics
include B. bidum, B. lactis, B. longum, B. breve, B. infantis, B. thermophilum, and B. pseudolongum.
Saccharomyces boulardii is the only yeast probiotic. It was previously identied as a unique
species of yeast but is now believed to be a strain of Saccharomyces cerevisiae (bakers yeast).
Commercially marketed probiotics are available either as single species or combination of
multiple species. Some of the more commonly used probiotics in the US are listed in the Table.
Probiotic mechanisms of action

There are a number of mechanisms of action for probiotics that confer potential benecial effects
on the gut23 (Fig. 2). By transiently colonizing the gastrointestinal tract, probiotics serve to correct
dysbiosis that contributes to underlying disease. This may occur as the consequence of colonization
resistance, a term that refers to the ability of certain bacteria to interact with gut epithelial cells to
prevent adherence of enteric pathogens to binding sites on the epithelial surface. Colonizing
probiotics may also exert a direct antimicrobial effect by secreting products such as bacteriocins that
inhibit the growth and virulence of enteric pathogens. Certain probiotics have been demonstrated to
increase the release of antibacterial peptides called defensins from Paneth cells (a type of epithelial
cell present in the crypts of the small intestine). Lactic acid-producing probiotics (e.g., Lactobacillus
spp. and Bidobacterium spp.) may exert an antimicrobial effect on pathogens by reducing the local
pH of the gut lumen. Some strains of probiotics have been discovered to interfere with quorum
sensing, a mechanism by which bacteria enhance their virulence.24 Probiotics have also shown the
ability to enhance the production of mucins from gut epithelial cells. Mucins serve as an
antibacterial barrier that prevent binding of pathogens. Probiotics promote the production of
secretory IgA in gut that binds to pathogens; they also exert an anti-inammatory effect in the gut
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Table
Common probiotic products.
Product
Contents
Activia yogurt (Dannon, Canada)
B. lactis DN-173 010

Z 100 Million live bacteria/gram
Align (Procter & Gamble)
Bi. infantis 35624

1 Billion CFU/capsule
Bacid (Erfa, Canada Inc.)
L. rhamnosus
1 Billion bacteria per capsule
Bio-K (Bio-K international)
L. acidophilus CL 1285, L. casei LBC80R

12.5 Billion/capsule (regular strength)
25 Billion/capsule (extra strength)
50 Billion/98 g bottle beverage
Culturelle (ConAgra Foods)
LGG
10 Billion bacteria 200 mg insulin/capsule
DanActive (Dannon, Canada)
L. bulgaricus, S. thermophiles, L casei

4 10 Billion L. casei/bottle
Florajen (American Lifetime, Inc., US)
L. acidophilus
20 Billion bacteria/capsule
Florastor (Biocodex)
S. boulardii
250 mg/capsule or packet
Howaru, Howaru Protect (Danisco)
L. acidophilus NCFM, B. lactis Bi-07

10 Billion bacteria/capsule or stick
5 Billion bacteria/tablet
Jamieson Probiotic Sticks (Jamieson Natural Sources, Canada)
L. helveticus and B. longum

1 Billion CFU/powder stick
Ker (Lifeway)
L. rhamnosis, L. plantarum, L. casei,

L. acidophilus,
L. reuteri, Leuconostoc cremoris,
Strep diacetylactis, S. orentinus, B. longum,
B. brevis, and B. lactis
710 Billion CFU/cup
Lactinex (Benton, Dickinson & Co.)
L. acidophilus and L. bulgaricus

1 Million CFU/tablet, 100 million CFU/packet
VSL#3 (Sigma-Tau Pharmaceuticals)
L. acidophilus, L. plantarum, L. paracasei,

L. bulgaricus, B. breve, B. infantis, B. longum,
and Strep thermophilus
450 Billion bacteria/packet
225 Billion per two capsules
Yakult (Yakult USA, Inc.)
L. casei Shirota
8 Billion active bacteria per 80 ml bottle
Adapted with permission from Pharmacists Letter/Prescribers Letter July 2012.
by preventing the activation of NFB (a proinammatory transcription factor) and IL-8 (a neutrophil
chemoattractant). Finally, it has been noted that some probiotics may activate opioid and
cannabinoid receptors in gut that could prove useful in ameliorating visceral pain, which is a
prominent feature in some patients with irritable bowel syndrome.
Therapeutic use of probiotics in specic diseases

A large number of studies have assessed the utility of probiotics in the prevention or
treatment of certain clinical conditions. However, at this point in time the results have been
267
Fig. 2. Probiotic mechanisms of action.
mixed. The diseases that currently have the strongest positive evidence are: antibioticassociated diarrhea, infectious childhood diarrhea, inammatory bowel disease (especially for
maintenance of remission in ulcerative colitis), and pouchitis. These conditions will be discussed
below; entities in which probiotic therapy is of potential value will also be reviewed. Current
consensus and societal practice guidelines for probiotic therapy will be summarized.
Diarrheal illnesses
Diarrheal illnesses are perhaps the best documented indication for probiotic therapy,
particularly in the pediatric population. The following discussion will focus on clinical trials and
meta-analyses that support the utility of probiotics in the prevention and/or treatment of
diarrhea. These clinical settings include Clostridium- and non-Clostridium-associated antibiotic
diarrhea, acute infectious diarrhea in children, and travelers diarrhea.
Antibiotic-associated diarrhea
Diarrhea is a common side effect of antibiotic use, ranging from 10% to 30% in the outpatient
setting to as high as 39% in hospitalized patients. Some authorities lump Clostridium-associated
antibiotic diarrhea (CDAD) with non-Clostridium difcile-associated antibiotic diarrhea (NCDAD),
while others classify these as separate entities. NCDAD has been dened as a benign, self-limited
diarrhea typically following the use of oral antimicrobials (especially amoxicillin/clavulanate).
Symptoms may begin as early as 24 h after the rst dose. Typically, no pathogens are identied
and the diarrhea is caused by changes in the composition and the function of the intestinal ora.
Most patients respond to supportive measures and discontinuation of antibiotics. In contrast,
CDAD diarrhea refers to a wide spectrum of diarrheal illnesses caused by the toxins produced by
268
this organism, including cases of severe colitis with or without the presence of pseudomembranes. CDAD accounts for 1025% of AAD, and the presence of a hypervirulent strain (NAP1/
027/B1) additionally increases the severity of the disease. The pathophysiology of CDAD and
colitis results from a disruption of the normal bacterial ora of the colon, colonization with C.
difcile, and the release of toxins that lead to mucosal damage and inammation. CDAD may
begin during antibiotic therapy or 510 days after the antibiotic is stopped. The antibiotics most
commonly associated with CDAD are the uoroquinolones, cephalosporins, carbapenems, or
clindamycin.
The most signicant studies of probiotics in prophylaxis of AAD have been in children, with L.
rhamnosus GG (LGG) and S. boulardii being the most effective agents. Vanderhoof et al.25 found
that administration of LGG concurrent with an oral antibiotic in children signicantly reduced
stool frequency and increased stool consistency during antibiotic therapy by the 10th day
compared with placebo. Kotowska et al.26 observed that when S. boulardii was administered in
conjunction with antibiotics for upper respiratory infection in children (aged 6 months to 14
years), 8% in the treatment group developed diarrhea versus 23% in the control group.
A Cochrane Database System Review in 2011 assessed the efcacy and safety of probiotics
(any strain or dose) used for the prevention of NCAD in children.27 Overall, 16 trials were
analyzed that included treatment with Bacillus spp., Bidobacterium, Lactobacilli, Saccharomyces,
or Streptococcus, either alone or in combination. Results from 15/16 trials showed a large benet
from probiotics compared to placebo or no treatment control. The incidence of diarrhea in the
probiotic group was 9% compared with 18% in the control group (RR 0.81). Subgroup analysis
showed high dose ( Z5 billion CFUs/day) is more effective than low dose.
The results of probiotic prophylaxis of AAD in adults have been somewhat mixed. Positive
results were found by Gao et al.28 who performed a study in adults assessing the dose-response
efcacy of L. acidophilus and L. casei for prophylaxis of NCDAD and CDAD. A total of 225 patients
were randomized to one of the three groups: two probiotic capsules/day, one probiotic and one
placebo/day, or two placebo capsules/day. Prophylaxis began within 36 h of initial antibiotic
administration and continued for 5 days after the last antibiotic dose. Patients were followed up
for an additional 21 days. Patients getting two probiotic capsules/day had the lowest incidence of
diarrhea. In addition, each probiotic group had a lower diarrhea incidence versus placebo. Ojetti
et al.29 studied the impact of L. reuteri supplementation in patients undergoing anti-Helicobacter
pylori (HP) therapy. The incidence of diarrhea was reduced in the probiotic-supplemented group
relative to those who did not receive the probiotic. Armuzzi et al.30 also found the benet of oral
administration of the probiotic LGG on antibiotic-associated gastrointestinal side effects during
HP eradication therapy.
A Cochrane review published in 2013 studied probiotics for the prevention of CDAD in adults
and children.31 A total of 23 trials were entered. The results demonstrated that probiotics
signicantly reduced the risk of diarrhea by 64% (2% incidence in the probiotic group compared
to 5.5% in the placebo or no treatment control group). It was concluded that moderate quality
evidence suggests that probiotics are both safe and effective for preventing CDAD.
Regarding treatment of CDAD, there is no good evidence that probiotics are efcacious either
as a primary therapy for CDAD or as an adjunct to standard antibiotic therapy for initial therapy.
A Cochrane Database System review in 2008 examined four studies that met inclusion criteria.32
Probiotics were administered in conjunction with conventional antibiotics for the treatment of
CD colitis in adults. Four studies were entered but were small and had methodological problems.
It was concluded that insufcient evidence existed to recommend probiotic therapy either as an
adjunct to antibiotic therapy or used alone for the treatment of C. difcile colitis.
Recurrent CDAD is dened as a return of signs and symptoms of CDAD along with a positive
stool test within a month of a successful treatment of an initial episode. Recurrent CDAD is
extremely difcult to treat and one recurrence increases the likelihood of further recurrences.
Treatment with oral metronidazole or vancomycin is increasingly associated with treatment
failures, and recurrence has been observed in up to 30% of patients after their rst episode and in
up to 60% after two or more recurrences. The emergence of a virulent strain of the organism
(NAP1/027/B1) has been associated with even higher rates of treatment failure. Probiotics have
269
shown promise as adjunctive therapy for preventing recurrent CDAD; clinical trials using S.
boulardii have provided the best evidence for efcacy. One of the largest trials was done by
McFarland et al.33 who studied 124 patients with active CDAD (64 patients had an initial episode
of CDAD and 60 had a history of at least one prior CDAD episode). Patients received standard
antibiotics and either S. boulardii (1 g/day) or placebo for 4 weeks and were followed up for an
additional 4 weeks after therapy. Effectiveness was based on the recurrence rate of CDAD. The
patients with CDAD who received standard antibiotics plus S. boulardii had a signicantly lowerrisk ratio of recurrence (RR 0.43) compared to placebo. The efcacy of probiotic therapy was
signicant in those with recurrent CDAD (19% versus 24%), but not in patients with the initial
episode of CDAD.
Practice guidelines for the prevention and treatment of AAD were provided by the Yale/
Harvard workshop in 2014.34 Probiotics were given a level A recommendation for effectiveness
in prevention of AAD. Specic strains of organisms most effective for this condition included S.
boulardii, LGG and a combination of L. casei DN114 G01, L. bulgaricus, and S. thermophilus. For
prevention of recurrent CDAD, S. boulardii, LGG and fecal bacteriotherapy (stool transplantation)
were given a level B/C rating. For prevention of CDAD, probiotics were given a level B/C rating;
LGG and S. boulardii are the most effective organisms.
The 2010 recommendations on probiotic therapy from the American Academy of Pediatrics
state: there is some evidence to support the use of probiotics to prevent AAD but no evidence
that it is benecial for treatment.35 A guideline from the AAP in 2013 stated: Because there is a
lack of controlled studies in children, probiotics are not recommended for either the prevention
or the treatment of C. difcile infection.
Prevention of travelers diarrhea
Up to 35% of the individuals who travel to developing countries may experience bouts of
diarrhea. Most cases occur within the rst 2 weeks of travel and last about 4 days. Regions with
the highest risk are Africa, South Asia, Latin America, and the Middle East. Bacteria are the most
frequent cause of travelers diarrhea (TD), and enterotoxigenic E. coli is the most common
pathogen. Up to 10% of the travelers who suffer from TD go on to develop persistent diarrhea and
about 10% eventually evolve to suffer from post-infectious irritable bowel syndrome.
Clinical data conrming the effectiveness of probiotics in preventing TD is relatively limited.
Nevertheless, prophylaxis of TD constitutes one of the largest markets for probiotics in Europe.
McFarland et al.36 performed a meta-analysis of 12 studies and found that probiotics
signicantly prevented TD (RR 0.85, p o 0.001). The yeast S. boulardii and a mixture of
Lactobacillus acidophilus and Bidobacterium bidum appeared to have the greatest efcacy. In
contrast, a meta-analysis by Takahashi et al.37 did not show that probiotics were effective in
preventing TD.
No practice guidelines for the use of probiotics in prophylaxis of TD are currently available.
Treatment of acute infectious diarrhea in children
A few probiotic strains have shown good evidence of efcacy in the treatment of acute-onset,
infectious diarrhea in children. This appeared to be particularly true for the treatment of
rotavirus-induced diarrhea, where early administration of probiotics showed efcacy. In
contrast, data demonstrating efcacy of probiotics in adults are sparse.
A 2010 Cochrane review examined studies that compared a specied probiotic agent with a
placebo or no probiotic in individuals with documented or suspected acute infectious diarrhea.38
A total of 63 randomized clinical trials met inclusion criteria; of these 56 recruited infants and
young children. Probiotics reduced the duration of diarrhea, although the size of the effect varied
considerably between studies. The signicant benecial effects related to the mean duration of
diarrhea (mean difference 24.8 h), reduction of diarrhea lasting Z 4 days, and reduced stool
frequency on day 2. It was noted that the difference in effect size between studies was not
explained by study quality, probiotic strain, the number of different strains, the viability of the
organism, dosage of organism, the causes of diarrhea, severity of diarrhea, or country where the
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study was performed. No adverse events were attributed to the probiotic intervention. The
review concluded When used in conjunction with rehydration therapy, probiotics appeared to
be safe and have clear benecial effects in shortening the duration and reducing stool frequency
in acute infectious diarrhea.
Szajewska et al.39 performed a meta-analysis of LGG for treating acute gastroenteritis in
children (an update of their 2007 meta-analysis). A total of 11 randomized clinical trials (RCT)
were entered. LGG signicantly reduced the duration of diarrhea compared with placebo or no
treatment (mean difference 1.05 days). Notably, LGG was more effective when used at a daily
dose Z 1010 CFU/day.
Despite the fact that probiotics appear to be benecial in acute infectious diarrhea, several
caveats should be mentioned: (1) the clinical relevance of such effect is moderate, because no
more than one day of reduction of diarrhea is to be expected, (2) only a few specic strains have
evidence-based proof of efcacy (e.g., LGG and S. boulardii), and (3) dosage is crucial; only doses
for LGG and S. boulardii mentioned above seem to be effective.
The 2014 Yale/Harvard workshop gave probiotics a level A rating for the treatment of
infectious childhood diarrhea in children (S. boulardii, LGG, and L. reuteri SD2112) and a level B
rating for prevention of infection (S. boulardii, LGG, and L. reuteri SD2112).34
The 2010 recommendations on probiotics and prebiotics from the American Academy of
Pediatrics state: there is some evidence in otherwise healthy infants and young children to
support the use of probiotics early in the course of diarrhea from acute viral gastroenteritis and
that use of probiotics reduces its duration by one day. However, the available evidence does not
support the routine use of probiotics to prevent infectious diarrhea unless there are special
circumstances.35
Inammatory bowel disease

Inammatory bowel disease (IBD) consists of two disorders: ulcerative colitis (UC) and
Crohns disease (CD). The key feature of IBD is chronic, uncontrolled inammation of the gut
mucosa. The central characteristic that distinguishes IBD from inammatory responses seen in
the normal gut is an inability to downregulate those responses, resulting in a chronically
inamed gut. Pathologically, CD is characterized by focal transmural inammatory lesions and
ulcerations that can be present anywhere in the gastrointestinal tract, whereas UC is more
supercial and limited to the colon, beginning in the rectum with proximal continuous
extension.
Genetics, dietary factors, and alterations in the gut microbiome play a pathogenetic role in
IBD. Evidence supporting a genetic basis for IBD includes familial clustering and racial and ethnic
differences in risk. A family history is present in 1020% of those aficted with IBD. Certain
genetic variants correlate with an increased risk of disease. Some of these variants (e.g., NOD2)
are involved in bacterial recognition as well as in innate and adaptive immunity. Variants
associated with IBD lead to disordered immune responses that in turn contribute to loss of
intestinal homeostasis. A dramatic rise in the incidence and prevalence of IBD has been noted
over the past 2 decades in Western Europe and North America. Epidemiologic studies have
noted a predominance of CD over UC in developed nations, notably in children. The typical
Western diet that is high in fat and simple sugars has been associated with IBD, due in part to
effects on the intestinal microbiome. Increased consumption of omega-6 fatty acids (e.g., corn
oil) and decreased intake of omega-3 fatty acids may also play a role. Breast-feeding may have a
protective effect on the development of IBD in childhood due in part on its benecial effects on
the developing microbiome.40
Although intestinal dysbiosis is generally recognized as playing a central role in the
pathogenesis of IBD, it remains to be determined whether it is the cause or consequence of IBD.
It is thought that the chronic inammatory state associated with IBD selects against benecial
commensal microbes in favor of those that are able to ourish in this environment. Many of
these opportunistic bacteria have properties that are highly proinammatory. The term
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pathobiont was introduced by Chow and Mazmanian41 to dene bacteria that are normally
symbiotic but have the potential to be pathologic under certain conditions, including IBD.
Human studies have indicated that patients with IBD have reduced diversity of the phylum
Firmicutes with a notable reduction in organisms that synthesize the anti-inammatory SCFA
butyrate (e.g., Clostridial groups IV and XIVa).42 An abundance of sulte-reducing bacteria have
also been observed in humans with IBD, and their metabolic product hydrogen sulde is toxic to
the colonic epithelium. Metagenomics studies have demonstrated functional alterations in IBD
that could also play a pathogenic role.43
Based on some of the alterations described above, an ideal probiotic would need to be a good
intestinal colonizer that produces high levels of butyrate levels at the site of action. Additionally,
utilizing a combination of a probiotic along with a prebiotic that stimulates butyrate production
might be more benecial than either agent alone.
Probiotics for induction and maintenance of remission in UC

Both small anecdotal trials and larger randomized controlled trials have shown efcacy with
two specic probiotics: VSL#3 (a combination probiotic containing B. breve, B. longum, B. infantis,
L. acidophilus, L. planetarium, L. paracasei, L. bulgaricus, and S. thermophilus) and E. coli Nissle
1917. A trial conducted by Sood et al.44 was one of the rst to show benet of a probiotic in
inducing remission in UC. VSL#3 or placebo was administered to patients with mild to moderate
active UC. At week 6, more subjects randomized to VSL#3 had at least a 50% decrease in the UC
Disease Activity Index (UCDAI) compared to placebo. By week 12, more subjects randomized to
VSL#3 achieved remission (43%) compared to placebo (16%). Furthermore signicantly more
patients given VSL#3 responded with a decrease in their UCDAI by at least three points
compared to placebo, and a greater proportion of subjects in the VSL#3 group achieved mucosal
healing (32%) compared to the placebo group (15%) by week 12. The authors speculated that
since the vast majority of VSL#3 users were concurrently on mesalamine, it is possible that
VSL#3 effectiveness is maximized when these agents are given together.
Tursi et al.45 performed a study of similar design but only 8 weeks duration. Subjects on
concomitant therapy (usually with mesalamine) with mildly to moderately active UC were
randomized to VSL#3 or placebo. The number of patients with a decrease in UCDAI scores of 50%
or more was greater in the VSL#3 group (63%) than in the placebo group (41%). However,
outcomes on endoscopic scores were not different between the groups. A trend toward greater
remission at 8 weeks was noted relative to placebo but did not reach statistical signicance.
Bibiloni et al.46 in an open-label study found that VSL#3 induces remission in patients with
active UC. A total of 34 patients were entered who received VSL#3 twice daily for 6 weeks. Intent
to treat analysis demonstrated remission in 53%, response in 24%, no response in 9%, worsening
in 9%, and failure to complete in 5%. No biochemical or adverse clinical events were noted. A
combined induction of remission/response rate of 77% was found and no adverse events were
reported.
Miele et al.47 investigated the effect of VSL#3 on induction and maintenance of remission in
children with UC. Overall, 29 patients, aged 1.716 years with newly diagnosed UC were
randomized to receive VSL#3 or placebo, in conjunction with steroid induction and mesalamine
maintenance treatment. On induction of remission, patients continued to receive concomitant
therapy of VSL#3 and mesalamine, or mesalamine and placebo for 1 year or until relapse. All 29
patients responded to induction therapy. Remission was achieved in 13 patients (92.8%) treated
with VSL#3 and mesalamine, and in four patients (36.4%) treated with placebo and mesalamine.
A total of 21% of patients treated with VLS#3 relapsed within 1 year while 73.3% treated with
placebo relapsed.
Kruis et al.48 compared E. coli Nissle 1917 with mesalamine regarding the ability to maintain
remission in UC. Over the course of 12 weeks, the relapse rate of the two agents was not
signicantly different (14% versus 16%). The same group subsequently performed a similar but
larger study lasting 12 months and again found a comparable clinical relapse rate (36%
versus 34%).
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Shen et al.49 performed a meta-analysis of 23 RCT of UC. A signicantly higher remission rate
in patients with active UC who were treated with probiotics was noted when compared to
placebo. Only VSL#3 signicantly increased the remission rates compared with controls in
patients with active UC. No signicant difference in adverse effects were detected between
probiotic and control subjects. It was concluded that maintaining remission of UC with
probiotics was as effective as with mesalamine and superior to placebo.
Fujiya et al.50 performed a meta-analysis that investigated the effects of probiotics on the
induction or maintenance of remission in IBD (UC and CD). A total of 20 RCTs were entered. In
patients with UC, probiotics decreased the disease activity, increased the remission induction
rate, and prevented relapse of disease as effectively as mesalamine. In addition, probiotic
therapy decreased the development of pouchitis in post-operative UC patients.
Mardini et al.51 performed a meta-analysis of 5 studies of patients with mild-moderately
active UC who were treated with VSL#3. A greater than 50% decrease in the UC disease activity
index was achieved in 44.6% of the VSL#3-treated patients versus 25.1% of the patients given
placebo (OR 2.8, NNT: 45). The response rate was 53.4% in VSL#3-treated patients versus
29.8% in patients given placebo (OR 2.4, NNT: 45). No serious side effects were reported. It
was concluded that VSL#3 (at a daily dose of 3.6 1012 CFU/day) added to conventional therapy
is safe and more effective than conventional therapy alone in achieving higher response and
remission rates in mild to moderately active UC.
Despite these promising ndings, a Cochrane analysis performed in 2011 concluded that
there was insufcient evidence to make conclusions about the efcacy of probiotics for
maintenance of remission in UC.52
Pouchitis
The surgical treatment of choice for patients with refractory UC is proctocolectomy with ileal
pouch-anal anastomosis (IPAA). The most common long-term complication after IPAA for UC is
inammation of the ileal reservoir, called pouchitis. Symptomatic manifestations of pouchitis
include increased stool frequency, rectal bleeding, urgency, tenesmus, incontinence, and
abdominal pain. The clinical diagnosis of pouchitis is usually conrmed by endoscopy. A
pouchitis disease activity index (PDAI) based on clinical symptoms and endoscopic and
histologic ndings has been developed to grade the severity of pouchitis. About half of the
patients who undergo IPAA will have at least one episode of pouchitis. About 60% of patients
suffer one or more recurrences, and 532% of them develop chronic pouchitis, which in turn
may require pouch excision in 10% of cases.
Pouchitis typically occurs only after the diverting ileostomy is closed and usually responds to
treatment with antibiotics. These observations suggest that alterations in the gut microbiome
play a pathogenic role that in turn could be amenable to treatment with probiotics. Dysbiosis in
pouchitis is characterized by a decreased ratio of anaerobic to aerobic bacteria and reduced fecal
concentrations of lactobacilli and bidobacteria.53
Several small RCT and a meta-analysis have provided evidence that probiotics are effective for
the prevention of pouchitis. Among the various probiotic agents, VSL#3 has been the most
extensively studied probiotic for prophylaxis. Gionchetti et al.54 performed a double-blind study
of 40 patients to compare the efcacy of VSL#3 with placebo in the maintenance treatment of
chronic pouchitis. At 9 months of follow-up, all 20 patients treated with placebo relapsed, while
17 of 20 patients treated with VSL#3 were still in remission. However, all of the 17 patients
relapsed within 4 months of suspension of active treatment. The same group performed a
double-blind RCT on the effectiveness of VSL#3 (at a daily dose of 1.8 1013 CFU) in the
maintenance of antibiotic-induced remission in patients with refractory or recurrent pouchitis
and found similar results.55 In a third study, treatment with high-dose VSL#3 (3.6 1012 CFU/
day) was administered for 4 weeks in patients with mild pouchitis (PDAI 7-12).56 At the end of
the study period, 69% of patients were in remission after treatment. This suggested that the high
doses of VSL#3 are effective in the treatment of mild pouchitis. Nevertheless, antibiotics remain
the treatment of choice for acute and chronic pouchitis.
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Mimura et al.57 studied 36 patients with at least two episodes of pouchitis in the previous
year who were randomized while in remission to either VSL#3 or placebo. Remission was
maintained in 85% of the VSL#3 group and in one patient (6%) in the placebo group.
Shen et al.58 studied 31 patients with antibiotic-dependent pouchitis. All patients
received 2 weeks of ciprooxacin followed by VSL#3 3.6 g/day for 8 months. At the 8-month
follow-up, six patients were still on VSL#3 therapy and the remaining 25 had discontinued
the therapy, due to either recurrence of symptoms while on treatment or development of
adverse effects. All the six patients who completed the 8-month course had repeat clinical
and endoscopic evaluation; these patients had a mean PDAI and endoscopy scores that were
not statistically different from baseline. Thus in this study, only a minority of patients with
antibiotic-dependent pouchitis remained on the probiotic therapy and in symptomatic
remission after 8 months.
Elahi et al.59 performed a meta-analysis investigating the benet of probiotics in preventing
pouchitis in the patients who underwent IPAA; 5 RCT were included. The primary outcome was
a PDAI Z 7. The results yielded an OR of 0.04 with a 95% CI of 0.010.14 (p o 0.0001) in the
treatment group compared to placebo, conrming the benet of probiotics in management of
pouchitis after IPAA.
The meta-analysis by Fujiya et al.50 found that probiotic treatment was useful for relieving
the disease activity, increasing the remission induction rate and preventing the relapse of
disease in UC patients as effectively as mesalamine and could decrease the development of
pouchitis in post-operative UC patients.
It appears therefore that the major benet for probiotics in pouchitis is in prevention and
maintenance of remission, while evidence for benet in treating acute pouchitis is less
compelling.
Crohns disease
In contrast to UC, there is a paucity of studies assessing the utility of probiotics for induction
of remission in CD. A 2006 Cochrane review concluded that there was no evidence to suggest
that probiotics are benecial for the maintenance of remission in CD.60 A subsequent Cochrane
review in 2008 also concluded that there was no evidence to support the use of probiotics for
induction of remission in CD.61
A number of studies have assessed the utility of probiotics in maintaining remission in CD.
Prantera et al.62 randomized 37 patients who had undergone ileocecal resection to treatment
with LGG or placebo. No difference in endoscopic or clinical recurrence was found.
Marteau et al.63 studied 98 patients with CD who had undergone resection within the prior
3 weeks. Patients were randomized to either L. johnsonii or placebo. No signicant difference in
endoscopic appearance at 6 months was found.
In a study by Van Gossum et al.,64 70 patients undergoing ileocecal resection of CD were
randomized postoperatively to either L. johnsonii or placebo. At 12 weeks, no difference in
endoscopic recurrence rates was found.
A meta-analysis by Fujiya et al.50 entered 20 RCTs that investigated the effects of probiotics
on the induction or maintenance of remission in IBD. No signicant effect of probiotic
treatments were shown in either the induction or maintenance of remission in CD.
Ghouri et al.65 performed a meta-analysis to assess the therapeutic effect of probiotics,
prebiotics, and synbiotics relative to placebo in patients with IBD. No signicant difference in
clinical outcomes in patients with CD was found. The authors concluded that there is insufcient
data to recommend probiotics for use in CD.
Updated practice guidelines for the use of probiotic therapy in patients with IBD were
provided by the Yale/Harvard Workshop in 2014.34 Probiotics had B-level evidence for inducing
remission in UC, and A-level evidence for maintenance of remission in UC. The best-studied
organisms were E. coli Nissle 1917 and VSL#3. Probiotic therapy of pouchitis in UC received an
A-level rating for preventing and maintaining remission, and a C-level rating for inducing
remission (VSL#3 was the most often studied probiotic agent). Since the majority of studies
274
failed to show a signicant difference for probiotics for maintenance of remission in CD, a C-level
rating was given for this indication.
The 2011 World Gastroenterology Organization guidelines gave level 1b recommendations
for three clinical settings in IBD: (1) for maintenance of remission in UC (E. coli Nissle 1917dose
5 1010 viable bacteria twice daily), (2) for treatment of mildly active UC or pouchitis (VSL#3
dose 29 1011 CFU twice daily), and (3) for prevention and maintenance of remission in
pouchitis (VSL#3dose of 24.5 1011 CFU twice daily).66
Irritable bowel syndrome

The Irritable bowel syndrome (IBS) is one of the more common disorders encountered by
clinicians. Prevalence estimates in North America range from 5% to 15%, with peak prevalence
occurring between 20 and 39 years of age. IBS affects 1.5 times more women than that of men
and is more common in lower socioeconomic populations. Although IBS does not predispose
patients to severe illness, it can profoundly affect the quality of life.
IBS is dened as an abdominal discomfort or pain associated with altered bowel habits for at
least three days per month in the previous three months, with the absence of organic disease.
IBS cannot be diagnosed by an objective test or biomarker. Therefore, diagnosis currently rests
entirely on clinical grounds. Symptoms relate to disordered bowel motility producing spasm,
visceral hypersensitivity, alterations in brain processing of pain, stress, and underlying
psychiatric disorders (e.g., anxiety). Low-grade mucosal inammation may also play a role in
the pathogenesis of visceral hypersensitivity and altered motility in IBS. Patients are divided
clinically into three symptom subtypes: diarrhea-predominant, constipation-predominant, and
a mixed presentation with alternating diarrhea and constipation. A prior history of an episode of
acute infectious gastroenteritis is associated with an almost four-fold increase in the odds of
developing IBS within the next 2 years.67
Alterations in the gut microbiome have been noted in patients with IBS based on fecal
cultures.68 The most consistent nding was instability of the fecal microbiota reecting a loss of
homeostasis in which the host is unable to maintain a healthy intestinal microbiota.
Advances in microbial analysis using gene-cloning techniques have provided valuable
information regarding the microbiome in IBS.68 Studies utilizing this methodology revealed
different alterations of microbial populations in the symptom subtypes. Those individuals with
the diarrhea-predominant subtype manifest the greatest deviation from healthy control, while
the constipation-predominant subtype has the least deviation. Functional analysis will likely
provide further insight into the interaction between microbiota and symptoms. For example,
organisms that produce large quantities of organic acids or suldes may be more likely to cause
abdominal pain and bloating.68,69
Animal studies have suggested that probiotics may inuence both visceral hypersensitivity
and dysmotility through a direct action by bacterial metabolites on sensitive nerve endings in
the gut mucosa or via indirect pathways that inhibit mucosal immune activation and visceral
sensitization.70 Trials of probiotics in IBS began in the early 2000s, and a large number of clinical
investigations followed. However, drawing conclusions from these studies has been confounded
by differences in study design, dose, and strain of probiotics. In addition, interpreting results is
difcult due to a large placebo response that often develops during the study. Therefore, clear
evidence of consistent benet is lacking.
A number of meta-analyses of probiotics in patients with IBS have been performed. Most
provide evidence for a benecial effect on abdominal pain and atulence, whereas probiotics
have an equivocal effect on bloating. Moayyedi et al.71 found a statistically signicant effect in
favor of probiotics over placebo in improving pain scores. Many of the trials entered utilized
combinations of probiotics, most often Bidobacteria and Lactobacilli. The meta-analysis
suggested that Bidobacteria constituted the active agent in the probiotic combinations studied.
A meta-analysis performed by Brenner et al.72 found that B. infantis 35624 promoted
signicant improvement in the composite score for abdominal pain/discomfort, bloating/
275
distention, and/or bowel movement difculty compared with placebo. No other probiotic
showed signicant improvement in IBS symptoms. The dose of B. infantis may be important;
administration of at least 108 CFU/day is required for a therapeutic response.
A 2014 monograph published by the American College of Gastroenterology concluded that
probiotics improve global symptoms, bloating, and atulence in IBS.73 However, the
recommendation was deemed to be weak based on low quality of evidence. Additionally, it is
likely that only some patients will respond. Regarding prebiotics or synbiotics, it was concluded
that there is insufcient evidence to recommend these agents in IBS.
The 2014 Yale/Harvard Workshop on probiotic use gave Bidobacterium infantis B35624 and
VSL#3 a level B rating in IBS, while Bidobacterium animalis and Lactobacillus plantarum 299V
were given a level C rating.34
The 2010 guidelines from the American Academy of Pediatrics stated: The sustained or longterm benet of using probiotics to treat disorders such as irritable bowel syndrome requires
further study; currently, use is not recommended in children.35
Allergic diseases
The clinical classication of allergy includes entities such as atopic dermatitis, allergic
asthma, allergic rhinitis, and food allergies. These diseases are quite common in children and in a
substantial proportion of adults as well. The International Study of Asthma and Allergies in
Childhood published in 2013 found that the global prevalence for current asthma,
rhinoconjunctivitis, and eczema in the 1314 year age group was 14.1%, 14.6%, and 7.3%
respectively, while in the 67 year age group the prevalence was 11.7%, 8.5%, and 7.9%.74
Evidence for an inverse association between infections in early life and allergic disease has
led to interest in the hygiene hypothesis as proposed by Strachan75 in 1989. In this hypothesis,
reduced microbial exposure due to improved sanitary conditions has made children more
vulnerable to develop atopic sensitization. In contrast, children with more exposure to microbes
in their environment (e.g., those who attend daycare centers or live on farms) have a lower
prevalence of allergic disease. It is believed that microbial exposures at an early age may activate
innate immune pathways, which in turn suppresses Th2 lymphocyte expansion and development of IgE antibodies. However, others have suggested that the hygiene hypothesis is unlikely
to be the sole explanation for the allergic diseases since asthma prevalence has begun to decline
in both children and adults in Western countries, but there is little evidence that sanitary
conditions in these countries has worsened. In addition, the decline in prevalence of asthma in
Western countries is not matched by a similar change in atopic eczema and food allergy, where
the prevalence continues to increase.76
A pediatric study indicated that children who later developed atopic sensitization had fewer
Bidobacteria, more Clostridia, and different bacterial cellular fatty acid proles in stool during
the rst few weeks of life.77 The gastrointestinal tract is typically the route for the initial allergic
responses, and food allergy is common in infants with atopic eczema. Breast-feeding exclusively
during the rst few months of life (o 4 months) has been shown to reduce the risk and severity
of eczema and asthma.78,79 It has been suggested that this effect relates to passage of commensal
bacteria from mother to infant through breast milk that in turn helps to establish and maintain
gut barrier integrity. By blunting the leaky gut, which results from a local inammatory
response to dietary antigens in predisposed individual, these bacteria reduce intestinal
absorption of sensitizing substances and promote immune tolerance.
Probiotics have been investigated both in prevention of immune sensitization (i.e., primary
prevention) and as a means to reduce symptoms after sensitization (secondary prevention).
Probiotics for primary prevention
Kalliomaki et al.80 studied 132 pregnant women with a family history of atopic disease. The
subjects were randomized to receive two capsules of either LGG or placebo daily for 24 weeks
prior to expected delivery. The mothers then either continued the treatment while breast-feeding
276
or administered the probiotic or placebo to their infants for 6 months. The primary endpoint was
chronic recurring atopic eczema. At 2 years of age, the frequency of atopic eczema of children in
the probiotic group was half that of the placebo group with a number needed to treat (NNT) of
4.5. A signicant reduction in the rate of atopic eczema was also seen in the infants who were
never directly given probiotics for the rst 3 months but were breast-fed (15% in probiotic group
versus 47% in the placebo group). It was concluded that LGG was effective in prevention of early
atopic disease in children at high risk.
In contrast, a study by Kopp et al.81 failed to nd benet of supplementation with LGG during
pregnancy (46 weeks before expected delivery) and early infancy (6 months) on the incidence
of atopic dermatitis. In addition, children treated with probiotics had an increased rate of
recurrent episodes of wheezing bronchitis.
Tang et al.82 performed a meta-analysis of studies that evaluated combined prenatal and
post-natal treatment and found a signicant protective effect with probiotic/prebiotic treatment
for both IgE- and non-IgE-associated eczema. Treatment with L. reuteri or a combination of B.
lactis BB12 and LGG both signicantly reduced sensitization in infants of allergic or sensitized
mothers. L. reuteri was also associated with a trend to reduced sensitization for all infants in the
treatment group. Administration of probiotics exclusively in the post-natal period appeared to
be much less effective than when administered prenatally or pre-and postnatally.83,84
Foolad et al.85 performed a meta-analysis of studies examining nutritional supplementation
in prevention and amelioration of atopic dermatitis among children younger than 3 years of age.
A total of 21 studies were analyzed. Nutritional supplementation was shown to be an effective
method to prevent atopic dermatitis or decreasing its severity. The best evidence for probiotics
appeared to be for supplementation with LGG to mothers and infants as a means to prevent the
development and reducing severity of atopic dermatitis.
A 2007 Cochrane meta-analysis included 12 studies that investigated probiotics administered
to infants for prevention of allergic disease and food hypersensitivity.86 The subjects who were
given probiotics had a signicant reduction in development of eczema (RR 0.82) but not food
hypersensitivity, asthma, or allergic rhinitis. However, due to signicant heterogeneity in the
studies, it was concluded that there was insufcient evidence to recommend the addition to
probiotics to infant feeds for prevention of allergic disease or food hypersensitivity. Another
Cochrane meta-analysis found that there was insufcient evidence to determine the role of
prebiotic supplementation of infant formula for prevention of allergic disease and food
hypersensitivity.87
Probiotics for secondary prevention

Attempts to treat allergic disease once manifested using probiotics have been less successful
than when used for primary prevention. Nevertheless, positive results were found in infants
with atopic eczema who received LGG.88
A 2008 Cochrane review of pediatric patients treated with probiotics for eczema included 12
studies.89 No signicant difference was found that would conrm the efcacy of probiotic
therapy in improving symptom scores or eczema severity. Subgroup analysis did not identify a
population with different treatment outcomes. It was concluded that probiotics are not an
effective treatment for eczema. In addition, probiotic treatment carries a small risk of adverse
events (infections and bowel ischemia). It was concluded that effective treatment of allergic
disease is ideally initiated during infancy.
The American Academy of Pediatrics guidelines on probiotics concluded that although the
results of some studies support the prophylactic use of probiotics during pregnancy and
lactation and during the rst 6 months of life in the infants who are at risk of atopic disorders,
further conrmatory evidence is necessary before a recommendation for routine use can be
made.35 The AAP recommendations also stated: Prebiotics and probiotics are generally
recognized as safe for healthy infants and children. However, probiotics should not be given to
children who are seriously or chronically ill until the safety of administration has been
established. Long-term health benets of probiotics in the prevention of allergy beyond early
277
infancy remain to be proven. Questions remain regarding the optimal duration of probiotic
administration as well as preferred microbial dose and species. It also remains to be established
whether there is signicant biological benet in the administration of probiotics during
pregnancy and lactation, with direct comparison to potential biological benet derived from
probiotic-containing infant formulas.35
The 2014 Yale/Harvard workshop gave probiotic therapy to treat atopic eczema associated
with cows milk allergy a grade A rating (LGG or B. lactis are the most effective agents).34
Atherosclerosis
Atherosclerosis is the most important cause of cardiovascular diseases, and among the
leading causes of death worldwide. Pathologically, atherosclerosis is characterized by
accumulation of cholesterol and macrophage recruitment to the arterial wall. It can therefore
be considered both a metabolic and an inammatory response in the in the vascular
endothelium.
The pathogenesis of atherosclerotic vascular disease is not entirely known. An intriguing
hypothesis involves a central role of the gut microbiome in metabolizing elements contained in
high-fat foods to an end product that is highly atherogenic90 (Fig. 3). The key features of this
hypothesis includes the following elements: (1) high-fat foods contain increased quantities of
phosphatidylcholine, choline, and L-carnitine, which are substrates for synthesis of trimethyamine (TMA); (2) the gut microbiome of the individuals who chronically consume high-fat diet
is altered, favoring species that more efciently produce TMA from these substrates; (3) TMA
subsequently undergoes hepatic metabolism to trimethylamine-N-oxide (TMAO); and
Fig. 3. Pathway linking high-fat diet to atherosclerotic cardiovascular disease. TMA: trimethylamine, TMAO:
trimethylamine-N-oxide.
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(4) elevated plasma TMAO levels are associated with an increased risk of incident major adverse
cardiovascular events in humans. The atherogenic mechanism of TMAO appears to involve its
ability to inhibit macrophage reverse cholesterol transport.90 Probiotics may prove effective in
preventing atherosclerosis by targeting this pathway. Animal data has shown that administration of L. rhamnosis or L. paracasei probiotics decreased TMAO levels.91
Some of the more impressive clinical data of probiotics in cardiovascular disease were
published by Jones et al.92 who evaluated the cholesterol-lowering efcacy of a yogurt
formulation containing microencapsulated bile salt hydrolase-active L. reuteri NCIMBB 30242
taken twice daily over 6 weeks in hypercholesterolemic adults. Overall, 114 subjects completed
the double-blind RCT. Over the intervention period, subjects consuming the probiotic yogurt
attained signicant reductions in LDL-C of 8.92%, total cholesterol of 4.8%, and non-HDL
cholesterol of 6% compared to placebo. A drop in the atherogenic lipoprotein apoB-100 of
0.19 mmol/L was also observed. A second study performed by Jones et al.93 investigated the
cholesterol-lowering efcacy and mechanism of action of L. reuteri NCIMBB 30242 capsules
(200 mg/day) in hypercholesterolemic adults. A total of 127 subjects completed the study. L.
reuteri reduced LDL cholesterol by 11.6%, total cholesterol by 9.14%, non-HDL cholesterol by
11.3%, and apoB-100 by 8.4% relative to placebo. Triglyerides and HDL were unchanged. Highsensitivity C-reactive protein and brinogen were reduced by 1.05 mg/L and 14.25%, respectively.
This study also explored potential mechanisms of action of L. reuteri. One mechanism involves
the ability of L. reuteri to deconjugate bile via bile salt hydrolase (BSH). This in turn results in
increased fecal excretion of deconjugated bile salts with a compensatory increase in the
utilization of cholesterol to produce new bile acids. Mean plasma deconjugated bile acids were
found to be increased by 1.0 nmol/L relative to placebo in this study.
DiRienzo94 reviewed clinical trials that examined the effects of probiotics on LDL-C in order
to explore their potential as a therapeutic agent. A total of 26 clinical studies and two metaanalyses were reviewed. Of the probiotics examined, L. reuteri NCIMB 30242 was found to best
meet therapeutic lifestyle change dietary requirements by: (1) signicantly reducing LDL-C and
total cholesterol with robustness similar to that of existing TLC (therapeutic lifestyle changes,
dietary options). (2) improving other coronary heart disease risk factors such as inammatory
biomarkers, and (3) being generally recognized as safe. Based on these results, the authors
concluded that L. reuteri NCIMB 30242 is a viable candidate for both future dietary studies
and as a potential option for inclusion in dietary recommendations in patients with
hypercholesterolemia.
Although probiotics hold promise in prevention and treatment of cardiovascular disease,
there are currently no societal guidelines supporting their use.
Bacterial vaginosis and vulvovaginal candidiasis

The normal vaginal mucosa is colonized mainly by Lactobacillus species (e.g., L. crispatus and
L. jensenii) but other bacteria may also be present, albeit in lower numbers. However, the
population of the vaginal microbiota is not constant and may undergo a variety of changes
depending in age, pregnancy, sexual activity, and medications such as antibiotics. This in turn
may result in vaginal dysbiosis, resulting in clinical conditions such as bacterial vaginosis (BV)
and vulvovaginal candidiasis (VVC).
BV refers to overgrowth of one of the several types of bacteria normally present in the vagina,
thereby upsetting the natural balance (vaginal dysbiosis). Species such as Gardnerella and
Atopobium have been implicated in BV. BV is predominately seen in premenopausal women,
especially during pregnancy. BV differs from VVC in that there is no inammatory reaction with
the former. Nevertheless, there is often an overlap in symptoms between the two conditions.
The reported incidence of BV ranges from 5% to 50%. Common local symptoms include vaginal
discharge, dysuria, and pruritus. More serious complications include ascending infections (e.g.,
pelvic inammatory disease), obstetrical complications (e.g., chorioamnionitis and premature
birth), as well as with urinary tract infection. BV is usually treated with oral or intravaginal
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antibiotics (e.g., metronidazole) but is often associated with treatment failure and high rates of
recurrence, especially over the long term. BV recurs in up to 40% within 3 months and in up to
50% within 6 months after initiation of antibiotic therapy. VVC (vaginal thrush) is the excessive
growth of yeast in the vagina that results in irritation. Both acute and recurrent VVC are
common. The prevalence of VVC is difcult to determine because the clinical diagnosis is often
based on symptoms and not conrmed by microscopic examination or culture. Many women
have an identiable cause of VVC such as antibiotics, pregnancy, uncontrolled diabetes, or
immunosuppression. However, one-third to half of the recurrent VVC cases have no obvious
cause.95
Observations that the women who suffer from BV or VVC have depleted levels of Lactobacillus
species prompted trials, investing the use of oral or intravaginal probiotic Lactobacillus strains for
treatment and prevention. The mechanism by which orally consumed probiotics are effective is
thought to involve entry into the vagina, following excretion from the rectum. Intravaginal
administration of probiotic suppositories enables direct replacement of the unhealthy vaginal by
probiotic bacteria. The mechanism of action of probiotics is multifactorial and appears to involve
production of lactic acid (which maintains low pH), bacteriocins, and hydrogen peroxide.
Two approaches for the treatment of BV with probiotics have been used: treatment with
probiotics alone or administration of probiotics following a conventional regimen of antibiotic
treatment (adjuvant therapy). Most of the studies using probiotics for treatment administered a
vaginal suppository containing various Lactobacillus species, most commonly L. acidophilus, L.
rhamnosus, or L. reuteri RC-14, given from 5 days to 4 weeks. The best results occurred when
probiotics were used as adjuvant therapy, where better cure rates of symptomatic BV were
found as well as diminished frequency of recurrences during 16 months of follow-up.96
In contrast to BV, there is a lack of good studies supporting the effectiveness of lactobacillus
in treating VVC. Ehrstrom et al.97 performed a RCT assessing the efcacy of vaginal colonization
with probiotics and effects on clinical outcome. A total of 45 women with diagnosed VVC were
entered. Patients were randomized to vaginal capsules containing multiple Lactobacillus species
or placebo for 5 days, following completion of conventional treatment. Lactobacillus strains were
present 23 days after administration in 89% of women receiving the probiotic capsule. Less
recurrences and less malodorous discharge were noted. Hilton et al.98 performed an unblinded
crossover trial of probiotic yogurt in 33 women with a history of VVC. Daily consumption of
probiotic yogurt reduced recurrences. However, interpretation of the results was limited by
small size and high dropout rate.
In summary, it appears that in BV and VVC, the preferred route of administration of probiotics
is intravaginal. Although the evidence supporting the use of probiotics in VVC is not as strong as
BV, the empirical use of probiotics may be considered in women with frequent recurrence of
VVC or in those with contraindications to antifungal agents.
The 2014 Yale Workshop on probiotic use gave a Level C recommendation for the use of
probiotics (L. acidophilus, LGG, and L. reuteri) for the treatment of BV.34
The 2012 UK guidelines for the treatment of BV suggest that probiotics can be considered for
the treatment of relapsed BV but no recommendations could be made.99
Colorectal cancer
The incidence of colorectal cancer (CRC) is increasing in all Western countries and in many
developing countries. CRC cancer is found in 5% of population in the US and ranks second only to
lung cancer as a cause of mortality. Certain types of CRC have an inherited basis. However,
sporadic CRC is much more common, representing 8590% of all forms of CRC. It appears that
environmental factors such as high intake of animal fat (especially red meat and processed
meat) and a low intake of ber and sh play a role in the pathogenesis of CRC. Recent research
has suggested an association between intestinal dysbiosis and colorectal carcinoma, thus raising
the question, could colon cancer be considered a bacteria-related disease?100 Bacteria that
have been found to be more abundant in stools of patients with CRC compared with healthy
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controls include anaerobes such as Bacteroides and Clostridium species and sulfur-reducing
bacteria. Enterococcus, Escherichia, Shigella, Klebsiella, Streptococcus, and Peptostreptococcus have
also been reported to be present in increased quantities in stool of patients with CRC.101 High
levels of fecal bile acids have also been associated with higher CRC risk in humans. Bacterial
genome sequencing techniques have added further evidence, strengthening the association of
CRC with alterations in the normal gut microbiome.
Tjalsma et al.102 have proposed that CRC can be initiated by driver bacteria that are
eventually replaced by passenger bacteria that promote tumorigenesis. Bacterial drivers in CRC
can be dened as intestinal bacterial with pro-carcinogenic features that may initiate CRC
development by producing carcinogenic factors such as DNA-damaging compounds. Candidate
drivers include members of Enterobacteriaceae. Bacterial passengers are dened as gut bacteria
that are relatively poor colonizers of a healthy intestinal tract but have a competitive advantage
in the tumor microenvironment, allowing them to outcompete bacterial drivers of CRC. The
initial drivers of this process may therefore disappear with time as they are outcompeted by
passenger species. Fusobacterium spp. and other potentially pathogenic bacteria such as
Salmonella, Citrobacter, and Shigella are considered as passenger bacteria.
The importance of diet in promoting CRC is well recognized. Schulz et al.103 demonstrated
that administration of a high-fat diet to mice caused dysbiosis that promoted intestinal
carcinogenesis that was independent of obesity. High saturated fat intake appears to alter the
intestinal microbiota that in turn favors the production of bacterial metabolites (e.g., hydrogen
sulde, ammonia, and reactive oxygen species) that are genotoxic and promote mutations.
Numerous species of lactic acid-producing bacteria have been shown to possess cancerpreventing attributes. Animal studies have investigated mechanisms by which lactic acid
bacteria prevent or slow progression of CRC. Potential mechanisms include a reduction in
aberrant crypt foci, enhanced apoptosis of damaged cells, inactivation of carcinogenic
compounds, competition with pathogenic microbiota, improvement of the hosts immune
response, fermentation of undigested food, inhibition of tyrosine kinase signaling pathways, and
antioxidant effects.104 L. reuteri may prevent CRC by downregulating NFB-dependent gene
products that regulate cell proliferation and survival.105 Lactobacillus and Bidobacterium contain
bile salt hydrolases that blunt the carcinogenic effects of bile acids produced as the consequence
of a high-fat diet. Animal models of CRC have indicated that the efcacy of probiotics in
preventing tumorigenesis varies, depending on the time of administration.106 The optimal
effects occur if the probiotic is given prior to the carcinogen or early following administration.
Dietary ber and prebiotics (especially inulin and oligofructose) also play a role in protection
against development of CRC.106 Proposed mechanisms include a reduction in transit time of
feces in the gut, absorption of bile salts and bacterial toxins, and anticarcinogenic effects of the
prebiotic metabolite, butyrate.
Human data regarding the effect of probiotics in preventing or treating CRC are more difcult
to interpret due to heterogeneity between studies. Supportive evidence has been reported in
clinical studies where probiotics or synbiotics have been used to prevent CRC, reduce postoperative complications, decrease toxicity related to therapy, and improve quality of life. Rafter
et al.107 investigated the effects of dietary synbiotics on cancer risk factors in polypectomized
and CRC patients. Administration of a synbiotic preparation containing L. rhamnosus, B. lactis,
and inulin resulted in a signicant change in fecal ora with a decrease in C. perfringens. This in
turn reduced colorectal cellular proliferation and improved epithelial barrier function in
polypectomized patients. Genotoxic assays of biopsy samples also indicated favorable changes.
The Italian Yogurt trial investigated the potential benecial effects of yogurt in prevention of
CRC.108 This trial was a large prospective study of 45,000 volunteers of the EPIC-Italy cohort who
completed a dietary questionnaire, including questions on yogurt intake. The investigators found
that yogurt intake was inversely associated with CRC risk. The hazard ratio for CRC in the highest
versus the lowest tertile of yogurt intake was 0.62. The protective effect of yogurt was noted to
be stronger in men than that of women. It was concluded that high yogurt intake was
signicantly associated with decreased CRC risk, suggesting that yogurt should be part of a diet
to prevent the disease.
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Redman et al.109 performed a meta-analysis of the efcacy and safety of probiotics in people
with cancer. A total of 11 studies were included. Probiotics signicantly reduced the incidence of
common toxicity criteria (CTC) grade Z 2 diarrhea, reduced the incidence of CTC grade Z 3
diarrhea, and may have reduced the average frequency of daily bowel movements and need for
anti-diarrheal medication. However, the authors cautioned that most of the evidence was not
clinically convincing.
In summary, there is considerable animal and human evidence that suggests that dietinduced alterations in the gut microbiome contribute to the development of CRC. Furthermore,
in vitro studies and animal models demonstrate that probiotics, prebiotics, and synbotics have
therapeutic potential in preventing CRC. However, the data obtained from human studies is not
strong enough to justify a recommendation that these agents should be used in prevention or
therapy of CRC or other gastrointestinal malignancies.
To date, there are no existing societal guidelines that recommend the use of probiotics in the
prevention or treatment of CRC.
Critical illness
Critical illness especially in the setting of ischemia, tissue injury, or antibiotic therapy
promotes intestinal dysbiosis; as a result, the protective effect of benecial commensal bacteria
on the gut epithelium (colonization resistance) is diminished. These alterations in the gut
microbiome may be linked to increased morbidity and mortality. Under conditions of extreme
stress and nutrient deprivation, activators of virulence gene expression (quorum sensing) are
turned on in opportunistic pathogens such as Pseudomonas aeruginosa.110 Binding of
pathogenic bacteria to the intestinal epithelium activate a local inammatory response with
release of pro-inammatory mediators. This in turn promotes increased permeability of the
intestinal epithelium due to alterations in the tight junctions between enterocytes. The resulting
enteritis facilitates the passage of luminal antigens into the portal circulation that activates
hepatic macrophages and promotes a systemic inammatory response that can lead to multiple
system organ failure. Meakins and Marshall111 characterized the inammatory response in gut
as the motor of the multiple organ failure syndrome.
Administration of probiotics has been investigated as a means of improving outcome
(especially by reducing hospital-acquired infections) in the setting of organ transplantation,
major abdominal surgery, and severe trauma. Administration of probiotics is potentially
benecial by improving barrier function and restoring normal intestinal permeability. Probiotics
may also be benecial by producing antimicrobial molecules, by lowering intestinal luminal pH
through formation of lactic acid, or by interfering with quorum sensing in bacterial pathogens.
Several probiotics have been investigated in the setting of critical illness, with the majority of
studies utilizing various species of Lactobacillus. However, it is unclear whether one species is
superior to another since existing studies are often of small sample size, comprised of differing
ICU populations, and have utilized a variety of administration techniques.
One area in which probiotics have been extensively investigated is prevention of respiratory
infection in mechanically ventilated patients. Ventilator-associated pneumonia (VAP) complicates the clinical course in up to 30% of critically ill patients and is a major cause for increased
length of ICU stay, as well as increased costs. Randomized controlled studies of probiotics as a
preventative measure in VAP have used a variety of probiotics but most contained Lactobacillus
species (e.g., L. plantarum, L. rhamnosus, and L. casei). The majority of the trials showed a trend
for decreased incidence of VAP in the probiotic group but a signicant difference was found only
in a few.112114
Meta-analyses also have provided variable results. Siempos et al.115 performed a metaanalysis of ve randomized controlled trials and found that probiotic therapy was benecial in
terms of reduced incidence of VAP (OR 0.61), length of ICU stay, and colonization of the
respiratory tract with Pseudomonas aeruginosa. However, no difference was found regarding ICU
mortality, in-hospital mortality, or duration of mechanical ventilation. Gu et al.117 performed a
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meta-analysis of seven trials and found that probiotics did not signicantly decrease the
incidence of VAP.116 However, the authors cautioned that rm conclusions from the results could
not be made due to heterogeneity among study designs. In a subsequent study, the same authors
performed a meta-analysis of effects of probiotics on outcomes of trauma. The use of probiotics
was associated with a reduction in the incidence of nosocomial infections (RR 0.65), VAP, and
length of ICU stay. No effect on reducing mortality was seen. Petrof et al.118 performed a
systematic review of 23 RCTs and found that probiotics were associated with reduced infectious
complications in 11 trials. Seven trials reported data on VAP and the VAP rate was also
signicantly reduced with probiotics. Probiotics had no effect on ICU or hospital length of stay.
As with the previous meta-analyses, clinical and statistical heterogeneity precluded rm
recommendations.
Probiotics have also been investigated as a means of preventing post-operative infection. The
most promising results were in patients undergoing liver transplantation or elective upper
gastrointestinal surgery.119 Perioperative provision of probiotics and synbiotics resulted in a
three-fold reduction in post-operative infection.
Despite the fact that probiotics have been proven to be safe in healthy patients, concern has
been raised regarding the safety of probiotics in critically ill patients, immunocompromised
patients (including transplant), and premature neonates. Theoretical risks include the risk of
dissemination and systemic infection, as well as the potential to transfer antibiotic resistance
genes. Issues regarding administration of probiotics to patients with acute pancreatitis will be
discussed below (see Therapeutic considerations).
The Canadian Clinical Practice Guidelines recommended that the use of probiotics should be
considered in critically ill patients.120 However, no recommendation for dose or a particular type
of probiotic could be made with the exception of S. boulardii, which should not be used as it is
considered unsafe in ICU patients. The Canadian guidelines also stated that addition of probiotics
to enteral nutrition is associated with a reduction in overall infectious complications and a trend
toward a reduction in the incidence of VAP. Guidelines provided in 2009 by The Society of
Critical Care Medicine and American Society for Parenteral and Enteral Nutrition stated that
administration of probiotic agents has been shown to improve outcome, most consistently by
decreasing infection in specic critically ill patient populations such as transplantation, major
abdominal surgery, and severe trauma (grade C level of evidence).121 However, no
recommendation can currently be made for the use of probiotics in the general ICU population
due to lack of consistent effect on outcome. The guidelines further added that no
recommendation can currently be made for use of probiotics in patients with severe acute
necrotizing pancreatitis, based on the disparity of evidence in the literature and the
heterogeneity of the bacterial strains utilized.
Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from noninammatory accumulation of fat in hepatocytes to hepatic steatosis with inammation
(steatohepatitis) that may have associated brosis. It is now the most common cause of liver
disease in Western countries. The prevalence of NAFLD has risen rapidly in parallel with the
increase in diabetes and obesity, and accumulating evidence supports an association with the
metabolic syndrome. The reported prevalence of NAFLD varies between 20% and 30%, with
values approaching 90% in patients with morbid obesity.
The pathogenesis of NAFLD relates in large part to obesity and insulin resistance in which an
increased hepatic inux of free fatty acids (FFA) occurs. These FFA form triglycerides, leading to
hepatic fat accumulation. FFA can be hepatotoxic by increasing oxidative stress and activating
inammatory pathways thereby causing steatohepatitis.
Several studies have provided evidence that supports the relationship between obesity and
associated changes in the intestinal microbiome with insulin resistance and NAFLD.
Experimental evidence has suggested that dysbiosis leads to increased permeability of the
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intestinal epithelial barrier due to direct effects on tight junctions as well as loss of protective
commensals such as Bidobacterium. This in turn results in increased ux of proinammatory
molecules via the portal circulation to the liver. Hepatic inammation appears to be mediated by
inammasomes, which are intracellular protein complexes expressed in hepatic cells that
regulate responses to pathogens and stress. Inammasomes and IL-18 appear to inuence the
progression from NAFLD to steatohepatitis; they also induce changes in the gut microbiome that
promote development of the metabolic syndrome.122
Regulation of intestinal microbiome by using probiotics and prebiotics has been explored
as a treatment of NAFLD. The rationale for the use of probiotics stems from their ability to
maintain gut epithelial barrier integrity and reduce the production of proinammatory
cytokines. Loguercio et al.123 studied patients with either NAFLD or alcoholic liver cirrhosis
and compared them to HCV positive patients with chronic hepatitis (with or without
cirrhosis). All of the subjects were treated with VSL#3 for 3 months followed by another
month of washout in an open-label fashion without controls. Plasma levels of transaminases
improved signicantly in all subjects after treatment with VSL#3, with the effect being
maintained after washout in the NAFLD, chronic hepatitis, and alcoholic cirrhosis groups.
Eslamparast et al.124 studied the effects of a synbotic supplementation in patients with
NAFLD. The subjects received either a twice-daily supplement of a synbiotic containing
multiple probiotics plus fructooligosaccharide or placebo for 28 weeks. At the end of the
study, alanine aminotransferase (ALT) decreased in both groups, with the reduction being
signicantly greater in the synbiotic group. Tumor necrosis factor, NF-kappaB (NFB), and a
brosis score were also lower in the synbiotic group.
Vajro et al.125 performed a study of probiotics in obese children with NAFLD. Subjects were
treated with LGG or placebo for 8 weeks. A signicant decrease in ALT with normalization was
observed in 80% of subjects in the probiotic group. Aller et al.126 studied 30 adult patients with
NAFLD (diagnosed by liver biopsy) who were either given L. bulgaricus, S. thermophilus, or
placebo for 3 months. They found that probiotic therapy resulted in improved liver
aminotransferases (ALT, AST, and gammaglutamine transferase) in patients with NAFLD.
Malaguarnera et al.127 studied the effect of administration of synbiotic therapy in patients
with non-alcoholic steatohepatitis. A total of 66 patients were randomly divided into two groups
receiving either B. longum with fructooligosaccharide and lifestyle modication (diet and
exercise) versus lifestyle modication alone. Liver biopsies were performed at entry and
repeated after 24 weeks of treatment. At the end of study, the synbiotic group showed
signicant differences in AST, LDL cholesterol, CRP, TNF, insulin resistance, steatosis, and the
steatohepatitis (NASH) activity index.
Ma et al.128 performed a meta-analysis of effects of probiotics on NAFLD. Four randomized
trials involving 134 NAFLD/NASH patients were included. The results showed that probiotic
therapy signicantly decreased ALT, AST, total cholesterol, HDL, TNF, and insulin resistance. The
use of probiotics was not associated with changes in BMI, glucose, and LDL. The authors
concluded that probiotic therapies can reduce liver aminotransferases, total cholesterol, TNF, and
improve insulin resistance in NAFLD patients.
The 2012 practice guideline by the American Association for the Study of Liver Diseases, the
American College of Gastroenterology, and the American Gastroenterological Association made
no mention of probiotics as a therapeutic agent in NAFLD.129 It is therefore difcult to make rm
therapeutic recommendations regarding the utility of probiotics in NAFLD. Future conrmatory
studies may strengthen the recommendations for probiotics as a therapeutic agent in NAFLD.
Radiation enteritis
Pelvic malignancies are commonly treated with radical modes of radiation therapy (RT).
Patients at risk include those with malignancies of the rectum, bladder, cervix, pancreas,
prostate, vulva, and uterus. Acute gastrointestinal side effects occur in over 70% of patients,
while up to 30% of patients experience chronic effects, notably diarrhea.
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RT causes intestinal dysbiosis, as well as decreased absorptive surface for nutrients, and
decreased gut transit time; the consequence is signicant malabsorption of various nutrients
and malnutrition. A study of pelvic RT in gynecological cancer utilized pyrosequencing (a
method of DNA sequencing) to assess the effects of RT on the overall composition and alterations
of the gut microbiota.130 Signicant differences were found between the RT patients and healthy
controls. RT markedly reduced the numbers of species-level taxa as well as the abundance of
each community. Notably, the phyla Firmicutes and Fusobacteria were signicantly reduced, and
dysbiosis was linked to health status.
There have been a number of recent RCTs investigating the utility of probiotics in
amelioration of radiation-induced small bowel disease.131133 These studies assessed the effect
of probiotics on the acute rather than chronic effects of pelvic RT. Probiotic agents that have
shown promise include VSL#3, LGG, and a combination of L. acidophilus and B. bidum. In
addition to the type and dose of probiotic, the time of initiation (e.g., 12 weeks before RT) and
duration of treatment may prove to be important in establishing and maintaining a favorable gut
microbiome, thereby mitigating adverse effect of RT on the gut. The major benet of probiotic
therapy appears to be an improvement in diarrhea and decreased use of anti-diarrheal
medication.
Several meta-analyses have been performed to assess the efcacy of probiotics in prophylaxis
of radiation enteritis. All were limited by signicant heterogeneity between studies. The metaanalysis by Wedlake et al.134 assessed the efcacy of nutritional interventions (elemental, low
fat, high ber, low lactose, and probiotics) to counteract acute gastrointestinal toxicity during
therapeutic pelvic RT. The authors concluded that although probiotics offered promise,
insufcient high-grade evidence existed to recommend nutritional intervention during pelvic
RT. A meta-analysis performed by the Mucositis Study Group reviewed studies of agents for the
management of gastrointestinal mucositis in cancer patients.135 The panel concluded that
probiotic treatment containing Lactobacillus species might be benecial for the prevention of
chemotherapy and RT-induced diarrhea in patients with pelvic malignancies. Hamad et al.136
performed a meta-analysis of probiotics for prevention of radiation-induced bowel disease after
RT. Four outcomes were analyzed: incidence of diarrhea, loperamide use, watery, and soft stools.
The pooled OR for incidence of diarrhea signicantly favored the use of probiotics over control.
They concluded that probiotic supplementation demonstrates a probable benecial effect in
prevention, and a possible benet in the treatment of radiation-induced diarrhea.
The 2014 recommendations of the Yale/Harvard Workshop gave probiotics a level C rating for
prophylaxis of radiation enteritis (preferred agents: VSL#3, L. acidophilus).34
Therapeutic considerations for probiotic use

Risks of probiotic therapy
Currently marketed probiotics have a long track record of safety. However, there may be
minimal risk in certain situations that relates to the quality of the product rather than to the
probiotic per se. One of the more commonly mentioned safety concerns of probiotic therapy is
sepsis. The cases of sepsis that have been associated with probiotics containing Lactobacilli or
Bidobacteria have been reported but are rare. Administration of probiotics to immunosuppressed (e.g., HIV, premature infants, the elderly, and inammatory bowel disease) has been a
topic of concern, but even in this setting, the incidence of sepsis is quite low. Avoidance of S.
boulardii probiotics in patients with central venous catheters or synthetic cardiac valve
replacement has been recommended based on several reports of fungemia.137
Another concern relates to the potential for transfer of antibiotic resistance from probiotics to
the indigenous gut microbiota. However, the risk appears to be minimal with currently available
probiotics.
Much concern relating to probiotic therapy was generated by publication of the PROPATRIA
trial published in Lancet in 2008.138 This study investigated the effect of probiotic prophylaxis in
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predicted severe acute pancreatitis. An increased mortality was observed in the patients who
received the multispecies probiotic (Ecologic 641) relative to placebo that was attributed to
bowel ischemia. Another possible explanation for this outcome is that more patients in the
probiotic group had established organ failure at the time treatment began. The journal
subsequently published an expression of concern related to major shortcomings in the design,
approval, and conduct of the study. Nevertheless, the results should provoke caution when
probiotic administration is being considered in certain groups of critically ill patients.
Probiotics for health
The consumption of food and supplements containing live bacteria for general health
purposes has long been popular in Northern Europe, perhaps due to the tradition of consuming
fermented foods such as yogurt. The consumption of probiotics drinks is also very popular in
Japan. In the US, interest in probiotic supplements is increasing due in part to the use of
probiotics to treat common disease such as IBS as well as media ads promoting the health
benets of consuming probiotic yogurt.
Probiotics hold interest for two main groups: those with underlying disease where data
supporting the therapeutic effect of specic probiotics is available (e.g., UC) and a second group
that is interested in probiotics to improve their general health (e.g., to improve gut health and
immune function). In 1948, the World Health Organization dened health as a state of complete
physical mental and social well-being and not merely the absence of disease or inrmity. This
denition that has yet to be revised and has been criticized because it leaves no room for
improvement. It would therefore be impossible for probiotics to have any signicant benecial
effect in those who are already healthy. Since there are no clear markers of health, it is difcult to
provide hard evidence documenting benecial effects of probiotics in improving general health
status. Nevertheless, some manufacturers have made claims regarding their products that are
unsubstantiated by clinical research, and national health agencies often demand retraction of
these claims. Fortunately for the consumer, probiotics are considered generally recognized as
safe by the FDA, so there is little risk of adverse effects in healthy individuals. The individual
who consumes probiotics for general health should therefore take comfort in the fact that
probiotics are not likely to be harmful and may confer unspecied benecial benets on
digestive or immune health. However, they should also be aware that the effects of probiotics are
strain specic and any positive effects depend on the preparation chosen and also on the dose. In
addition, a reputable brand should be selected since some probiotics currently available do not
contain adequate amounts of viable bacteria or may contain other bacteria that are not listed on
the label. Consultation with their primary provider or a dietician may facilitate choosing the
optimal product.
Microencapsulated probiotics
One of the major problems associated with delivery of viable probiotic bacteria to the gut is
surviving transit through the hostile environment of the stomach. The technique of microencapsulation has been effective in reducing probiotic destruction by gastric acid.139 This
process involves surrounding probiotic bacteria by a coating to produce microcapsules, which
are resistant to degradation by gastric acid, thereby improving the ability to colonize the gut.
Microencapsulated probiotic bacteria have been shown to be ve times more efcient than nonencapsulated strains in colonizing the gut.139 In addition, microencapsulation may be effective in
improving shelf-live stability of probiotic strains.
Clostridium probiotics
One of the problems that probiotic bacteria encounter is surviving in the anaerobic
conditions of the colon, while remaining stable in the aerobic conditions of the environment
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(e.g., on the shelf). This may be the reason many probiotic products are consumed in
association with fermented and dairy food products. Certain Clostridial bacteria (e.g., C. coccoides
and C. leptum groups) populate the healthy human gut and are able to form spores that enable
survival in diverse environments. Spores would be stable on the shelf and also would be likely
to survive transit through the stomach. Once they reach the colon, they germinate and evolve
into metabolically active vegetative cells that can survive in the anaerobic environment of the
colon. Unfortunately, there is little data in humans, although the probiotic C. butyricum MIYAIRI
588 has been approved for use in Europe as a supplement to animal feed.140 Experimental data
has shown this probiotic to be protective against AAD and to antagonize pathogenic effects of E.
coli 0157:H7, and C. difcile.141143 Certain Clostridial species have anti-inammatory effects that
could be effective in treatment of IBS.140
Engineered probiotics
Bioengineered probiotics are usually lactic acid bacteria that have been genetically modied
to serve as delivery vectors for therapeutic proteins. One of the mechanisms underlying the
pathogenesis of IBD involves abnormally high proteolytic activity. Research in animals has
indicated that L. lactis or L. casei can be programmed to deliver protease inhibitors (e.g., elan) to
the gut mucosa, thereby inhibiting local inammation.144 These bacteria have also been
programmed to deliver antioxidant enzymes to the gut mucosa, thereby reducing oxidative
stress.145 Engineered probiotics have also been used to improve self-tolerance in autoimmune
diseases such as type 1 diabetes by delivering autoantigenic peptides through the intestinal
mucosa.146 E. coli Nissle 1917 has been modied to produce a lipid compound normally
synthesized in the small intestine in response to feeding that reduces food intake and weight
gain.147 Probiotic bacteria could also be engineered to function as a vaccine or as a delivery
vehicle for therapeutic drugs.
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Disease-a-Month 61 (2015) 259290

Contents lists available at ScienceDirect

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Ecology of gut microbiota

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Intestinal dysbiosis, obesity, and diabetes

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Fig. 1. Intestinal bacterial fermentation and butyrate production.

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Probiotic mechanisms of action

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Activia yogurt (Dannon, Canada)

B. lactis DN-173 010

Align (Procter & Gamble)

Bi. infantis 35624

Bacid (Erfa, Canada Inc.)

Bio-K (Bio-K international)

L. acidophilus CL 1285, L. casei LBC80R

Culturelle (ConAgra Foods)

DanActive (Dannon, Canada)

L. bulgaricus, S. thermophiles, L casei

Florajen (American Lifetime, Inc., US)

Howaru, Howaru Protect (Danisco)

L. acidophilus NCFM, B. lactis Bi-07

Jamieson Probiotic Sticks (Jamieson Natural Sources, Canada)

L. helveticus and B. longum

L. rhamnosis, L. plantarum, L. casei,

Lactinex (Benton, Dickinson & Co.)

L. acidophilus and L. bulgaricus

VSL#3 (Sigma-Tau Pharmaceuticals)

L. acidophilus, L. plantarum, L. paracasei,

Yakult (Yakult USA, Inc.)

Adapted with permission from Pharmacists Letter/Prescribers Letter July 2012.

Therapeutic use of probiotics in specic diseases

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Fig. 2. Probiotic mechanisms of action.

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Inammatory bowel disease

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Probiotics for induction and maintenance of remission in UC

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Irritable bowel syndrome

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Probiotics for secondary prevention

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Bacterial vaginosis and vulvovaginal candidiasis

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Non-alcoholic fatty liver disease

B.A. Mizock / Disease-a-Month 61 (2015) 259290

B.A. Mizock / Disease-a-Month 61 (2015) 259290

Therapeutic considerations for probiotic use

B.A. Mizock / Disease-a-Month 61 (2015) 259290