S104 • CID 2008:46 (Suppl 2) • Snydman
S U P P L E M E N T A R T I C L E
The Safety of Probiotics
David R. Snydman
Division of Geographic Medicine and Infectious Diseases and Department of Medicine, Tufts–New England Medical Center, and Tufts University
School of Medicine, Boston, Massachusetts
Probiotics are generally defined as microorganisms that, when consumed, generally confer a health benefit
on humans. There is considerable interest in probiotics for a variety of medical conditions, and millions of
people around the world consume probiotics daily for perceived health benefits. Lactobacilli, bifidobacteria,
and lactococci have generally been regarded as safe. There are 3 theoretical concerns regarding the safety of
probiotics: (1) the occurrence of disease, such as bacteremia or endocarditis; (2) toxic or metabolic effects on
the gastrointestinal tract; and (3) the transfer of antibiotic resistance in the gastrointestinal flora. In this
review, the evidence for safety of the use of or the study of probiotics is examined. Although there are rare
cases of bacteremia or fungemia related to the use of probiotics, epidemiologic evidence suggestsnopopulation
increase in risk on the basis of usage data. There have been many controlled clinical trials on the use of
probiotics that demonstrate safe use. The use of probiotics in clinical trials should be accompanied by the
use of a data-safety monitoring board and by knowledge of the antimicrobial susceptibilities of the organism
Lactobacilli have a long history of safe use in foods and
dairy products . There is a natural association of
lactobacilli with human flora, and lactobacilli arefound
in animals as well as plants . Lactic acid bacteria
have traditionally been used in fermented milks and by
different societies around the world for the treatment
of intestinal disturbances, especially in children .
Rarely, lactic acid bacilli will cause infection in humans,
which has manifested as either bacteremia or endocar-
ditis, particularly in immunocompromised hosts [4–9].
Lactobacilli fall into the category of organisms clas-
sified as “generally regarded as safe” . Organisms
that are generally regarded as safe include lactobacilli,
lactococci, Bifidobacterium, and yeast. There are other
probiotic organisms, such as Enterococcus, Bacillus, and
other spore-forming bacteria, as well as streptococci,
that are not generally regarded as safe but have been
used as probiotics. In this review, I will focus on the
Reprints or correspondence: Dr. David R. Snydman, Box 238, Tufts–NewEngland
Medical Center, 750 Washington St., Boston, MA 02111 (DSnydman@tufts-
Clinical Infectious Diseases 2008;46:S104–11
? 2008 by the Infectious Diseases Society of America. All rights reserved.
data regarding the safety of probiotics. In addition, I
will pay particularattentiontothesafetyofLactobacillus
rhamnosis GG (Lactobacillus GG), given that this is the
organism for which the most extensive number of hu-
man studies have been published [11–15]. It is also the
organism that our group is currently pursuing in a
series of research studies .
Table 1 provides the list of human populations in
which Lactobacillus GG has been studied and in whom
there is evidence of safety [11–15, 17–24]. The popu-
lations studied include pregnant women,prematurene-
onates, elderly individuals, children with rotavirus di-
arrhea, children and adults hospitalized with diarrhea,
malnourished children from Peru, patients with rheu-
matoid arthritis, adults with Crohn’s disease, adults
with Helicobacter pylori infection, and adults with Clos-
tridium difficile–associated diarrhea. There are also a
number of studies in which the safe use of other pro-
biotics has been studied [25–30] (table 2). One subject
of these studies has been the use of Lactobacillus casei
Shirota to treat critically ill children. There are a num-
ber of studies of adults with C. difficile–associated di-
arrhea and the use of probiotics. The organismsstudied
in this context include Lactobacillus plantarum, Sac-
charomyces boulardii, and Lactobacillus acidophilus plus
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Probiotic Safety • CID 2008:46 (Suppl 2) • S105
ied and has shown evidence of safety.
Populations in whom Lactobacillus GG has been stud-
Children with rotavirus diarrhea
Finnish and other tourists
Malnourished Peruvian children
Patients with rheumatoid arthritis
Adults with Crohn’s disease
Adults with Helicobacter pylori infection
Adults with Clostridium difficile–associated diarrhea
Populations in whom safe use of other probiotics has
Critically ill children (Lactobacillus casei Shirota)
Patients with Clostridium difficile–associated diarrhea (Lactobacil-
lus plantarum, Saccharomyces boulardii, and Lactobacillus aci-
dophilus plus Bifidobacterium)
Patients with Crohn’s disease (Lactobacillus johnsonii LA 1,
Adult women with urinary tract infections
Children attending day care
Liver transplant recipients (L. plantarum 299V)
Adults in the intensive care unit (L. plantarum 299 V)
Patients with liver failure (L. plantarum 299 V)
Patients with rotavirus diarrhea (Bifidobacterium lactis BB-12, Lac-
tobacillus reuteri SD 2222, and many others)
Patients with necrotizing enterocolitis (L. acidophilus, Bifidobacter-
Patients with HIV infection–associated diarrhea (S. boulardii)
Adults with diarrhea (S. boulardii, L. casei, Streptococcus thermo-
philus, Bacillus bulgaricus, L. acidophilus)
Adults with antibiotic-associated diarrhea (L. plantarum, S. boular-
dii, L. acidophilus, B. bulgaricus)
Patients with bacterial vaginosis and candida vaginitis (Lactobacil-
lus fermentum RC-14 plus Lactobacillus rhamnosus GR-1, L.
Patients with Helicobacter pylori infection (many)
Patients with irritable bowel syndrome (many)
Bifidobacterium. Studies have been performed in patients with
Crohn’s disease, employing a wide array of agents, including
Lactobacillus johnsonii LA1 and VSL#3 (VSL Pharmaceuticals).
There have been a large number of studies of the prevention
and treatment of urinary tract infections in adult women, as
well as of children attending day care, in whom the occurrence
of both respiratory illness and diarrhea has been examined[31–
35]. L. plantarum 299V has been studied in liver transplant
recipients, adults in the intensive care unit, and adults with
of studies of treatment of rotavirus diarrhea, including treat-
ment with Bifidobacterium lactis (BB-12), Lactobacillus reuteri
SD 2222, and many other probiotics [39, 40]. S. boulardii has
been studied in patients with HIV-associated diarrhea and in
adults with diarrhea and antibiotic-associated diarrhea[41,42].
Intervention with probiotics in the treatment of bacterial va-
ginosis and vaginal candidiasis has also been well studied, with
include Lactobacillus fermentum (RC-14), L. rhamnosis GR-1,
and L. plantarum [43, 44]. Many agents have been studied in
patients with H. pylori infections, as well as in patients with
irritable bowel syndrome [45–47].
THEORETICAL ADVERSE RISKS OF
There are some theoretical adverse risks that have been raised
with respect to the use of probiotics in humans [2, 3, 48–52].
These theoretical risks include the potential for transmigration
and the fact that colonization with probiotics may have a neg-
ative impact on gastrointestinal physiology and function, in-
cluding metabolic and physiologic effects [1,3,49].Therecould
also be adverse immunologic effects, both localized and gen-
eralized [1, 50]. Finally, there is also the potential forantibiotic-
resistance transfer within the gastrointestinal tract from com-
mensal or probiotic bacteria to other bacteria or potential
pathogens [3, 53].
icity due to transmigration, there is no evidence that probiotics
have more adhesive properties than do clinical strains [10, 54].
There are a number of studies in animal models that dem-
onstrate that there is no increase in the translocation of other
bacteria when probiotics are given . In addition, probiotics
mitigate the transmigration of pathogens during their use .
There are some human studies showing that patients who are
taking probiotics are actually less likely to have transmigration
than are those who are not . Animal evidence suggests that
there is actually a reduction in the translocation of other bac-
teria, as opposed to the transmigration of probiotic bacteria
into the bloodstream. There is no evidence, from population-
based studies, of any increased risk of bacteremia or endocar-
ditis due to probiotics . There is also no evidence of any
negative impact on the permeability of gut proteins in studies
performed both in animals and in humans .
Bacteremia and endocarditis potential.
lactic acid bacteria, including bifidobacteria, have been isolated
as causes of bacteremia and also as causes of endocarditis [5–
8, 49, 59, 60]. The list of organisms that have been associated
with endocarditis or bacteremia includes L. rhamnosis, L. plan-
tarum, L. casei, Lactobacillus paracasei, Lactobacillus salivarius,
With respect to potential tox-
We do know that
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S106 • CID 2008:46 (Suppl 2) • Snydman
L. acidophilus, and many other lactobacilli . In addition,
Lactococcus lactis and Leuconostoc species, as well as Pediococcus
species have been demonstrated to cause bacteremia and en-
docarditis. Bifidobacterium species have also been isolated from
the blood and in patients with endocarditis . Enterococcus
species, of course, are well known as causes of bacteremia and
With respect to sepsis related to probiotics, there have been
3 reports of Lactobacillus GG–associated bacteremia in children
with short gut syndrome, 2 cases of bacteremia in children who
have central venous catheters, 1 case of endocarditis, and 1 case
of a liver abscess [6, 7, 60, 63, 64]. In addition, there has been
a case of endocarditis caused by a strain of L. rhamnosis whose
subspecies could not be completely specified. There have been
5 cases of bacteremia associated with Bacillus subtlis .There
has also been a case of L. acidophilus bacteremia in a patient
who had HIV infection and Hodgkin disease  and a case of
Lactobacillus infection after a bone marrow transplant .
Among the cases of Lactobacillus GG bacteremia in patients
with short gut syndrome, 4 occurred in 3 separate events [6,
8, 58]. All of the cases were characterized by the presence of
central venous catheters and intestinal feeding tubes. Two of
the isolates were verified by PFGE as being Lactobacillus GG,
and 1 was verified by both PFGE and PCR as beingLactobacillus
GG. One of the isolates was not specifically verified as being
Lactobacillus GG. Two of the 4 cases involved central venous
catheter infections, and 2 had positive catheter culture results.
These reports underscore the possible risk of Lactobacillus GG
bacteremia related to the short gut syndrome. The source of
the organisms might have been contamination of central ve-
nous catheters during manipulation, especially during feeding.
Data from surveillance in Finland suggest that there was no
increase in Lactobacillus bacteremia during the decade 1990–
2000 . Lactobacilli represented 0.02% of all positive blood
cultures. There was no temporal change over the decade. An-
other study from the National Public Health laboratory dem-
onstrated that lactobacilli were present in 0.24% of positive
blood cultures referred to the laboratory . Although these
cultures were reported to have lactobacilli, 27% could not be
confirmed. Lactobacillus GG accounted for 11 of the 26 L.
rhamnosis strains that were recovered from the blood. L. rham-
nosis constituted 54% of all the lactobacilli that were isolated.
The absence of any change in the prevalence of Lactobacillus
bacteremia and, specifically, the absence of a change in Lac-
tobacillus GG bacteremia is remarkable, given that the con-
sumption of Lactobacillus GG increased in Finland from 1 L
per person per year to 6 L per person per year over the period
Of the 89 cases of Lactobacillus bacteremia in Finland from
1990 to 2000, 53% had species identification ; 25 had L.
rhamnosis confirmed, and 22 had otherlactobacilli.Elevencases
were indistinguishable from Lactobacillus GG by PFGE. None
of these cases was associated with endocarditis. Most of the
patients had serious comorbidities. Appropriate therapy was
shown to improve survival . Mortality appeared to be as-
sociated with the severity of underlying illness.
Lactobacillus bacteremia in Sweden was examined over a 6-
year period, during which time there was an introduction of
3 probiotic strains into clinical use . The probiotics studied
were L. paracasei paracasei, L. acidophilus NCFB 1478, and
Lactobacillus GG. There was no change in the rate of lacto-
bacillemia, and no case in which Lactobacillus was isolatedfrom
the blood stream was identified as being related to the probiotic
strains. The authors of the study recognized that most cases of
lactic acid bacteremia are actually polymicrobial.
There have, however, been cases of sepsis related to pro-
biotics. The most prominent have been associated with S. bou-
lardii [68–72]. There have been 16 reports of candidemia, en-
compassing 23 patients. Some of these patientsdevelopedseptic
shock. Many of the cases had some degree of molecular iden-
tification and confirmation of the probiotic strain [73, 74].
Gastrointestinal toxicity studies.
tential impact of the use of probiotics on gastrointestinal phys-
iology, there is the possible production of metabolites that
might be undesirable, especially in patients with short small
bowel syndrome . There is a theoretical risk that the pro-
biotic bacteria might lead to malabsorption due to deconju-
gation of bile salts . This might, therefore, increase the risk
of colon cancer . However, there is no epidemiologic or
clinical evidence to support this hypothesis , and there are
experimental data to demonstrate some inhibitory effect of
probiotics for colon cancer in animal models [79, 80].
Among the additional potential toxicities, there is also a the-
oretical possibility that d-lactate production might occur, with
the development of lactic acidosis . Studies have been per-
formed in healthy humans with an ileostomy. L. acidophilus
and Bifidobacterium species have been shown to transformcon-
jugated bile acid into nontoxic secondary salts . In patients
with short small bowel syndrome, it is possible that the con-
jugated bile acid metabolites might accumulate and lead to
malabsorption . This might lead to the risk of the lactate
accumulation and a theoretical risk of colon cancer. There is
also the theoretical possibility that there may be degradation
of intestinal mucus . However, in studies both in vitro and
in gnotobiotic rats, there is no evidence that probiotics will
degrade intestinal mucus [50, 84].
Studies suggest that probiotics may modulate the immune
response of individuals and boost response to vaccines or alter
the natural history of the allergic response. Probiotic bacteria
can modify humoral, cellular, and nonspecific immune re-
sponses and may have an impact on the local secretion of
cytokines as well as the local immune response . It is thought
With respect to the po-
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Probiotic Safety • CID 2008:46 (Suppl 2) • S107
that some of these responses are strain specific and host specific
. The role of intestinal microflora in immune development
suggests that a theoretical possibility exists that manipulations
caused by probiotics could have an adverse immunomodula-
tory effect. An additional population in which a theoretically
adverse immunologic impact might be postulated is pregnancy.
However, the use of probiotics during pregnancy, in neonates,
and in children has not been associated with any adverse im-
munologic effects [18–21, 23–25, 30, 51, 52, 85].
been the potential for antibiotic-resistance transfer in the gas-
trointestinal tract that might take place between probiotics and
pathogenic bacteria [53, 86]. When one examines the potential
for transferable antibiotic resistance in lactic acid bacteria, one
can find the presence of plasmids with antibiotic-resistance
genes, including genes encoding resistance to tetracycline,
erythromycin, chloramphenicol, and macrolide-lincosamide-
streptogramin . These resistance plasmids have been found
in L. reuteri, L. fermentum, L. acidophilus, and L. plantarum in
raw meat, silage, and feces of animals . Streptomycin re-
sistance, tetracycline resistance, and chloramphenicol resis-
tance, as well the plasmid mef 214, have been found in L. lactis
in raw milk and soft cheese. Tetracycline resistance has been
found in L. plantarum 5057 .
The transfer of native Lactobacillus plasmids is quite rare. Lac-
tose fermentation plasmids have been transferred toL.casei.
is some evidence that Leuconostoc species and Pediococcusspecies
can accept broad-host-range antibiotic-resistance plasmids from
Lactococcus species . Conjugation transfer from enterococci
to lactobacilli and lactococci can occur in the gut of animals, as
well as in vitro; however, the transfer to lactobacilli is quite rare
[86, 92]. There have been some attempts to transfer antibiotic
resistance with a broad-host-range plasmid pAMB. Of 14 strains
of Lactobacillus delbrueckii, 44 strains of L. acidophilus, 1 strain
of Lactobacillus helveticus, 1 strain of Lactobacillusbrevis,6strains
of L. casei rhamnosis, 5 strains of L. plantarum, and 1 strain of
L. fermentum, only 1 strain each of L. helveticus and L. brevis
accepted the plasmid with low efficiency (10?7) . A tetra-
cycline-resistance determinant has been found in Lactobacillus
organisms isolated from dried sausages. Seven of 14 strains were
able to transfer resistance from Lactobacillus to Enterococcus at
to L. lactis but were unable to transfer to Staphylococcus aureus
There have also been attempts at molecular identification of
vancomycin-resistance genes in lactobacilli. Five strains of L.
reuteri and 1 strain of L. rhamnosis were probed for vanA,vanB,
and vanC genes. None were found . Lactobacillus GG has
been studied specifically, and no plasmids have been found;
A major area of concernhas
there is no evidence of vanA, vanB, vanH, vanX, vanZ, vanY,
and vanS, by hybridization or PCR .
THE SAFETY OF LACTOBACILLUS GG
Lactobacillus GG has been the given to several thousands of
individuals in clinical trials [11–15, 17–24]. It has been ad-
ministered to travelers with diarrhea in Mexico, as well as to
travelers to Turkey. It has been administered to children with
chronic inflammatory disease, including Crohn’s disease and
juvenile rheumatoid arthritis, to adults with inflammatory
bowel disease, and to patients with HIV infection . It has
also been administered to children and pregnant women and
adults with multiple food allergies. To date, no significant ad-
verse events have been demonstrated in these and other con-
trolled trials .
There are a number of intrinsic properties that are a testa-
ment to the safety of Lactobacillus GG, including the absence
of any plasmids. There appear to be no plasmids that contain
transferable or other antibiotic resistance. The vancomycin re-
sistance that has been found appears to be nontransferableand
chromosomal . The organism has a good enzyme profile.
It elaborates b-glucoronidase and urease, and it also secretes
an antimicrobial agent [98, 99]. It appears to prevent attach-
ment or invasion of pathogens in cell culture systems in vitro
. It has also not been associated with platelet aggregation
. There is no breakdown of human intestinal glycoprotein
or hog gastric mucin in vitro . There has been no dem-
onstration of mucus degradation in germ-free animals .
In addition, there is no invasionof Caco-2 orHeLacellcultures,
and there is evidence of prevention of pathogen invasion in
cell culture systems .
There is no acute toxicity in mice, and, in fact, one cannot
achieve a lethal oral dose in a mouse . It has been given
orally to lethally irradiated mice and actually prolongs survival
[104, 105]. It does not translocate to either spleen or lymph
nodes. It also inhibits tumor formation and binds aflotoxin
[106, 107]. It has been administered to well more than 3000
healthy volunteers [16, 65, 103, 104]. There is also some evi-
dence of phenotypic differences between commercial Lacto-
bacillus GG and L. rhamnosis isolated from blood . In
these studies, it appears that Lactobacillus GG has decreased in
vitro adhesion and has greater resistance to serum-mediated
killing. It also induces a respiratory burst .
In conclusion, Lactobacillus GG has been proven safe both
in vitro and in vivo (in animal models), as well as in a number
of human studies [16, 65]. Although there have been rare cases
of bacteremia and liver abscess in patients with short gut syn-
drome, overall, it is a safe probiotic. There is no other probiotic
that has undergone extensive safety evaluation to a degreecom-
parable to that undergone by Lactobacillus GG.
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S108 • CID 2008:46 (Suppl 2) • Snydman
GENETICALLY ENGINEERED PROBIOTICS
Genetic modification of probiotics has been undertaken to in-
crease certain physiologic or immunologic properties within
the organism and to use the probiotic as a mucosal delivery
system or a vaccine vector . The use of these genetically
engineered products has been quite limited to date, but the
steps enumerated below should be taken for the use of any
engineered strains introduced into human studies. As with any
genetically engineered product, some caution must be em-
ployed when assessing safety.
STEPS TO MONITOR SAFETY OF PROBIOTICS
To monitor the safety of probiotics as they are introduced and
increasingly used around the world, it is important to conduct
teria from patients with infection. There should be knowledge
of the susceptibility profile for any strain used in clinical trials
[110, 111]. There should be the ability to compare the clinically
isolated strain with the probiotic strain by use of molecular
methods. Any trial employing a probiotic strain should have
active surveillance for cases of infection associated with such
use and should have active surveillance for the occurrence of
other adverse effects. Although some caution may be necessary
in any trial of probiotics, concern about toxicity should not
preclude their study. Rather, each study should be evaluated
on a case-by-case basis, examining the risk benefitandpotential
toxicity. There is a list of patients for whom caution might be
warranted, such as those with immune compromise,premature
infants, those with short bowel syndrome, those with central
venous catheters, elderly patients, and those with cardiac valve
disease. However, the presence of any of these factors may not
necessarily preclude a clinical trial. Each study should be eval-
uated on a study-by-study basis, with the appropriate involve-
ment of a human investigation review committee and a data-
safety monitoring committee, as well as specific hypotheses to
be tested and surveillance for bloodstream infection with the
probiotic strain. Ideally, there should be population-based sur-
veillance for Lactobacillus bacteremia, including the use of a
reference laboratory and molecular confirmation.
plement entitled “Developing Probiotics as Foods and Drugs: Scientificand
Regulatory Challenges,” sponsored by the Drug Information Association,
the National Institutes of Health National Center for Complementary and
Alternative Medicine (1R13AT003805-01 to Patricia L. Hibberd), the Cal-
ifornia Dairy Research Foundation, Chr. Hansen, the Dannon Company,
General Mills, Institut Rosell, and Yakult International.
Potential conflicts of interest.
D.R.S.: no conflicts.
National Institutes of Health (1R21 AT001892).
This article was published as part of a sup-
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