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Food Research and Development Centre, Agriculture and Agri-Food Canada, Saint Hyacinthe, QC, Canada
* To whom correspondence should be addressed. E-mail: farnworthed{at}agr.gc.ca.
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ABSTRACT |
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 TOP ABSTRACT IntroductionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionLITERATURE CITED |
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The objective of this article is to outline the main challenges associated with accumulating evidence in support of health claims for probiotics and to give a perspective of the scientific gaps that need to be addressed to advance these functional foods. This article addresses probiotics in a food or beverage format. Unless otherwise stated, references to regulations apply to Canadian regulations or to those that apply worldwide.
Challenges associated with establishing health claims for probiotics
Identification of microorganisms. Worldwide, food manufacturers are developing new functional foods. An important part of the marketing of these new products is the ability to label these foods with a health claim. Any petition to a regulatory agency for a health claim will have to name or describe the active ingredients in the product to be approved and provide evidence of efficacy. Companies seeking approved label health claims for probiotics may find this somewhat problematic. For example, definitive identification of the microorganisms contained in the probiotic product often requires rigorous molecular biology and informatics techniques (11). Polyphasic characterization combining phenotypic, biochemical, genotypic, and sequencing results is now being used to reliably identify bacteria to the strain level (12). This is particularly important because it is now evident that even closely related bacterial species can have different properties. Properties such as pH sensitivity and resistance to bile salts or other characteristics may affect their ability to survive in the gastrointestinal (GI) tract and exert their beneficial effects (13,14). It is essential, therefore, that the bacteria included in a probiotic be identified to the species or subspecies level. In some cases, the bacterial strain used is proprietary, which can make verification of its identity by regulatory agencies more difficult.
To obtain a health claim for a probiotic product, food manufacturers will have to precisely define their microorganism. Identification methods are constantly being improved, and this will make definitive identification easier.
Enumeration of microorganisms. The definition of probiotic emphasizes that the organism must be taken in adequate amounts to be effective. To support a health claim, it is thus imperative that the product manufacturer provides data about the total number of live microorganisms in the product when consumed as well as methodology that can be used to verify these values. To the consumer, "more is better," and so efforts are often made by food manufacturers to highlight the large numbers of bacteria in their product. Enumerating bacteria or other microorganisms in a food matrix is not easy (15), and if the product contains more than 1 microorganism, individual methods may have to be used to enumerate each microorganism. Although there are accepted methods for the counting and reporting of pathogenic and spoilage organisms in food, such universally accepted methods do not exist for probiotic bacteria.
At this time, in many other jurisdictions, there is no requirement for a company to state which bacteria are contained in its product, no requirement to use accepted nomenclature for the bacteria in the product, no requirement to state the number of bacteria in the product, and no requirement to ensure that the numbers of bacteria quoted on the label are alive.
Stating the type, viability, and number of bacteria contained in a probiotic product is important to both the consumer and health regulatory officials. At the present time, there is little incentive for manufacturers to include this information on their product; the costs for such quality assurance would be high. As regulations become clearer as they relate to probiotics, manufacturers can expect that they will be required to state this information. Consumers are also becoming more educated about probiotics, and so, they too will be pressuring food manufacturers for this information.
Efficacy testing. No single biomarker has been identified that applies to all clinical trials involving probiotics because of the wide variety of diseases and conditions that have been studied.
The efficacy of probiotics has been studied for a variety of diseases and metabolic problems including Crohn's disease (16–18), irritable bowel syndrome (19,20), cholesterol metabolism (21,22), anticancer properties (23,24), and diverticulitis (25). It must be noted, however, that the degree of success that has been obtained for these conditions/diseases in probiotic feeding trials has not been uniform, and it would be wrong to assume that there exists good evidence to suggest that all of these conditions may be improved with probiotics. In many cases the GI tract has been the primary target (26,27), but it is becoming evident that other conditions including allergies, obesity, and urogenital infections not initially associated with the gut microbiota might also be affected (28–30). A variety of mechanisms have been proposed to explain the responses to probiotics, including production of organic acids, production of bacteriocins (bacterial substances produced by a strain of certain bacteria and harmful to another strain within the same family), and reduction of toxin-producing organisms (31) as well as effects on the mucosal epithelium and the gut-associated lymphoid tissue (32). The suggestion that probiotics may be stimulating the immune system has generated a great deal of interest because of possible consequences to health and metabolism. However, studies are not often replicated, and therefore, efficacy is hard to establish. Some articles often lacked details such as the bacterial strain fed, the numbers of live bacteria consumed, or the timing of the consumption, e.g., with or without other foods, which limits their usefulness to prove efficacy. Hove et al. (33) concluded, after their review of the current literature, that a scientific consensus was being achieved concerning the beneficial effects of some probiotic bacteria for 2 applications in particular: lactose intolerance and diarrhea. Several studies have reported that the consumption of certain probiotic bacteria resulted in reduced lactose intolerance symptoms in human subjects (34,35). Furthermore, a meta-analysis of the treatment of both childhood and rotavirus-associated childhood diarrhea with probiotic bacteria showed a significant reduction in the duration of the diarrhea episode (36). These 2 applications of probiotics appear to be the best documented and have enough reliable data to support a human health claim.
Despite the long list of conditions that have been tested with various probiotic products, very few health/metabolism conditions have been studied enough to obtain a label health claim. Efficacy experiments must be replicated and have appropriate numbers of subjects to achieve scientific consensus. The claim of efficacy will be greatly enhanced if a plausible mechanism can be suggested, or demonstrated, that explains the beneficial effect.
Clinical trials and active ingredients. A double-blind, placebo-controlled clinical trial is considered as the "gold standard" for most efficacy experiments, but researchers testing probiotics, like most trials testing foods, have difficulty finding an appropriate control (37,38). Adding to this problem is the fact that it is often difficult to define what is the active ingredient in a probiotic food (Fig. 1). If the product has undergone fermentation, the number of possible candidates include the live bacteria themselves, components such as the cell wall, metabolites of the bacteria including exopolysaccharides, or ingredients produced during the fermentation process such as bioactive peptides. Most probiotic products today emphasize the number of live bacteria. However, in some cases, the ingredients responsible for the beneficial effects, such as a product of fermentation or a bacterial metabolite, may not require that the probiotic bacteria be viable when consumed.
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Health regulation officials worldwide require scientific evidence before they will approve a label health claim. Although biochemical, animal, and in vitro data can be used as supporting evidence, data from double-blind, placebo-controlled experiments are required. These experiments are expensive, but there is no substitute for these trials. Both from a scientific and a regulatory perspective, the identification of the active ingredient in a probiotic product is necessary. The probiotic producer also needs this information so that the active ingredient can be protected or extracted to be used in other products including nutraceuticals.
Dosage of probiotic bacteria. The number and the status of the bacteria to be consumed to obtain a beneficial effect are important characteristics of probiotic products that are often not well defined.
There is no consensus as to the minimum number of bacteria that need to be consumed to produce a beneficial effect on human metabolism and health. Each application for a health claim will be different. It can be anticipated that recommended doses will differ depending on the application (e.g., prevention vs. treatment of diarrhea). Differences between the properties (e.g., pH sensitivity) of bacterial strains will also have to be considered when recommendations on dosage levels are made.
The Fermented Milks and Lactic Acid Bacteria Beverages Association of Japan has set a minimum of 107 bifidobacteria/g or mL (43), but others have suggested a lower level of 105 (44). The harsh conditions in the GI tract and negative environment associated with low stomach pH, bile salts, and digestive enzymes require that large numbers of probiotic bacteria be consumed to ensure that an adequate number survive and reach their site of action in the lower GI tract. A wide range of numbers of bacteria fed can be found in the scientific literature. Many studies have shown that probiotics must be consumed every day because they do not colonize the gut and are quickly flushed out of the GI tract when consumption is stopped (45).
At this time, microbiological analyses of fecal material are the only way to show that the probiotic bacteria have remained viable during their passage through the GI tract. This is a major limitation because the site of action of probiotics is the large intestine or even higher up the GI tract. Therefore, even if companies are able to report how many viable bacteria are contained in their product when consumed, they are not able to report how many bacteria actually produce the beneficial effect at the site of action.
Probiotics are food products, but because their benefits impact on health, the concept of dose becomes important. At the present time, no probiotic bacterium has been shown to colonize the gut and persist after the cessation of consumption. Data from efficacy and clinical experiments will be needed to advise consumers how much of the product needs to be consumed each day to obtain a beneficial effect.
Safety aspects. The final aspect of probiotics of concern to both consumers and regulators is that of safety. Lactococcus and Lactobacillus are most commonly given "generally recognized as safe" status, but some of the genera Streptococcus and Enterococcus and some other genera of LAB that could be potential probiotics contain opportunistic pathogens (46). The absence of pathogenicity of any potential probiotic strain must be shown to prove its safety. There are very few reports in the literature of adverse reactions resulting from consumption of probiotic bacteria, particularly Lactobacilli and Bifidobacteria; however, the possibility of transmitting plasmid-associated antibiotic resistance has been noted as a possible concern in the development of probiotic products (47).
At this time, there are laws and regulations related to the pathogens and microbial food contaminants. No jurisdiction will allow the sale of unsafe food. Probiotics already enjoy an implied good health claim that cannot be jeopardized by possible questions of food safety. Most LAB are considered safe for human consumption, and so their inclusion in probiotic products presents no problems. However, before any new probiotic microorganisms will be approved, data will have to be submitted that clearly show they are safe for human consumption.
Health claims worldwide
Around the world, although the number of functional foods is growing, the number of probiotics carrying approved health claims is not large (48). The jurisdictions of the European Community, Japan, the United States, and Canada all have legislation to cover the approval of health claims for functional foods, but it has been observed that only a limited number of claims have been approved (49). The Japanese Foods for Specific Health Use (FOSHU) system allows several health claims for probiotics (Table 2). As a result, by 1999, 21 probiotic products had received FOSHU approval in Japan (48).
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Health Canada regulations related to probiotics
Health Canada (HC) is the regulator responsible for food label claims in Canada. Schedule 1 of the legislation creating the Natural Health Products Directorate (NHPD) of HC lists "probiotic" as 1 of the substances under their jurisdiction (7). NHPD has its own working definition of a probiotic (Table 1). For HC, a probiotic is limited to nonpathogenic microorganisms. Foods such as yogurt that contain "microbes" are controlled by the Food Products Directorate of HC.
As with other food products regulated by HC, probiotics can carry a structure/function claim, a risk reduction claim, or a treatment claim (Table 3). This compares with the United States, where a probiotic is regulated at the federal level as a dietary supplement, a food, or as a drug, depending on the intended use. Efficacy data to support any label health claim in Canada are judged based on a hierarchy of criteria used to measure the scientific rigor of the research that generated the data (50). The amount and quality of the data to be supplied depend on the claim that is sought (51).
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Probiotic products in either capsule or liquid form as nutraceuticals or as functional foods can be found in the marketplace in Canada today. It is not known how many petitions HC has received from companies related to probiotics. However, since its inception in 2004, HC/NHPD has not issued an approved health claim for any probiotic product (55).
Probiotics: is there evidence to support health claims?
The experimental evidence to identify probiotic microorganisms and to demonstrate their efficacy in clinical trials is more challenging than for other potential functional foods because effects are mediated by living microorganisms and may therefore be influenced by the status of these microorganisms. Mechanisms are seldom known, markers are generally not available, and matrix effects may be pronounced. Because of the lack of well-controlled studies in humans, health regulatory officials in most jurisdictions have not yet been convinced that there are sufficient consistent data to support health claims for probiotics, and so very few approved health claims on probiotic food products have been granted to date.
Probiotics have been tested on a long list of diseases and conditions, and it appears that a scientific consensus is approaching for the use of certain probiotics for lactose intolerance and rotavirus diarrhea. Claims related to these benefits may be the first to be accepted in many jurisdictions. Before other claims are approved, manufacturers will have to invest considerable time and money to obtain data to show the efficacy and safety of their probiotic product. The data and documentation required to obtain a label health claim will be different in different jurisdictions because of differences in legislation. These discrepancies will add to the challenges faced by probiotics producers and consumers.
Other articles in this supplement include references (56–64).
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FOOTNOTES |
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2 Author disclosures: E. R. Farnworth, no conflicts of interest.
3 Abbreviations used: FOSHU, Foods for Specific Health Use; GI, gastrointestinal; HC, Health Canada; LAB, lactic acid bacteria; NHPD, Natural Health Products Directorate.
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LITERATURE CITED |
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TOPABSTRACTIntroductionLITERATURE CITED |
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