PROBIOTICS

BY
M.MITHUN
BIO-TECH(4/4)
07311A2359
SNIST
ABSTRACT

Probiotics are live nonpathogenic microorganisms administered to improve microbial balance,

particularly in the gastrointestinal tract. They consist of Saccharomyces boulardii yeast or lactic
acid bacteria, such as Lactobacillus and Bifidobacterium species, and are regulated as dietary
supplements and foods. Probiotics exert their beneficial effects through various mechanisms,
including lowering intestinal pH, decreasing colonization and invasion by pathogenic organisms,
and modifying the host immune response. Probiotic benefits associated with one species or strain
do not necessarily hold true for others. The strongest evidence for the clinical effectiveness of
probiotics has been in the treatment of acute diarrhea, most commonly due to rotavirus, and
pouchitis. More research is needed to clarify the role of probiotics for preventing antibiotic-
associated diarrhea, Clostridium difficile infection, travelers' diarrhea, irritable bowel syndrome,
ulcerative colitis, Crohn's disease, and vulvovaginal candidiasis. There is no consensus about the
minimum number of microorganisms that must be ingested to obtain a beneficial effect;
however, a probiotic should typically contain several billion microorganisms to increase the
chance that adequate gut colonization will occur. Probiotics are generally considered safe and
well tolerated, with bloating and flatulence occurring most frequently. They should be used
cautiously in patients who are critically ill or severely immunocompromised or those with central
venous catheters since systemic infections may rarely occur. Bacteria-derived probiotics should
be separated from antibiotics by at least two hours.
TABLE OF CONTENTS

1. INTRODUCTION

2. USES

3. PHARMACOLOGY

4. ACUTE DIARRHEA

5. AAD AND C.DIFFICILE INFECTION

6. TRAVELER’S DIARRHEA

7. INFLAMMATORY BOWEL SYNDROME

8. ALLERGY

9. GENITOURINARY INFECTIONS

10. DOSAGES AND PRODUCT SELECTION

11. ADVERSE EFFECTS AND SAFETY

12. DRUG INTERACTIONS

13. PRECAUTIONS AND CONTRAINDICATIONS

14. LIMITATIONS

15. REFERENCE
INTRODUCTION

Probiotics are live microorganisms (in most cases, bacteria) that are similar to beneficial
microorganisms found in the human gut. They are also called "friendly bacteria" or "good
bacteria". The term probiotic was initially used in the 1960s and is thought to be derived from
the Latin “PRO” and the Greek adjective “BIOS”, which means “for life”. In simple terms,
probiotics are defined as the good bacteria in our body.

Microbes are used as probiotics, and the most common are bifido Bacteria and Lactic Acid
Bacteria. Along with these, some variants of yeast and bacilli are also found to be helpful.
Probiotics are best found in fermented products like yogurt, which contains live cultures that are
specially added.

Probiotics can help with a variety of problems by restoring the balance of bacteria in the
gastrointestinal tract. They can, for example, help with diarrhea as well as constipation. They can
help with people who have ulcers. Probiotics can sometimes even help with skin problems, such
as eczema, especially when those skin problems are related to a food allergy.

Probiotics, which are regulated as dietary supplements and foods, consist of yeast or bacteria.
They are available as capsules, tablets, packets, or powders and are contained in various
fermented foods, most commonly yogurt or dairy drinks. Probiotic products may contain a single
microorganism or a mixture of several species. The most widely used probiotics include lactic
acid bacteria, specifically Lactobacillus and Bifidobacterium species. The yeast Saccharomyces
boulardii also appears to have health benefits.

In order for probiotics to be successful, they must possess certain characteristics. Probiotic
organisms must be able to withstand passage through the gastrointestinal tract (i.e. survive acid
and bile degradation), colonize and reproduce in the gut, attach and adhere to the intestinal
epithelium, and stabilize the balance of the gut flora. Furthermore, probiotic strains must be safe
and effective in humans, remain viable for the shelf life of the product, and not have pathogenic
properties.

USES

Probiotics have been used for the prevention and treatment of various medical conditions and to
support general wellness. Some of their beneficial health effects have been validated, while other
uses are supported by limited evidence. Not only are probiotic effects strain specific, probiotic
products may vary from each other, and greater benefits may be seen with one lot of probiotics
versus another due to the complexity of quality control with live microorganisms. Furthermore,
combination agents can make it challenging to quantify particular clinical benefits.
Illnesses associated with the gastrointestinal tract have been a common target of probiotics,
mainly due to their ability to restore gut flora. The strongest evidence for the use of probiotics
lies in the treatment of certain diarrheal diseases, especially rotaviral diarrhea in children.
Clinical studies have also supported the role of probiotics in treating pouchitis. Data are
inconsistent regarding the efficacy of probiotics for antibiotic-associated diarrhea (AAD) and
travelers' diarrhea. Although clinical trial results are conflicting, probiotic therapy may also be
beneficial in the treatment of Crohn's disease, ulcerative colitis (UC), irritable bowel syndrome
(IBS), and Helicobacter pylori infections. Probiotics have also been shown to decrease the
symptoms of lactose intolerance.

Other illnesses not associated with the gastrointestinal tract or gut microbiota, including various
urogenital problems (e.g., bacterial vaginosis, candidal vaginitis, urinary tract infections), may
also respond to probiotics. Probiotics have also been studied for their role in treating upper
respiratory infections (e.g. acute otitis media); reducing the risk of colon and bladder cancer,
allergic diseases, and atopy; boosting immune response; and preventing dental caries.

Pharmacology

Although the exact mechanisms of action of probiotics are not known, several have been
proposed. As mentioned previously, the most frequently used probiotics include lactic acid
bacteria, particularly Lactobacillus and Bifidobacterium species. These bacteria produce lactic
acid, acetic acid, and propionic acid, which lower the intestinal pH and suppress the growth of
various pathogenic bacteria, thereby reestablishing the balance of the gut flora.

Another mechanism of bacterial interference involves the production of various substances, such
as hydrogen peroxide, organic acids, bacteriocins, and biosurfactants, that are toxic to pathogenic
microorganisms. One probiotic with this ability is Lactobacillus species strain GG, which has
been shown to secrete a low-molecular-weight compound that inhibits a broad spectrum of gram-
positive, gram-negative, and anaerobic bacteria. In addition, S. boulardii, a nonpathogenic yeast,
may have a role in Clostridium difficile infection by producing a protease that decreases the
toxicity of C. difficile toxins A and B.

Probiotics also decrease colonization of pathogenic organisms in the urinary and intestinal tracts
by competitively blocking their adhesion to the epithelium. Lactobacilli have been shown to
inhibit the attachment of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa
to uroepithelial cells and intestinal epithelial cells. This inhibition may occur because lactobacilli
cause steric hindrance and upregulate intestinal mucins, which are high-molecular-weight
glycoproteins produced by epithelial cells; the result is the formation of a protective barrier. In
addition, lactobacilli strengthen the gut mucosal barrier by stabilizing tight junctions between
epithelial cells and decreasing intestinal permeability.
Another proposed mechanism of action of probiotics involves immunomodulation. Animal
studies have found that some probiotic strains augment the immune response by stimulating the
phagocytic activity of lymphocytes and macrophages. Probiotics also increase immunoglobulin
A (IgA) and stimulate cytokine production by mononuclear cells. Kaila et al found that children
with acute rotaviral diarrhea who were given Lactobacillus rhamnosus strain GG (LGG) had an
increased IgA, immunoglobulin G, and immunoglobulin M response, resulting in a shortened
duration of gastroenteritis symptoms.

Numerous health effects are associated with probiotic use. While some of these indications are
well documented, probiotics are often used to treat conditions for which data regarding the
efficacy of probiotics are lacking or conflicting. This article focuses on the more-common uses
of probiotics.

Acute Diarrhea

There is convincing evidence from multiple studies supporting the efficacy of probiotics in the
treatment of acute diarrhea, especially in children with rotavirus infection. The probiotics most
frequently studied for treating acute diarrhea include LGG and Lactobacillus reuteri. The
European Society for Pediatric Gastroenterology, Hepatology, and Nutrition conducted a double-
blind, placebo-controlled, multicenter study involving 287 children age 1–36 months from 10
countries who were admitted to the hospital with moderate-to-severe diarrhea, most commonly
due to rotavirus or an unknown pathogen. The patients were randomized to receive oral re-
hydration solution plus placebo or oral rehydration solution plus a live preparation of LGG.
Patients who were given LGG versus placebo had a shorter mean ±S.D. duration of diarrhea
(58.3 ± 27.6 hours versus 71.9 ± 35.8 hours, p = 0.03) and a shorter hospital stay (78.8 ± 22.2
hours versus 96.3 ± 21.4 hours, p = 0.04). In addition, patients treated with LGG were less likely
to have persistent diarrhea (i.e., diarrhea lasting longer than seven days) (2.7% versus 10.7% of
those receiving placebo, p < 0.01).

Van Niel conducted a meta-analysis of nine clinical trials (n = 765) involving children younger
than three years with acute infectious diarrhea who received Lactobacillus species, most
frequently LGG. The studies examined were randomized, blinded, controlled trials that measured
diarrhea duration and the frequency of diarrheal stools on the second day of treatment. The meta-
analysis revealed a reduced mean duration of diarrhea by 0.7 day (95% confidence interval [CI],
0.3–1.2 days) and a decrease in diarrhea frequency by a mean of 1.6 stools per day on day 2 of
treatment (95% CI, 0.7–2.6 fewer stools) in children who received probiotics.

All probiotics are not equally effective in treating acute diarrhea in children. Canani illustrated
this point and emphasized that the particular probiotic preparation should be chosen based on
solid efficacy data. In their study, 571 children age 3–36 months with acute diarrhea were
randomized to one of six different treatment groups: oral rehydration solution alone (control
group) or one of five probiotic preparations, which were prescribed for five days. Only two
preparations—LGG and a mixture of four bacterial strains (Lactobacillus delbrueckii var
bulgaricus, Streptococcus thermophilus, Lactobacillus acidophilus, and Bifidobacterium
bifidum)—were associated with a significantly shorter median duration of diarrhea (78.5 and 70
hours, respectively; p < 0.001) compared with children who received oral rehydration solution
alone (115.5 hours). One day after initiation of probiotics, children who were given LGG or the
probiotic mixture also had a significantly lower daily stool output compared with the other
groups (p < 0.001). The other three preparations (S. boulardii, Bacillus clausii, and Enterococcus
faecium SF 68) did not significantly affect the duration and severity of diarrhea.

AAD and C. Difficile Infection

There is evidence that probiotics can prevent AAD and treat C. difficile infection (CDI);
however, data are conflicting or inconclusive. The most common probiotic microorganisms used
for these diseases include lactobacilli and S. boulardii. Two meta-analyses of studies examining
the use of probiotics to prevent AAD suggested that concurrent administration of probiotics
(most commonly lactobacilli and S. boulardii) with antibiotics resulted in a reduced frequency of
diarrhea. The first meta-analysis, which examined 7 trials (n = 881), revealed a combined
relative risk (RR) of 0.3966 (95% CI, 0.27–0.57) in favor of a beneficial effect of probiotics for
reducing the risk of AAD. The other meta-analysis yielded a combined odds ratio of 0.37 (95%
CI, 0.26–0.53; p < 0.001) for pooled data from all 9 trials (n = 1214), supporting probiotic
treatment over placebo in the prevention of AAD.

A third meta-analysis reviewed 25 randomized controlled trials (n = 2810) examining the use of
probiotics for the prevention of AAD and 6 randomized controlled trials (n = 354) of probiotic
therapy for the treatment or prevention of CDI. The meta-analysis revealed that LGG, S.
boulardii, and various mixtures of two probiotic strains significantly reduced the frequency of
AAD. However, only S. boulardii in combination with oral vancomycin or metronidazole or both
significantly decreased the recurrence of CDI. Other probiotics tested, including LGG and
Lactobacillus plantarum 299v in combination with oral vancomycin or metronidazole, were not
effective in decreasing CDI recurrence rates. On the other hand, a recent study found that the rate
of C. difficile colonization in 44 critically ill patients receiving antibiotics was significantly
reduced by enteral administration of L. plantarum 299v (p < 0.05). It is important to note that
this study was stopped prematurely due to the low rate of enrollment and reduced funding.

In contrast to the previous studies that found that probiotics reduced the rate of CDI, a systematic
review of 8 randomized controlled trials did not find sufficient evidence for routine probiotic use
in CDI. A Cochrane Library review also concluded that there was inadequate evidence to support
the adjunctive use of probiotics for CDI. While results have been inconsistent, some studies have
indicated that probiotics, especially S. boulardii, may prevent C. difficile overgrowth and
decrease CDI recurrence.
Travelers' Diarrhea

Results of studies evaluating the effectiveness of probiotics for preventing travelers' diarrhea
have been inconsistent, possibly due to the probiotic strain used and the various trip destinations.
Similar to AAD and CDI, the most commonly studied probiotics for travelers' diarrhea include
lactobacilli and S. boulardii. Hilton et al. randomized 245 American tourists traveling to various
developing countries to receive LGG or placebo. Those travelers who ingested LGG had a mean
daily risk of developing diarrhea of 3.9%, compared with 7.4% for travelers taking placebo (p =
0.05). In contrast, Katelaris found that ingestion of L. acidophilus or Lactobacillus fermentum
strain KLD did not reduce the frequency of diarrhea among 282 British soldiers deployed to
Belize. McFarland conducted a meta-analysis of 12 studies (n = 4709), which included the two
above-mentioned studies, on the role of probiotics in the prevention of travelers' diarrhea. The
types of probiotics in the meta-analysis included S. boulardii (4 studies), various types of
lactobacilli (6 studies), and probiotic mixtures (2 studies). The meta-analysis revealed that
probiotics significantly prevented travelers' diarrhea (pooled relative risk [RRpooled], 0.85; 95%
CI, 0.79–0.91; p < 0.001).

IBS

IBS is characterized by abdominal pain, bloating, flatulence, and altered bowel habits. These
symptoms may be due to bacterial overgrowth in the small intestine, causing increased
fermentation activities and gas production. Some studies suggest that probiotics may be
beneficial in reducing bloating and flatulence associated with IBS. The probiotics used most
frequently in the treatment of IBS include lactobacilli and bifidobacteria. In addition, a
combination product (VSL#3, VSL Pharmaceuticals, Inc., Towson, MD) has reduced abdominal
bloating and flatulence. This preparation contains eight bacterial organisms in large numbers:
three bifidobacteria (Bifidobacterium longum, Bifidobacterium infantis, and Bifidobacterium
breve), four lactobacilli (L. acidophilus, Lactobacillus casei, L. bulgaricus, and L. plantarum),
and S. thermophilus.

A recent meta-analysis involving 20 trials (n = 1404) found that probiotics (most commonly
lactobacilli and bifidobacteria) improved global IBS symptoms (RR pooled, 0.77; 95% CI, 0.62–
0.94) and reduced abdominal pain (RRpooled, 0.78; 95% CI, 0.69–0.88) compared with placebo.
This meta-analysis was not able to examine other types of individual IBS symptoms (e.g.,
bloating or distension, flatulence, stool frequency) or the effectiveness of specific probiotic
strains due to insufficient data. A review of 14 clinical trials also revealed that probiotics (most
commonly lactobacilli, bifidobacteria, and VSL#3) improved overall symptoms associated with
IBS compared with placebo; however, the contributing studies had methodological limitations.
Although probiotics may be beneficial in treating IBS symptoms, limitations exist in interpreting
trial results due to the lack of standardization of strains, dosages, treatment durations, and
assessment of clinical outcomes. More data are needed before probiotics can be recommended as
typical care in the treatment of IBS.

Inflammatory Bowel Disease

Inflammatory diseases of the digestive tract include UC, Crohn's disease, and pouchitis. An
imbalance of intestinal microflora, specifically high numbers of enteroadhesive and
enterohemorrhagic E. coli with UC and reduced levels of bifidobacteria with Crohn's disease,
may contribute to the inflammation seen with these diseases. Probiotics may improve the
microbial balance of the indigenous flora. Although studies have been conflicting, probiotics
seem to be an attractive option in the treatment and prevention of inflammatory bowel disease,
providing an appealing alternative to the use of antibiotics.

Several studies examining the role of probiotics in UC have suggested that they can induce or
maintain disease remission. Three controlled trials compared the probiotic E. coli Nissle 1917
with mesalamine in UC and found that the two therapies were similar in preventing disease
relapse, suggesting that the probiotic was equivalent to standard therapy with mesalamine in
maintaining remission. Two of the studies had notable limitations—diverse patient population
and short study duration—but the more recent study was methodologically more sound and
confirmed the results of the other two studies. The particular nonpathogenic E. coli probiotic
strain used in these three studies has been shown to colonize the intestine and antagonize the
pathogenic bacteria seen with UC. Another study investigated the use of S. boulardii in 25
patients who developed a mild-to-moderate clinical flare-up of UC while taking standard
maintenance therapy with mesalamine. For various reasons, treatment with corticosteroids was
not suitable for these patients. Clinical remission, confirmed endoscopically, was attained in 68%
of patients after adding a four-week course of S. boulardii to mesalamine treatment. This study
was limited by its small sample size, lack of a control group, and open-label design. Bibiloni et
al. noted that a six-week course of VSL#3 was also effective in inducing remission or causing a
response in 77% of patients with active mild-to-moderate UC that was unresponsive to
conventional therapy. This open-label trial also lacked a control group and involved only 34
patients.

Studies have also investigated the role of probiotics in maintaining remission of Crohn's disease.
Guslandi noted that patients with inactive Crohn's disease had a significantly lower clinical
relapse rate when receiving a six-month regimen of S. boulardii plus mesalamine versus
treatment with mesalamine alone (6.25% versus 37.5%, p = 0.04), suggesting that the probiotic
yeast may be beneficial in the maintenance treatment of Crohn's disease. In contrast, Marteau et
al. found that a six-month regimen of Lactobacillus johnsonii LA1 was not effective in
preventing endoscopic recurrence of Crohn's disease after surgical resection.
Various studies support the use of probiotics, particularly VSL#3, in reducing relapse rates and
maintaining remission of pouchitis. Pouchitis is a nonspecific inflammation of the ileal reservoir,
which is formed surgically after an ileal pouch–anal anastomosis from a proctocolectomy. It is
characterized by increased stool frequency and abdominal cramping. Although the etiology of
pouchitis is unknown, it may be associated with decreased lactobacilli and bifidobacteria counts
as well as increased concentrations of other bacteria. In addition to modifying the endogenous
flora, VSL#3 alters the immune response in pouchitis by raising tissue levels of the
antiinflammatory cytokine interleukin 10 and reducing tissue levels of tumor necrosis factor,
interferon, and matrix metalloproteinase activity.

In a randomized, double-blind, placebo-controlled trial involving 40 patients with chronic

relapsing pouchitis, Gionchetti found that VSL#3 was significantly more effective than placebo
in maintaining remission after nine months. All 20 placebo-treated patients experienced a relapse
within four months, while 17 of the 20 patients treated with VSL#3 remained in remission after
nine months (p < 0.001). When the probiotic was discontinued at the study's end, these 17
patients also experienced relapse within four months. In addition, fecal concentrations of
lactobacilli, bifidobacteria, and S. thermophilus increased significantly from baseline in patients
treated with VSL#3 (p < 0.001). Mimura et al. confirmed the efficacy of VSL#3 in maintaining
remission in patients with recurrent or refractory pouchitis. In this study, 36 patients whose
pouchitis was in remission were randomized to receive VSL#3 or placebo for one year or until
relapse. Similar to the previous study, 17 of the 20 patients treated with VSL#3 remained in
remission at one year versus only 1 of 16 patients who received placebo (p < 0.0001). In addition
to preventing relapses, Gionchetti et al. showed that the probiotic mixture VSL#3 was
significantly more effective than placebo in preventing the occurrence of pouchitis (p < 0.05)
during the first year after pouch formation in this randomized, double-blind, placebo-controlled
study involving 40 patients.

In contrast to those studies with encouraging results using VSL#3 in pouchitis, a three-month
trial involving LGG did not show any benefit as primary therapy for ileal pouch inflammation.
This trial did not show differences in the mean pouchitis disease activity index scores between
treatment with LGG and placebo, and only 40% of patients who received the probiotic had LGG
recovered in their fecal flora.

Allergy

Several studies have found that probiotics have a beneficial effect on atopic eczema. Kalliomaki
et al conducted a double-blind, randomized, placebo-controlled trial in which 159 pregnant
women with a family history of atopic disease were given LGG or placebo daily for two to four
weeks before their expected delivery date, followed by administration of the probiotic or placebo
to the newborn infant for 6 months; 132 participants completed the trial. There was a 50%
reduction in the frequency of atopic eczema during the first two years of the children's lives in
those given probiotics compared with placebo (23% [15 of 64] versus 46% [31 of 68]; RR, 0.51;
95% CI, 0.32–0.84; p = 0.008). This cohort was reexamined after four years, and significantly
fewer children who had previously received LGG were diagnosed with atopic eczema compared
with placebo (26% [14 of 53] versus 46% [25 of 54]; RR, 0.57; 95% CI, 0.33–0.97), suggesting
that the protective effect of this probiotic on atopic eczema in at-risk children continues beyond
infancy. In another randomized double-blind study, 27 infants (mean age, 4.6 months) with
atopic eczema received formula supplemented with probiotics (either LGG or Bifidobacterium
lactis Bb-12) or the same formula without probiotics. After 2 months, the Scoring Atopic
Dermatitis index, which reflects the extent and severity of atopic eczema, was reduced
significantly in the infants given probiotic-supplemented formulas compared with those who did
not receive probiotic supplementation (p = 0.002).

Genitourinary Infections

Abnormal vaginal microbiota may lead to symptomatic infections, including vulvovaginal

candidiasis (VVC). Lactobacilli, especially Lactobacillus crispatus and Lactobacillus iners, are
the predominant vaginal microorganisms in healthy premenopausal women. When the normal
vaginal microflora is disrupted, such as with use of broad-spectrum antibiotics, overgrowth of
Candida albicans may occur, causing VVC. Restoring the normal flora with lactobacilli may help
treat this genital infection. Hilton et al. conducted a study involving 28 women with a history of
recurrent VVC who also had signs and symptoms of active VVC. After the administration of
vaginal suppositories containing LGG twice daily for seven days, all of the women reported an
improvement in vaginal symptoms and reduced vaginal erythema and discharge. Reid et al.
investigated the ability of an orally administered solution containing L. rhamnosus GR-1 and L.
fermentum RC-14 to colonize the vagina in 10 women who were asymptomatic for infection but
who had a history of recurrent urogenital infections, primarily recurrent VVC. The probiotic
solution was administered twice daily for 14 days. Within one week, one or both of the
Lactobaccillus strains were recovered from the vaginas of all 10 women, and no VVC occurred
during the study. Hilton et al. found that consumption of 8 oz of yogurt containing L.
acidophilus daily for six months reduced vaginal colonization and infection by Candida species
in a crossover trial involving 33 women with recurrent VVC, 13 of whom completed the
protocol. The mean number of candidal infections of the vagina and candidal colonization in the
vagina and rectum were significantly lower in the women who consumed yogurt versus the
control group (0.38 versus 2.54, p = 0.001 and 0.84 versus 3.23, p = 0.001, respectively).
However, these three studies had important methodological limitations, including small sample
sizes, inadequate controls, and lack of blinding. Two of the studies lacked detailed statistical
analyses, one study had a high attrition rate, and more than half of the women in one study had
recently completed treatment with antifungal medications. Therefore, it is difficult to reliably
conclude whether probiotics can prevent recurrent VVC.
Dosages and Product Selection

Probiotics are available as supplements (i.e., tablets, capsules, or powders) and as fermented
dairy products (i.e., yogurt and milk). Their efficacy relies on their ability to survive passage
through the gastrointestinal tract and colonize a tissue section. To prevent destruction by gastric
acid and intestinal bile salts, some probiotic preparations may be enteric coated or
microencapsulated. For colonization to occur, probiotics must contain living, viable organisms
and must be ingested on a regular basis in order to maintain effective concentrations.
Unfortunately, the manufacturing process may cause living organisms to become nonviable, thus
reducing probiotic effectiveness. The quantity, quality, and purity of the bacteria or yeast in
probiotics can vary among products due to the complexity of quality control with live
microorganisms and the lack of universal quality-assurance programs. One study analyzed 18
commercially available probiotic products available in the United States and found that 7 (39%)
had differences between the stated and actual concentrations of bacteria.

Probiotic dosing varies depending on the product and specific indication. No consensus exists
about the minimum number of microorganisms that must be ingested to obtain a beneficial
effect. Typically, a probiotic should contain several billion microorganisms to increase the
likelihood of adequate gut colonization. For lactobacilli, typical doses used in studies ranged
from 1–20 billion colony-forming units per day. For S. boulardii, most studies examined daily
doses ranging from 250 to 500 mg. Products should be stored according to the manufacturer's
recommendations, since some may require refrigeration. In addition, preparations may have a
limited shelf life, and many preparations contain several different species, so dosing may vary
depending on the product.

Various probiotics are available in the United States; however, only those products that have
been evaluated in controlled human studies should be recommended. Some examples of these
commercially available preparations include LGG (Culturelle, Amerifit Brands, Fairfield, NJ), S.
boulardii (Florastor, Biocodex, Inc., Beauvais, France), B. infantis 35624 (Align, JB
Laboratories, Holland, MI), and VSL#3. Yogurt products fermented with probiotics should be
labeled with a "Live and Active Cultures" seal, specifying that the preparation contains a
minimum of 100 million viable bacteria per gram at the time of manufacture. An example is
Activia yogurt (Dannon/Danone, Paris, France), which contains B. animalis DN-173 010,
marketed by Dannon/Danone as "Bifidus regularis."

Adverse Effects and Safety

When ingested orally, probiotics are generally considered safe and well tolerated. The most
common adverse effects include bloating and flatulence; however, these are typically mild and
subside with continued use. Constipation and increased thirst have also rarely been associated
with S. boulardii. One theoretical concern associated with probiotics includes the potential for
these viable organisms to move from the gastointestinal tract and cause systemic infections.
Although rare, probiotic-related bacteremia and fungemia have been reported. It is estimated that
the risk of developing bacteremia from ingested lactobacilli probiotics is less than 1 per 1 million
users, and the risk of developing fungemia from S. boulardii is estimated at 1 per 5.6 million
users. Another theoretical risk associated with probiotics involves the possible transfer of
antibiotic resistance from probiotic strains to pathogenic bacteria; however, this has not yet been
observed.

Although no serious adverse events have been described in clinical trials, systemic infections
associated with specific probiotics have been noted in isolated reports. These include sepsis or
endocarditis with lactobacilli, fungemia with S. boulardii, and liver abscess with LGG.
Bacteremia due to lactobacilli rarely occurs, but predisposing factors include
immunosuppression, prior hospitalization, severe underlying comorbidities, previous antibiotic
therapy, and prior surgical interventions. There have been several documented cases of fungemia
associated with use of S. boulardii. Those at greatest risk include critically ill or highly
immunocompromised patients or those with central venous catheters in place. When S.boulardii
capsules are opened at the bedside for administration through the nasogastric tube, central
venous catheters may become contaminated and serve as the source of entry for the organism.
Although there have been infrequent reports of lactobacillemia and fungemia, to date there have
been no reports of bifidobacterial sepsis associated with the use of a probiotic, supporting the
low pathogenicity of bifidobacteria species. Fortunately, most cases of probiotic bacteremia or
fungemia have responded well to appropriate antibiotic or antifungal therapy.

In a review of the literature, Boyle et al. identified major and minor risk factors for probiotic-
associated sepsis. Major risk factors included immunosuppression (including a debilitated state
or malignancy) and prematurity in infants. Minor risk factors were the presence of a central
venous catheter, impairment of the intestinal epithelial barrier (such as with diarrheal illness),
cardiac valvular disease (Lactobacillus probiotics only), concurrent administration with broad-
spectrum antibiotics to which the probiotic is resistant, and administration of probiotics via a
jejunostomy tube (this method of delivery could increase the number of viable probiotic
organisms reaching the intestine by bypassing the acidic contents of the stomach). The authors
recommended that probiotics be used cautiously in patients with one major risk factor or more
than one minor risk factor.

It is important to remember that the overall risk of developing an infection from ingested
probiotics is very low, particularly when used by generally healthy individuals. In Finland, LGG
has been routinely added to dairy products since 1990. Despite a substantial increase in the
consumption of LGG-containing products from 1995 through 2000, there was no significant
change in the incidence of Lactobacillus-associated bacteremia observed during the surveillance
period of 1990–2000.
A recent study found an increased risk of mortality when probiotics were used to prevent
infectious complications in patients with predicted severe acute pancreatitis. These patients had
acute pancreatitis and an elevated Acute Physiology and Chronic Health Evaluation (APACHE)
II score, Imrie/modified Glasgow score, or C-reactive protein value, predicting a severe disease
course and putting them at risk for developing infectious complications, including infected
pancreatic necrosis. This multicenter, randomized, double-blind, placebo-controlled trial
involved 298 patients who received a multispecies probiotic preparation (L. acidophilus, L. casei,
Lactobacillus salivarius, Lactobacillus lactis, B. bifidum, and B. lactis) or placebo, administered
enterally twice daily for a maximum of 28 days. The study found that this combination of six
probiotic strains did not decrease infectious complications in patients with predicted severe acute
pancreatitis but rather was associated with significantly more deaths than was placebo (24 versus
9, p = 0.01) and an increased risk of bowel ischemia in the probiotics group compared with
placebo (9 versus 0, p = 0.004). The authors stated that probiotics should not be routinely given
to patients with predicted severe acute pancreatitis and should be used cautiously in critically ill
patients or those at risk for nonocclusive mesenteric ischemia.

Drug Interactions

Since probiotics contain live microorganisms, concurrent administration of antibiotics could kill
a large number of the organisms, reducing the efficacy of the Lactobacillus and Bifidobacterium
species. Patients should be instructed to separate administration of antibiotics from these
bacteria-derived probiotics by at least two hours. Similarly, S. boulardii might interact with
antifungals, reducing the efficacy of this probiotic. According to the manufacturer, Florastor,
which contains S. boulardii, should not be taken with any oral systemic antifungal products.
Probiotics should also be used cautiously in patients taking immunosuppressants, such as
cyclosporine, tacrolimus, azathioprine, and chemotherapeutic agents, since probiotics could
cause an infection or pathogenic colonization in immunocompromised patients.

Precautions and Contraindications

Since probiotics contain live microorganisms, there is a slight chance that these preparations
might cause pathological infection, particularly in critically ill or severely immunocompromised
patients. Probiotic strains of Lactobacillus have also been reported to cause bacteremia in
patients with short-bowel syndrome, possibly due to altered gut integrity. Caution is also
warranted in patients with central venous catheters, since contamination leading to fungemia has
been reported when Saccharomyces capsules were opened and administered at the bedside.

Lactobacillus preparations are contraindicated in persons with a hypersensitivity to lactose or

milk. S. boulardii is contraindicated in patients with a yeast allergy. No contraindications are
listed for bifidobacteria, since most species are considered nonpathogenic and nontoxigenic.
Limitations

Probiotics are regulated as dietary supplements and not subjected to the same rigorous standards
as medications. A challenge with these products involves the complexity of quality control with
live microorganisms. As a result, individuals may obtain a product that is ineffective or that
contains varying quantities of bacteria or yeast. Published studies involving probiotics have often
utilized small sample sizes and lacked appropriate randomization, blinding, or control groups.
Therefore, the results from many probiotic studies should be interpreted cautiously due to
methodological limitations. There is also heterogeneity among studies, since different probiotic
doses, strains, treatment durations, and patient populations may have been used. Since probiotic
effects are specific to a particular strain, this may have important implications when interpreting
meta-analyses, particularly if strain designations were not provided. Future research needs to
encompass more well-designed clinical trials in larger populations and for longer durations to
better evaluate the efficacy of probiotics.
Reference

1. Guidelines for the evaluation of probiotics in food: report of a Joint FAO/WHO Working
Group. London, Ontario, Canada: Food and Agriculture Organization of the United
Nations and World Health Organization; 2002.
2. Senok AC, Ismaeel AY, Botta GA. Probiotics: facts and myths. Clin Microbiol Infect.
2005; 11:958–66.
3. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics—approaching a
definition. Am J Clin Nutr. 2001; 73(suppl):361S-364S.
4. Report of a Joint FAO/WHO Expert Consultation on evaluation of health and nutritional
properties of probiotics in food including powder milk with live lactic acid bacteria.
Cordoba, Argentina: Food and Agriculture Organization of the United Nations and World
Health Organization; 2001.
5. Santosa S, Farnworth E, Jones PJ. Probiotics and their potential health claims. Nutr Rev.
2006; 64:265–74.
6. Alvarez-Olmos MI, Oberhelman RA. Probiotic agents and infectious diseases: a modern
perspective on a traditional therapy. Clin Infect Dis. 2001; 32:1567–76.
7. Doron S, Gorbach SL. Probiotics: their role in the treatment and prevention of disease.
Expert Rev Anti Infect Ther. 2006; 4:261–75.
8. Pham M, Lemberg DA, Day AS. Probiotics: sorting the evidence from the myths. Med J
Aust. 2008; 188:304–8.
9. Vanderhoof JA, Young R. Probiotics in the United States. Clin Infect Dis. 2008; 46(suppl
2):S67–72.
10. Vanderhoof JA, Young RJ. Current and potential uses of probiotics. Ann Allergy Asthma
Immunol. 2004; 93(suppl 3):S33–7.
11. Goldin BR. Health benefits of probiotics. Br J Nutr. 1998; 80(suppl 2):S203–7.
12. Wald A, Rakel D. Behavioral and complementary approaches for the treatment of
irritable bowel syndrome. Nutr Clin Pract. 2008; 23:284–92.
13. Surawicz CM. Role of probiotics in antibiotic-associated diarrhea, Clostridium difficile-
associated diarrhea, and recurrent Clostridium difficile-associated diarrhea. J Clin
Gastroenterol. 2008; 42(suppl 2):S64–70.
14. MacIntyre A, Cymet TC. Probiotics: the benefits of bacterial cultures. Compr Ther. 2005;
31:181–5.
15. Scarpellini E, Cazzato A, Lauritano C et al. Probiotics: which and when? Dig Dis. 2008;
26:175–82.
16. Farnworth ER. The evidence to support health claims for probiotics. J Nutr. 2008;
138(suppl):1250S–4S.
17. Goldin BR, Gorbach SL. Clinical indications for probiotics: an overview. Clin Infect Dis.
2008; 46(suppl 2):S96–100.
18. Reid G, Jass J, Sebulsky MT et al. Potential uses of probiotics in clinical practice. Clin
Microbiol Rev. 2003; 16:658–72.
19. Silva M, Jacobus NV, Deneke C et al. Antimicrobial substance from a human
Lactobacillus strain. Antimicrob Agents Chemother. 1987; 31:1231–3.
20. Castagliuolo I, Riegler MF, Valenick L et al. Saccharomyces boulardii protease inhibits
the effects of Clostridium difficile toxins A and B in human colonic mucosa. Infect
Immun. 1999; 67:302–7.
21. Nancy Toedter Williams. American Journal of Health-System Pharmacy.