See “Human Milk Probiotic Lactobacillus fermentum CECT5716 Reduced the Incidence of Gastrointestinal and Upper Respiratory Tract Infections in Infants” by Maldonado et al on page 55.
Maldonado et al (1) report in this issue their work on Lactobacillus fermentum CECT5716. Literature on the topic of “the role of the gastrointestinal flora in health and disease” is exploding, but the increasing amount of data still fail to result in the expected high scientific evidence level for benefit. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Committee on Nutrition published in 2011: “at present, there are insufficient data to recommend the routine use of probiotics and/or prebiotic-supplemented formulae” (2). Nevertheless, it is virtually impossible to find formulae on the European market without pro- or prebiotics.
Probiotics are etymologically a composite of the Latin preposition pro (“for”) and the Greek adjective βιωτικóζ (biotic), the latter deriving from the noun βíοζ (bios, “life”). Probiotics are defined as “nonpathogenic live microorganisms that resist normal digestion to reach the colon alive, which, when consumed in adequate amounts, have a positive effect on the health of the host.” The knowledge that microorganisms can be harmful to health but also be beneficial has a long history. Plinius the Elder recommended the consumption of yoghurt for the treatment of diarrhea. The discovery of Saccharomyces boulardii, one of the best-studied probiotics listed by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition as effective for the treatment of diarrhea (3,4), was the consequence of observing traditional habits. When Henry Boulard was traveling in the Far East, he noticed that the local population was consuming the shells of litchis and mangosteen when they experienced diarrhea. Henry Boulard discovered that the yeast Saccharomyces was growing on these shells and was the reason for the reduction of diarrhea.
The knowledge that human milk also is a source of lactic acid bacteria is a recent discovery (5). As a consequence, human milk, which is also rich in prebiotic oligosaccharides (and differs in this aspect from animal milk), should be regarded as containing synbiotics, a combination of pre- and probiotics. When compared with formula-fed babies, breast-fed infants are known to differ in physical growth and cognitive, emotional, and social development and to have less infectious diseases and fewer allergies. As a consequence, the health care cost of formula-fed infants is considerably greater compared with breast-fed babies (6). Although many factors, such as more intense mother–infant interaction and lower attendance of day care centers, are contributing factors, it is generally accepted that it is the adaptive immune system, shaped by gastrointestinal (GI) flora composition, that leads to the lower infectious disease incidence in breast-fed compared with “classic” infant formula–fed infants (“classic” infant formula means infant formula without added prebiotic oligosaccharides and probiotics). Differences in GI flora development between breast-fed and classic infant formula–fed infants are no longer debated.
The exclusively breast-fed infant, and not the composition of mother's milk, should be considered the criterion standard or the reference (7). Therefore, it should be the goal of any alternative feeding to mimic the effects of mother's milk on the baby as closely as possible. There are many immunological components in mother's milk, but prebiotic oligosaccharides and (recently discovered) probiotics are among the most important (7). Because clinical studies show that the addition of specific prebiotic oligosaccharides reduces infections and atopy in otherwise healthy infants, prebioitic enrichment of infant formula seems reasonable (7). The study by Maldonado et al provides evidence that L fermentum CECT5716 added to infant formula, already containing prebiotic oligosaccharides, results in additional health benefits.
The use of probiotic microorganisms encompasses 2 major fields: prevention and treatment. Before probiotics can be prescribed as a treatment, the accumulated scientific evidence should be the same as for any medication. This means that phase I, II, and III clinical trials should have been performed and the data published. Carefully conducted randomized controlled prospective trials, with relevant inclusion/exclusion criteria and adequate sample sizes, are necessary. These studies should use validated clinical outcome measures to assess the effects. Such trials also should define the optimal dosage and intake durations. Trials should be performed with the commercialized product because of possible differences in number and viability of the strains between a commercialized product and “special study preparations.” Independent trials, preferentially financed jointly by national or European Union bodies or other international organizations, are preferable to company-funded research. Because most probiotics are registered as food supplements and not as drugs, they do not have to fulfill the legal criteria that have been established for medication. Obvious differences between legislation for food supplements and medication pertain to marketing and labeling. A simple example is the label of a food supplement lacks precision. Dosage and strain definition on the label may differ from the actual contents (8). It is unconceivable that physicians would prescribe medication to treat any disease when the quality and dosage of the product cannot be guaranteed, yet we may do so for probiotics. A relatively easy way to reduce confusion may be to call “probiotics that fulfill the mandatory criteria to be registered as drugs” by a different name, for example, “biotherapeutic agents.” The risk for abuse persists because criteria for drug registration differ by country. In some countries, probiotic products are registered as medication, although there is not 1 PubMed-listed publication to support efficacy.
Probiotics used in food are different. If for a drug, “efficacy” dominates to some extent “safety,” the opposite is true for food. When performing studies with food supplements, it is important to use the food product, as it will be or is commercialized, and not with probiotic capsules that were added to the food. For probiotics added to food, safety data are of major importance. There are reports of trials that had to be stopped because of the high incidence of GI adverse effects, even with heat-killed microorganisms (9). Available scientific data suggest that the administration of the presently evaluated probiotic- and/or prebiotic-supplemented formula to healthy infants does not raise safety concerns with regard to growth and adverse effects (2). However, because enrichment of infant formula with probiotics alters GI flora composition and because the latter is an important factor determining the development of the adaptive immune system, long-term data on safety are needed. Today, we know that probiotics taken in by children and adults do not colonize the GI tract. Once the intake is discontinued, the strains vanish after 1 to 2 weeks from the flora. There are no data on what happens when probiotics are administered to the newborn, with a sterile GI tract (after cesarean section) or who has been inoculated with maternal vaginal and GI flora (normal delivery). Although the probiotics in infant formula have been selected and isolated from the human GI tract, they are not present in every human and the amounts present in formula or in the human GI tract will differ. Moreover, in the GI tract, strains are part of a subtle balance of a complex flora with >1000 of different strains. Mother's milk seems to contain only a restricted number of strains (5). Therefore, the choice to enrich a formula with a probiotic strain from mother's milk seems more logical than using a strain from the GI flora. Moreover, the authors did prove that the strain under study was safe (10).
The question can be raised whether it is really important to demonstrate a statistically significant health benefit from probiotics used as food supplements. A major reason to raise this question relates to extrapolating the data. If a benefit is shown in a well-designed clinical trial, what will this mean for the daily clinical routine? Indeed, many factors will affect the outcome of studies evaluating the effect of probiotics in infant formula (food): way of delivery, breast-feeding or not, antibiotic and probiotic use during pregnancy, number of children in the household, living in a rural or urban area, age at intervention, duration of the intervention, preparation of the formula (microwave heating and effect on the probiotic), antibiotics given to the baby, day care visit, family history of atopy (children who will become atopic develop a different flora from nonatopics), and so on. This list remains incomplete and indicates that the number of confounding variables is almost endless. The intervention in the trial reported by Maldonado et al started at 6 months, including per definition a heterogeneous population, although the authors did exclude some groups. During a 6-month intervention period, there was a statistically significant reduction of 46% fewer GI infection events, but this means that instead of 33 events of GI infections in the control group, 19 events occurred in the intervention group, but this was on >15,000 observation days in each group. Thus, the question can be raised whether this “probiotic benefit” has any clinical relevance. Moreover, other clinically relevant parameters such as lower respiratory infection, urinary tract infections, febrile episodes, and antibiotic treatment did not differ in both groups. Because the intervention was started at the age of 6 months, the probiotic will not colonize the GI tract, which means that the effect will be limited to the period that the strain is administered. Every study design has shortcomings that hamper the application of the findings. In the study by Madonado et al, a probiotic strain present in mother's milk is given to infants between 6 and 12 months of age. However, in reality, only a minority of the babies is breast-fed at this age, although recommendations are to breast-feed longer. Although the selection of a strain present in mother's milk seems at first logic, the question can as well be asked why a strain is selected that is no longer ingested by the majority of babies at this age. No information is provided regarding the amount of L fermentum CECT5716 ingested with the formula and the amount present in mother's milk
There is broad consensus that strain specificity is important in probiotic research. However, clinical data to sustain this statement are limited. The definition of a probiotic states that the microorganism must reach the colon alive. However, this does not state in which amount. Most of the lactobacilli present in naturally fermented food, as is the case in yoghurt, kimchi (fermented coal), and ceviche (fermented fish), are killed by gastric acid and bile. Several studies also suggest the benefit of heat-killed microorganisms. Also, the “sufficient amount” by which a probiotic needs to be ingested is more relevant for therapeutic use than for alimentation. The literature frequently cautions about the possibility of interactions, both synergism and antagonism, between probiotic strains, but clinical data on this topic are scarce and this seems again more relevant for medication than for food. Microorganisms that are added to food should first of all be safe. Besides the fact that the authors did show safety of the added probiotic (10), the fact that the selected strain is present in mother's milk is a strong argument regarding safety. If in addition (a trend toward) a clinical benefit is shown, there seem to be few arguments to discourage its addition to infant formula.
In conclusion, the use of probiotics as food (supplement) or as drug are 2 different entities. Although for food, the demonstration of safety is a priority, for medication, the demonstration of efficacy is more relevant. To decrease the confusion, it may be preferable to rename microorganisms used as drugs differently. “Biotherapeutic agent” is an option.
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