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COMMENTARY |
Department of Pediatrics,
University of Washington School of Medicine,
Sea Mar Community Health Centers,
8720 14th Ave S,
Seattle, WA 98108
Probiotics, microorganisms that can have positive health effects when ingested, are increasingly studied and used in humans. Thus far, they have shown particular promise in the treatment of acute infectious diarrhea and the prevention of antibiotic-associated diarrhea, associations that have been investigated widely and have been subject to systematic review.1–4 Other conditions potentially treatable by probiotics include chronic diarrhea,5 inflammatory bowel disease,6 irritable bowel syndrome,7 and food allergy8; potentially preventable conditions range from travelers’ diarrhea9 and necrotizing enterocolitis10 to urogenital infections,11 atopic diseases,12 and dental caries.13 Vanderhoof14 and other leaders in the field propose future applications in cystic fibrosis, rheumatoid arthritis, and cancers.
The study reported by Weizman et al15 in this issue of Pediatrics is one of a handful of randomized, controlled trials that have examined probiotics as a prevention for acute infectious illnesses in otherwise healthy infants and children.16–20 This study aims to investigate whether a so-called functional food, infant formula containing either Bifidobacterium lactis or Lactobacillus reuteri, can decrease the risk of diarrhea, respiratory symptoms, fever, and other "morbidity parameters" when compared with a placebo formula. This represents a plausible future real-world scenario: infants attending child care centers, who may be at increased risk of these illnesses, could receive regular prophylaxis in the form of probiotic formula. The authors report a decrease in the numbers of episodes and numbers of days of both diarrhea and fever in the probiotic groups when compared with the placebo group. For example, the subjects in the placebo, B lactis, and L reuteri groups averaged 0.59, 0.37, and 0.15 days with diarrhea (presumably per child during the 12-week study period), respectively. This finding is interesting, although the analysis presented does not support the authors’ assertion that the infants receiving the probiotic formulas actually had "shorter episodes" of diarrhea, because "days with diarrhea" for any 1 subject may represent accumulated days over multiple diarrhea episodes. In any case, the effect sizes themselves are quite small: fractions of a day and fractions of an episode of diarrhea or fever over the 12-week study period. The authors conclude that optimizing the preventive probiotic regimen based on future studies could improve the effect sizes. It seems understandable, however, that large decreases in illness would not be seen in a trial of prevention in a population of healthy infants. Even with precise knowledge of dosing and duration, the real-world practicalities of probiotic administration and compliance could also limit effect size in actual clinical practice.
What can we take away from the study of preventive probiotics by Weizman et al? It shows that these particular probiotic formulas could benefit infants in a child care setting or infants who are not breastfeeding. These 2 groups may be considered at increased risk for respiratory and diarrheal illnesses. It is unclear whether other groups of children would benefit similarly, such as children not in child care or those who are breastfeeding. Could probiotic formula in fact add to the protection afforded by human milk? Also, these results might apply only to the specific probiotic agents studied and the dosing range used. This study was performed in Israel, and the pathogens found in the subjects with diarrhea are representative of the pathogens causing diarrhea in the United States,21 and thus the interactions between probiotic and pathogen would presumably be similar here.
If probiotics continue to demonstrate potential as preventive therapies, several questions arise that are different from those concerning probiotics used as treatments. First, when probiotics are given prophylactically over long periods of time, are they safe? In controlled trials of probiotics as short-term therapies, adverse events have not occurred more frequently with probiotics than with placebo.22 Longer-term prevention studies have demonstrated probiotic safety when used for several months in infants23 and when used for several years in general populations that consume probiotic-containing dairy products and are screened for bacteremia caused by probiotic bacteria.24 Before probiotics become a regular facet of health promotion and a component of foods, however, more longitudinal safety data are needed, especially in children and those with underlying diseases. One can speculate about secondary long-term effects of probiotics as well. For instance, would probiotic formula that prevents mild infections in infants and young children bring about changes in the risks of conditions later in childhood due to dysregulations in immunity that the "hygiene hypothesis" describes in children with fewer community-acquired infections?
A second question arises, as discussed above, in relation to the study by Weizman et al: In which populations will probiotic prevention be effective? It is very possible that probiotics would prevent illness in some groups better than others and not necessarily in those groups in which probiotic treatment works better. For instance, premature neonates, infants, children, and adults may have markedly different responses. With the smaller effect sizes anticipated in preventive trials, large studies are required to approach these questions. Another question resolved best by large randomized trials is that of probiotic dose. Although the dose for treatment of an illness by a particular probiotic agent may be known, its dose for prevention of the same illness may be lower or higher, on the order of 10-fold, 100-fold, or more in terms of colony-forming units. It seems that, at least for acute infectious diarrhea, higher doses of probiotics given for short courses are more effective than lower doses and are equally safe.2 Dose-effect and dose-safety relationships should be investigated also in preventive probiotics given on a long-term basis.
Which probiotic works best? As with probiotic treatment, a certain probiotic’s efficacy in prevention may be due in large part to its genus, species, and strain. Not all lactic acid bacteria have probiotic effects.25 As Weizman et al suggest in their head-to-head comparison of 2 probiotics and placebo, different probiotics may confer different degrees of benefit for various conditions. It is also possible, in the complex environment of the human intestine, that probiotic "cocktails" of multiple strains would be more effective than any single probiotic agent.26 As in probiotic treatment research, probiotic prevention studies will likely focus on diarrheal illness, and inconsistencies in the definition of diarrhea will need to be addressed in these studies as well.
Another crucial realm of science, if probiotics are to make a clinical impact in the future, is the study of mechanisms by which they improve intestinal and overall health. Theories abound and are reviewed by Isolauri et al27: they relate to immune modulation, mucin production, down-regulation of inflammatory responses, secretion of antimicrobial substances, regulation of intestinal permeability, inhibition of pathogens’ mucosal adherence, stimulation of immunoglobin A production, and many other proposed probiotic actions. Research should move forward in both in vitro and clinical areas so that knowledge of the ways that probiotics work in humans can better inform their investigation and use in clinical settings.
Probiotic therapies, once discussed primarily in the context of "complementary" or "integrative" medicine, are entering the therapeutic mainstream of pediatric disease. The American Academy of Pediatrics Subcommittee on Acute Gastroenteritis should be encouraged to include probiotics (Lactobacillus GG, for example) as a recommendation in their practice parameter28 in light of current evidence supporting the use of probiotics for this indication. Although treatment of bacterial gastroenteritis and treatment of children with moderate to severe gastroenteritis is not supported conclusively by studies,29–31 there is strong evidence for the treatment of children with gastroenteritis of viral origin, treatment using Lactobacillus GG, and treatment of children with mild diarrheal illness.29,32,33
With the rise of investigative interest in probiotics as prevention and the publication of positive study results, it seems that probiotics some day could play a significant role in the control of many common childhood conditions that have socioeconomic impacts. Acute infectious diarrhea, for example, is a disease for which no definitive treatment exists, for which the most common pathogen (rotavirus) has no current licensed immunization, and for which a prophylactic probiotic may prove safe and effective. Small effect sizes can be expected in studies of probiotics as prevention. As a result, not only are large randomized, controlled trials important, but it is also crucial to carry out careful cost-effectiveness studies before probiotics are accepted as routine health promotion or added to the foods we eat. Of course, not all probiotics available to the public have been studied rigorously. Although the Food and Drug Administration has jurisdiction over many probiotic products as dietary supplements and does not allow them to make claims of health benefits,34 advocacy for verification of contents and accurate labeling should be a priority. Nevertheless, the exciting possibilities for probiotics to not only treat but also prevent disease are just beginning to unfold.
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FOOTNOTES |
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Address correspondence to Cornelius W. Van Niel, MD, Sea Mar Community Health Centers, 8720 14th Ave S, Seattle, WA 98108. E-mail: cvanniel{at}u.washington.edu
No conflict of interest declared.
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REFERENCES |
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