Article

gastroenterology

Probiotics
Theresa L. Charrois, BSc Pharm, MSc,* Gagan Sandhu,* Sunita Vohra, MD, MSc*

Complementary and Alternative Medicine: A New Series

Pediatrics in Review is happy to present a new series. It is difcult to dene complementary and alternative medicine, but one perspective would be to include methods of treating or preventing 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 Alternative 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 scientic eye and an open mind that we present these articles, starting with a discussion of probiotics. Signicant 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

Author Disclosure Ms Charrois, Ms Sandhu, and Dr Vohra did not disclose any nancial relationships relevant to this article.

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 ora.

Denition and Description

Probiotics are nonpathogenic microbes, usually of the lactic acid-producing variety, that are used to improve or normalize the balance of gut microora. 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, Bidobacterium, and Saccharomyces 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, inammatory bowel disease, acute gastroenteritis, and antibiotic-related diarrhea. Although probiotic preparations are used commonly worldwide, specic use data for children are unavailable.

Evidence of Efcacy 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, radiationinduced diarrhea, necrotizing enterocolitis, prophylaxis against bacterial sepsis, and urinary 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. Pediatrics in Review Vol.27 No.4 April 2006 137

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Table.

Summary of Systematic Reviews of Probiotics in Children

Patient Population and Study Design Adults and children RCTs (n 23 studies) Adults and children R, DB, PC trials (n 9 studies) Children <5 y Controlled clinical trials (n 18 studies) Adults and children RCTs (n 22 studies) Results Risk of diarrhea at 3 days: RR 0.66; 95% CI 0.55, 0.77 (favor probiotics) Patients free of diarrhea: OR 0.37, 95% CI 0.26, 0.53 (favor probiotics) Reduction of diarrhea: 0.8 days, 95% CI 1.1, 0.6 days (favor probiotics) Presence of diarrhea at end of treatment: RR 0.40, 95% CI 0.27, 0.57 (favor probiotics) Risk of diarrhea: RR 0.40, 95% CI 0.28, 0.57 (favor probiotics) Conclusions Promising results; signicant heterogeneity of methods and outcomes Positive results; no information regarding adverse events Signicant heterogeneity of methods and outcomes; less rigorous systematic review Positive effects; some methodologic problems such as unclear inclusion and exclusion criteria Only Lactobacillus GG showed consistent benet (other studies included L reuteri, S boulardii, L acidophilus)

Citation Allen et al, 2002 (1) Probiotics for treating infectious diarrhea DSouza et al, 2002 (2) Probiotics in prevention of antibiotic-associated diarrhea: meta-analysis Huang et al, 2002 (3) Efcacy of probiotic use in acute diarrhea in children: a meta-analysis Cremonini et al, 2002 (4) The effect of probiotic administration on antibiotic-associated diarrhea: a meta-analysis Szajewska et al, 2001 (5) Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children

Infants and children RCTs (n 10 studies)

RCT randomized controlled trial, R randomized, DB double-blind, PC placebo-controlled, RR relative risk, OR odds ratio, 95% CI 95% condence interval.

Common empiric uses that have not yet been studied formally include acne, canker sores, colon cancer, heart disease, nonalcoholic fatty liver, and thrush.

Pharmacologic Action
Probiotics are believed to modulate immune activity via differential activation of epithelial and immune cell receptors. Postulated mechanisms of action include inhibition 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.

Evidence of Safety
Clinical trials have not revealed major adverse effects of probiotics in healthy individuals, and long-term consumption also appears to be safe and well tolerated. However, there are case reports of aggravation of existing 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, ker, and sauerkraut. However, supplemental forms usually provide higher doses of probiotic bacteria. Some probiotics (L acidophilus, Lactobacillus GG, Saccharomyces sp) have been found safe for use in children if administered in appropriate doses. Usage has been evaluated in randomized, controlled trials for children as young as 1 month of age. Information is insufcient to recommend safe probiotic supplement usage by women who are pregnant or lactating. Usage of probiotic-containing foods in this population generally is considered safe.
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Administration/Dosage Forms
The investigated dosages range from 1 million to 300 billion colony-forming units per day. Probiotic supplements usually are administered as capsules or powder. There is signicant discrepancy in the literature as to appropriate doses in children, and the dose varies according to probiotic. Moreover, variations are signicant between and within products because production generally 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 sprinkled on food or dissolved in beverages, which aids in administration to children. However, because some pro-

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probiotics

biotics are sensitive to gastric acid and bile, they should be administered on an empty stomach. This property is product-specic, and patients should refer to the labeling instructions. Treatment often is initiated at the same time as antibiotic therapy to prevent antibiotic-associated diarrhea. 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. Probiotics for treating infectious diarrhoea. Cochrane Database Syst Rev. 2003;4:CD003048 2. DSouza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic-associated diarrhoea: meta-analysis. BMJ. 2002;324:13611366 3. Huang JS, Bousvaros A, Lee JW, Diaz A, Davidson EJ. Efcacy

of probiotic use in acute diarrhea in children: a meta-analysis. Dig Dis Sci. 2002;47:26252634 4. Cremonini F, Di Caro S, Nista EC, et al. Meta analysis: the effect of probiotic administration on antibiotic-associated diarrhoea. Aliment Pharmacol Ther. 2002;16:14611467 5. Szajewska H, Mrukowicz JZ. Probiotics in treatment and prevention of acute infectious diarrhea in infants and children: a systematic review of published randomized, double-blind placebocontrolled trials. J Pediatr Gastroenterol Nutr. 2001;33(suppl 2): S17S25 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;11:5574 8. Salminen S, von Wright A, Morelli L, et al. Demonstration of safety of probiotics a review. Int J Food Microbiol. 1998;44: 93106

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 eld. We welcome your letters. LFN

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