ArticlePDF AvailableLiterature Review

Probiotics

Authors:
Probiotics
Theresa L. Charrois, BSc
Pharm, MSc,* Gagan
Sandhu,* Sunita Vohra,
MD, MSc*
Author Disclosure
Ms Charrois, Ms
Sandhu, and Dr Vohra
did not disclose any
financial relationships
relevant to this
article.
Complementary and Alternative Medicine: A New Series
Pediatrics in Review is happy to present a new series. It is difficult to define complementary and
alternative medicine, but one perspective would be to include methods of treating or prevent-
ing disease or improving wellness that have arisen from sources of experience and research
different from those traditionally taught in most medical schools and that have not been
incorporated into current practice by traditional practitioners. Many of these therapies have
arisen from the background of herbal use.
The series was proposed by Dr Sunita Vohra, Director of the Complementary and Alterna-
tive Research and Education Program at the University of Alberta, Canada, and the initial
articles will be written by Dr Vohra and her colleagues in cooperation with the Provisional
Section on Contemporary, Holistic, and Integrative Medicine of the American Academy of
Pediatrics (AAP SCHIM).
Dr Kathi Kemper, a member of the AAP who is a leading educator in the realm of holistic
and alternative medicine and who has been involved in establishing this series, urges colleagues
to focus not on the tradition from which any therapy emerges, but on whether the therapy has
been studied and proven. It is in the spirit of examining these therapies, which might appear
unfamiliar and unusual, with a scientific eye and an open mind that we present these articles,
starting with a discussion of probiotics. Significant numbers of our patients are using
alternative therapies, usually on their own, and it is important for us to educate ourselves as to
what is known about them.—LFN
Introduction
Increasing evidence supports the use of probiotics to treat and prevent gastrointestinal
(GI) disorders. The rationale behind probiotics usage is their ability to normalize microbial
flora.
Definition and Description
Probiotics are nonpathogenic microbes, usually of the lactic acid-producing variety, that
are used to improve or normalize the balance of gut microflora. They are available as
dietary supplements or in food products (eg, yogurt) as live active culture. A variety of
probiotic supplements are available, but Lactobacillus GG, Bifidobacterium, and Sac-
charomyces sp have been studied most extensively. Increasing evidence supports the use
of probiotics to prevent and treat various GI disorders such as irritable bowel
syndrome, inflammatory bowel disease, acute gastroenteritis, and antibiotic-related
diarrhea.
Although probiotic preparations are used commonly worldwide, specific use data for
children are unavailable.
Evidence of Efficacy in Pediatrics
A number of systematic reviews (Table) have evaluated the use of probiotic supplements to
treat diarrhea. Additionally, numerous randomized, controlled trials have examined their
use in constipation, irritable bowel syndrome, Crohn disease, ulcerative colitis, atopy and
eczema, Helicobacter pylori colonization and eradication, pancreatitis, cirrhosis, radiation-
induced diarrhea, necrotizing enterocolitis, prophylaxis against bacterial sepsis, and uri-
nary tract infections in preterm infants. (6)(7) More data are necessary before probiotics
can be recommended as primary therapeutic agents for these disorders.
*Complementary and Alternative Research and Education (CARE) Program, Department of Pediatrics, University of Alberta,
Canada, on behalf of the American Academy of Pediatrics Provisional Section on Complementary, Holistic, and Integrative
Medicine.
Article gastroenterology
Pediatrics in Review Vol.27 No.4 April 2006 137
Common empiric uses that have not yet been studied
formally include acne, canker sores, colon cancer, heart
disease, nonalcoholic fatty liver, and thrush.
Evidence of Safety
Clinical trials have not revealed major adverse effects of
probiotics in healthy individuals, and long-term con-
sumption also appears to be safe and well tolerated.
However, there are case reports of aggravation of exist-
ing symptoms, septicemia, pneumonia, and meningitis in
severely debilitated, immunocompromised children and
in neonates. (8) The safest forms of probiotic bacteria are
found in fermented foods, including buttermilk, yogurt,
kefir, and sauerkraut. However, supplemental forms usu-
ally provide higher doses of probiotic bacteria.
Some probiotics (L acidophilus, Lactobacillus GG,
Saccharomyces sp) have been found safe for use in chil-
dren if administered in appropriate doses. Usage has
been evaluated in randomized, controlled trials for chil-
dren as young as 1 month of age.
Information is insufficient to recommend safe probi-
otic supplement usage by women who are pregnant or
lactating. Usage of probiotic-containing foods in this
population generally is considered safe.
Pharmacologic Action
Probiotics are believed to modulate immune activity via
differential activation of epithelial and immune cell re-
ceptors. Postulated mechanisms of action include inhibi-
tion of adhesion and invasion by enteroinvasive species
into enteric cells, colonization of the gut, enhancement
of epithelial cytoprotection, and destruction of receptor
sites for toxins.
Administration/Dosage Forms
The investigated dosages range from 1 million to 300
billion colony-forming units per day. Probiotic supple-
ments usually are administered as capsules or powder.
There is significant discrepancy in the literature as to
appropriate doses in children, and the dose varies accord-
ing to probiotic. Moreover, variations are significant
between and within products because production gener-
ally is not standardized. Stability is an issue with most
probiotic preparations; some may require refrigeration
and others (such as S boulardii, which is a yeast product)
may not. Patients should be instructed to consider this
when selecting a product. Some products can be sprin-
kled on food or dissolved in beverages, which aids in
administration to children. However, because some pro-
Table. Summary of Systematic Reviews of Probiotics in Children
Citation
Patient Population and
Study Design Results Conclusions
Allen et al, 2002 (1)
Probiotics for treating
infectious diarrhea
Adults and children
RCTs (n23 studies)
Risk of diarrhea at 3 days:
RR 0.66; 95% CI 0.55,
0.77 (favor probiotics)
Promising results; significant
heterogeneity of methods
and outcomes
D’Souza et al, 2002 (2)
Probiotics in prevention of
antibiotic-associated
diarrhea: meta-analysis
Adults and children
R, DB, PC trials
(n9 studies)
Patients free of diarrhea:
OR 0.37, 95% CI 0.26,
0.53 (favor probiotics)
Positive results; no information
regarding adverse events
Huang et al, 2002 (3)
Efficacy of probiotic use
in acute diarrhea in
children: a meta-analysis
Children <5y
Controlled clinical trials
(n18 studies)
Reduction of diarrhea:
0.8 days, 95% CI
1.1, 0.6 days
(favor probiotics)
Significant heterogeneity of
methods and outcomes; less
rigorous systematic review
Cremonini et al, 2002 (4)
The effect of probiotic
administration on
antibiotic-associated
diarrhea: a meta-analysis
Adults and children
RCTs (n22 studies)
Presence of diarrhea at
end of treatment: RR
0.40, 95% CI 0.27,
0.57 (favor probiotics)
Positive effects; some
methodologic problems such
as unclear inclusion and
exclusion criteria
Szajewska et al, 2001 (5)
Probiotics in the
treatment and prevention
of acute infectious
diarrhea in infants and
children
Infants and children
RCTs (n10 studies)
Risk of diarrhea: RR 0.40,
95% CI 0.28, 0.57
(favor probiotics)
Only
Lactobacillus
GG showed
consistent benefit (other
studies included
L reuteri,
S boulardii, L acidophilus
)
RCTrandomized controlled trial, Rrandomized, DBdouble-blind, PCplacebo-controlled, RRrelative risk, ORodds ratio, 95% CI95% confi-
dence interval.
gastroenterology probiotics
138 Pediatrics in Review Vol.27 No.4 April 2006
biotics are sensitive to gastric acid and bile, they should
be administered on an empty stomach. This property is
product-specific, and patients should refer to the labeling
instructions. Treatment often is initiated at the same time
as antibiotic therapy to prevent antibiotic-associated di-
arrhea. The duration of treatment varies from 1 to
4 weeks following resolution of symptoms.
References
1. Allen SJ, Okoko B, Martinez E, Gregorio G, Dans LF. Probiot-
ics for treating infectious diarrhoea. Cochrane Database Syst Rev.
2003;4:CD003048
2. D’Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in
prevention of antibiotic-associated diarrhoea: meta-analysis. BMJ.
2002;324:1361–1366
3. Huang JS, Bousvaros A, Lee JW, Diaz A, Davidson EJ. Efficacy
of probiotic use in acute diarrhea in children: a meta-analysis. Dig
Dis Sci. 2002;47:2625–2634
4. Cremonini F, Di Caro S, Nista EC, et al. Meta analysis: the effect
of probiotic administration on antibiotic-associated diarrhoea. Ali-
ment Pharmacol Ther. 2002;16:1461–1467
5. Szajewska H, Mrukowicz JZ. Probiotics in treatment and pre-
vention of acute infectious diarrhea in infants and children: a
systematic review of published randomized, double-blind placebo-
controlled trials. J Pediatr Gastroenterol Nutr. 2001;33(suppl 2):
S17–S25
6. Probiotics. Natural Standard Monograph. Natural Standard
2005. Available at: www.naturalstandard.com. Accessed November
2005
7. Kullen MJ, Bettler J. The delivery of probiotics and prebiotics to
infants. Curr Pharm Des. 2005;11:55–74
8. Salminen S, von Wright A, Morelli L, et al. Demonstration of
safety of probiotics a review. Int J Food Microbiol. 1998;44:
93–106
Question From the Clinician
Experienced clinicians and specialists have much to teach us. Our Question From the
Clinician column offers readers an opportunity to submit questions regarding problems
they have encountered in their clinical practice to experts in the field. We welcome your
letters.
—LFN
gastroenterology probiotics
Pediatrics in Review Vol.27 No.4 April 2006 139
Chapter
Complementary and alternative medicine (CAM) is commonly used to prevent and treat various medical conditions worldwide. The chapter begins with a description of the epidemiology of CAM use among individuals with renal conditions, and discusses the legal and ethical considerations of CAM use. This is followed by a review of the scientific evidence regarding the efficacy and safety of CAM therapies (including natural health products, traditional Chinese medicine and massage) used to prevent and treat symptoms associated with various renal conditions (including urinary tract infections, nephrotic syndrome, chronic renal failure) with a special focus on pediatric populations. Some CAM therapies (e.g. cranberry, omega-3 fatty acids) considered have been researched more widely among pediatric populations than others; pediatric data are preferentially discussed when available. Some CAM therapies may be effective and relatively safe for use among pediatric populations (e.g. acupressure or acupuncture for uremic pruritus), while other CAM therapies have limited evidence and warrant further investigation (e.g. many traditional Chinese medicine herbal remedies).
Chapter
This chapter intends to provide a brief overview of the basic ethical principles that are applicable to natural health products (NHPs), including herbal medicines. Beneficence, nonmalfeasance (nonmaleficence), and patient autonomy are important pillars of biomedical ethics that also apply to the realm of natural medicines (Kemper and Cohen 2004). The data about herbal medicine utilization, pharmacology, safety, and efficacy are discussed, as well as conditions in which herbal medicines may be used as primary versus adjunct treatment. Issues of NHP–drug interactions are reviewed, as they may be synergistic or antagonistic and must be considered whenever concomitant use of products occurs. Gaps in knowledge are identified, and recommendations are suggested to further explore the issues related to NHP–drug interactions.
Article
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Article
Full-text available
To evaluate efficacy of probiotics in prevention and treatment of diarrhoea associated with the use of antibiotics. Meta-analysis; outcome data (proportion of patients not getting diarrhoea) were analysed, pooled, and compared to determine odds ratios in treated and control groups. Studies identified by searching Medline between 1966 and 2000 and the Cochrane Library. Studies reviewed Nine randomised, double blind, placebo controlled trials of probiotics. Two of the nine studies investigated the effects of probiotics in children. Four trials used a yeast (Saccharomyces boulardii), four used lactobacilli, and one used a strain of enterococcus that produced lactic acid. Three trials used a combination of probiotic strains of bacteria. In all nine trials, the probiotics were given in combination with antibiotics and the control groups received placebo and antibiotics. The odds ratio in favour of active treatment over placebo in preventing diarrhoea associated with antibiotics was 0.39 (95% confidence interval 0.25 to 0.62; P<0.001) for the yeast and 0.34 (0.19 to 0.61; P<0.01 for lactobacilli. The combined odds ratio was 0.37 (0.26 to 0.53; P<0.001) in favour of active treatment over placebo. The meta-analysis suggests that probiotics can be used to prevent antibiotic associated diarrhoea and that S boulardii and lactobacilli have the potential to be used in this situation. The efficacy of probiotics in treating antibiotic associated diarrhoea remains to be proved. A further large trial in which probiotics are used as preventive agents should look at the costs of and need for routine use of these agents.
Article
Antibiotic-associated diarrhoea can be attributed in part to imbalances in intestinal microflora. Therefore, probiotic preparations are used to prevent this diarrhoea. However, although several trials have been conducted, no conclusive evidence has been found of the efficacy of different preparations, e.g. Lactobacillus spp. and Saccharomyces spp. To conduct a meta-analysis of the data in the literature on the efficacy of probiotics in the prevention of antibiotic-associated diarrhoea. A literature search was performed of electronic databases, Abstract Books and single paper references. Data were also obtained from the authors. Only placebo-controlled studies were included in the search. The Mantel-Haenszel test was used to estimate the relative risk for single studies and an overall combined relative risk, each study being submitted to the Mantel-Haenszel test for homogeneity. Twenty-two studies matched the inclusion criteria. Only seven studies (881 patients) were homogeneous. The combined relative risk was 0.3966 (95% confidence interval, 0.27-0.57). The results suggest a strong benefit of probiotic administration on antibiotic-associated diarrhoea, but further data are needed. The evidence for beneficial effects is still not definitive. Published studies are flawed by the lack of a placebo design and by peculiar population features.
Article
Objective: To evaluate efficacy of probiotics in prevention and treatment of diarrhoea associated with the use of antibiotics. Design: Meta-analysis; outcome data (proportion of patients not getting diarrhoea) were analysed, pooled, and compared to determine odds ratios in treated and control groups. Identification: Studies identified by searching Medline between 1966 and 2000 and the Cochrane Library. Studies reviewed Nine randomised, double blind, placebo controlled trials of probiotics. Results: Two of the nine studies investigated the effects of probiotics in children. Four trials used a yeast (Saccharomyces boulardii), four used lactobacilli, and one used a strain of enterococcus that produced lactic acid. Three trials used a combination of probiotic strains of bacteria. In all nine trials, the probiotics were given in combination with antibiotics and the control groups received placebo and antibiotics. The odds ratio in favour of active treatment over placebo in preventing diarrhoea associated with antibiotics was 0.39 (95% confidence interval 0.25 to 0.62; P<0.001) for the yeast and 0.34 (0.19 to 0.61; P<0.01 for lactobacilli. The combined odds ratio was 0.37 (0.26 to 0.53; P<0.001) in favour of active treatment over placebo. Conclusions: The meta-analysis suggests that probiotics can be used to prevent antibiotic associated diarrhoea and that S boulardii and lactobacilli have the potential to be used in this situation. The efficacy of probiotics in treating antibiotic associated diarrhoea remains to be proved. A further large trial in which probiotics are used as preventive agents should look at the costs of and need for routine use of these agents.
Article
Probiotics are commonly defined as viable microorganisms (bacteria or yeasts) that exhibit a beneficial effect on the health of the host when they are ingested. They are used in foods, especially in fermented dairy products, but also in pharmaceutical preparations. The development of new probiotic strains aims at more active beneficial organisms. In the case of novel microorganisms and modified organisms the question of their safety and the risk to benefit ratio have to be assessed. Lactic acid bacteria (LAB) in foods have a long history of safe use. Members of the genera Lactococcus and Lactobacillus are most commonly given generally-recognised-as-safe (GRAS) status whilst members of the genera Streptococcus and Enterococcus and some other genera of LAB contain some opportunistic pathogens. Lactic acid bacteria are intrinsically resistant to many antibiotics. In many cases resistances are not, however, transmissible, and the species are also sensitive to many clinically used antibiotics even in the case of a lactic acid bacteria- associated opportunistic infection. Therefore no particular safety concern is associated with intrinsic type of resistance. Plasmid-associated antibiotic resistance, which occasionally occurs, is another matter because of the possibility of the resistance spreading to other, more harmful species and genera. The transmissible enterococcal resistance against glycopeptide antibiotics (vancomycin and teicoplanin) is particularly noteworthy, as vancomycin is one of the last effective antibiotics left in the treatment of certain multidrug-resistant pathogens. New species and more specific strains of probiotic bacteria are constantly identified. Prior to incorporating new strains into products their efficacy should be carefully assessed, and a case by case evaluation as to whether they share the safety status of traditional food-grade organisms should be made. The current documentation of adverse effects in the literature is reviewed. Future recommendations for the safety of already existing and new probiotics will be given.
Article
This review was designed to assess the evidence from randomized controlled trials on effects of probiotics in the treatment and prevention of acute infectious diarrhea in infants and children. A systematic review of published, randomized, double-blind, placebo-controlled trials on probiotics in the treatment or prevention of acute diarrhea defined as >3 loose or watery stools per 24 hours in infants and children. The use of probiotics as compared with placebo was associated with a significantly reduced risk of diarrhea lasting >3 days. The pooled estimate risk was 0.43 (95% CI, 0.34-0.53) with a fixed-effect model, and remained significant in a random-effect model (0.40; 95% CI, 0.28-0.57). Only Lactobacillus GG showed a consistent effect. Probiotics significantly reduced the duration of diarrhea when compared with placebo, particularly in rotaviral gastroenteritis-the pooled, weighted, mean difference (WMD) assuming the random-effect model was -20.1 hours (95% CI, -26.1 to -14.2) and -24.8 (95% CI, -31.8 to -17.9) respectively. A meta-analysis of the prevention studies was not feasible because of significant clinical and statistical heterogeneity. There is evidence of a clinically significant benefit of probiotics in the treatment of acute infectious diarrhea in infants and children, particularly in rotaviral gastroenteritis. Lactobacillus GG showed the most consistent effect, although other probiotic strains may also be effective. Further research is needed. Clinical and statistical heterogeneity of the prophylactic interventions preclude drawing firm conclusions about the efficacy of probiotics in preventing acute gastroenteritis.
Article
Our objective was to determine the efficacy of probiotic use in reducing the duration of increased stool output in children with acute diarrheal illness. Eligible studies were limited to trials of probiotic therapy in otherwise healthy children <5 years old with acute-onset diarrhea. The main outcome variable was difference in diarrhea duration between treatment and control groups. Our meta-analysis of 18 eligible studies suggests that coadministration of probiotics with standard rehydration therapy reduces the duration of acute diarrhea by approximately 1 day [random-effects pooled estimate = -0.8 days (-1.1, -0.6), P < 0.001]. Differences in treatment effect between studies was assessed by calculating the Q statistic (Q = 204. 1, P < 0.001). In subsequent analyses limited to studies of hospitalized children, to double-blinded trials, and to studies evaluating lactobacilli, the pooled estimates were similar (-0.6 to -1.2 days, P < 0.001). In conclusion, bacterial probiotic therapy shortens the duration of acute diarrheal illness in children by approximately one day.
Article
Objective To evaluate efficacy of probiotics in prevention and treatment of diarrhoea associated with the use of antibiotics. Design Meta›analysis; outcome data (proportion of patients not getting diarrhoea) were analysed, pooled, and compared to determine odds ratios in treated and control groups. Identification Studies identified by searching Medline between 1966 and 2000 and the Cochrane Library. Studies reviewed Nine randomised, double blind, placebo controlled trials of probiotics. Results Two of the nine studies investigated the effects of probiotics in children. Four trials used a yeast (Saccharomyces boulardii), four used lactobacilli, and one used a strain of enterococcus that produced lactic acid. Three trials used a combination of probiotic strains of bacteria. In all nine trials, the probiotics were given in combination with antibiotics and the control groups received placebo and antibiotics. The odds ratio in favour of active treatment over placebo in preventing diarrhoea associated with antibiotics was 0.39 (95% confidence interval 0.25 to 0.62; P < 0.001) for the yeast and 0.34 (0.19 to 0.61; P < 0.01 for lactobacilli. The combined odds ratio was 0.37 (0.26 to 0.53; P < 0.001) in favour of active treatment over placebo. Conclusions The meta›analysis suggests that probiotics can be used to prevent antibiotic associated diarrhoea and that S boulardii and lactobacilli have the potential to be used in this situation. The efficacy of probiotics in treating antibiotic associated diarrhoea remains to be proved. A further large trial in which probiotics are used as preventive agents should look at the costs of and need for routine use of these agents.
Article
Probiotics are microbial cell preparations or components of microbial cells that have a beneficial effect on the health and well being of the host. Probiotics may offer a safe intervention in acute infectious diarrhoea to reduce the duration and severity of the illness. To assess the effects of probiotics in proven or presumed infectious diarrhoea. We searched the Cochrane Infectious Diseases Group's trials register (December 2002), the Cochrane Controlled Trials Register (The Cochrane Library Issue 4, 2002), MEDLINE (1966 to 2002), EMBASE (1988 to 2002), and reference lists from studies and reviews. We also contacted organizations and individuals working in the field, and pharmaceutical companies manufacturing probiotic agents. Randomized controlled trials comparing a specified probiotic agent with placebo or no probiotic in people with acute diarrhoea that is proven or presumed to be caused by an infectious agent. Two reviewers independently assessed trial methodological quality and extracted data. Twenty-three studies met the inclusion criteria with a total of 1917 participants, mainly in countries with low overall mortality rates. Trials varied in relation to the probiotic(s) tested, dosage, methodological quality, and the diarrhoea definitions and outcomes. Probiotics reduced the risk of diarrhoea at 3 days (relative risk 0.66, 95% confidence interval 0.55 to 0.77, random effects model; 15 studies) and the mean duration of diarrhoea by 30.48 hours (95% confidence interval 18.51 to 42.46 hours, random effects model, 12 studies). Subgroup analysis by probiotic(s) tested, rotavirus diarrhoea, national mortality rates, and age of participants did not fully account for the heterogeneity. Probiotics appear to be a useful adjunct to rehydration therapy in treating acute, infectious diarrhoea in adults and children. More research is needed to inform the use of particular probiotic regimens in specific patient groups.
Article
A number of studies involving the feeding of probiotics and prebiotics to infants have been published over the last decade. These studies have examined a wide range of health outcomes, including growth and safety, prophylaxis and alleviation of diarrheal disease, reduction in atopic disease, reduction in necrotizing enterocolitis, and reduction in infection of the preterm infant. In addition, these studies have described microbiological alterations observed in response to probiotic and prebiotic feeding. Collectively, the reports demonstrate that probiotics show considerable promise in addressing several health outcomes of significance to both formula-fed and breastfed infants. As quantitative and qualitative differences appear to exist between the microfloras of human-milk fed and formula-fed infants, recent innovations to infant formula have involved the inclusion of probiotics and prebiotics as a means of making the flora of the formula fed infant more similar to that of the breastfed infant. To date, only a few probiotic- and prebiotic-containing infant formulas have been marketed, but as new safety and efficacy data emerge and the regulatory climate becomes more favourable, the number of products is expected to grow.