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3 Food Quality and Standards Service, Nutrition and Consumer Protection Division, Food and Agriculture Organization of the United Nations (FAO), 00153 Rome, Italy and 4 Teagasc, Dairy Products Research Centre, Moorepark, Fermoy, County Cork, Ireland
* To whom correspondence should be addressed. E-mail: maya.pineiro{at}fao.org.
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ABSTRACT |
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Because there was no international consensus on methodology to assess efficiency and safety of probiotics, the FAO and WHO have recently undertaken work to compile and evaluate the scientific evidence on functional and safety aspects of probiotics and generate "Guidelines for the Evaluation of Probiotics in Food." Recently, the FAO and WHO have collaborated to establish guidelines for probiotics in food, investigate the levels of scientific evidence needed to make a health claim, and present these results to Codex with recommendations on labeling and claims for probiotic foods.
This work started in 2001, with a joint FAO/WHO Expert Consultation on Health and Nutritional Properties of Powder Milk with Live Lactic Acid Bacteria, held in Córdoba, Argentina from October 1 to 4, 2001, at the request of the Government of Argentina. A total of 11 experts from 10 countries participated in the Consultation with Dr. Maya Pineiro representing the FAO and Jorgen Schlundt representing WHO.
The terms of reference of the Expert Consultation were 1) to examine the scientific information in relation to the dietary impact of the introduction of live lactic acid bacteria in milk for human consumption; 2) to evaluate the properties, benefits, safety, and nutritional features as well as the potential adverse effects of powdered milk with live lactic acid bacteria on the basis of available scientific data, taking into consideration work done by national authorities, FAO, WHO, other international organizations, and other relevant international organizations; 3) to review the scientific basis for health claims and legislative/regulatory needs; 4) To discuss existing strategies for the safety and nutritional assessment of this type of probiotic, taking into account ever increasing public concerns and experiences accumulated in food safety evaluation; and 5) to make recommendations on further research needs, priorities for evaluation of safety and nutritional aspects of probiotics, as well as regulatory actions if required. It was recognized that the properties, functionality, and benefits of selected probiotics are unique and that the benefits to be gained by ingestion of a particular strain, which are usually strain specific, cannot be extrapolated to other strains, even within the same species. For example, a study undertaken by Isolauri and coworkers (1) in Finland demonstrated that administration of Lactobacillus rhamnosus GG was effective at reducing duration of rotavirus diarrhea in children compared with placebo. Such an effect of LGG cannot be extrapolated to other Lb. rhamnosus strains without experimentation and proof of efficacy. In terms of the safety of probiotic ingestion, the Consultation recognized the need for guidelines for methodology to assess safety and efficacy of these products.
Definition
For the purpose of the meeting, the consultation (re)defined probiotics as "live microorganisms, which when consumed in adequate amounts, confer a health benefit on the host" but restricted its scope to discussion of probiotics consumed "as part of food." Therefore, the focus was on strains available as probiotics in food, which are mainly members of the genera Lactobacillus and Bifidobacterium, and excluded reference to the term biotherapeutic agents and beneficial microorganisms not used in food. Although issues related to genetically modified organisms were not specifically addressed, it was recognized that the concepts and principles are equally applicable to all probiotics.
The specific topics addressed in detail were properties of probiotic strains and their assessment, probiotic product specifications, quality assurance, and regulatory issues, and safety and beneficial human health effects.
For use in food, important criteria for probiotics were documented, in particular that they should not only be capable of surviving passage through the digestive tract, by exhibiting acid and bile tolerance, but also have the capability to proliferate in the gut. This means they must be resistant to gastric juices and be able to grow in the presence of bile under conditions in the intestines or be consumed in a food that affords them protection during passage through the stomach and exposure to bile. Probiotics must be able to exert their benefits on the host through growth and/or activity in the human body. However, it is the specificity of action, not the source of the microorganism, that is most important. It is the ability to remain viable at the target site and be effective that should be verified for each strain.
Classification and identification
It is recommended that probiotics be named according to the International Code of Nomenclature to ensure understanding on an international basis. It was strongly recommended that, for the sake of full disclosure, probiotic strains be deposited in an internationally recognized culture collection. Because probiotic properties are strain related, it was suggested that strain identification be performed using internationally recognized methods such as PFGE DNA/DNA hybridization and 16S RNA sequencing.
Defining and measuring health benefits
It was recognized that a number of health effects are associated with the usage of probiotics, in particular the alleviation of disorders associated with the gastrointestinal tract, such as reduction of acute diarrhea caused by pathogens and viruses, diarrhea caused by antibiotic therapy and Clostridum difficile, and reduction of infections. Other health benefits have also been demonstrated, including allergy reduction and immune stimulation, and furthermore, studies are showing potential for probiotics in such diseases as inflammatory bowel diseases and certain cancers, although further work is needed in these areas. The intestinal microflora plays a critical role in inflammatory conditions in the gut, and potentially, probiotics could remediate such conditions through modulation of the microflora.
Testing methods for establishing health benefits
It was recognized that proper in vitro studies should establish the potential health benefits of probiotics before in vivo trials are undertaken. Tests such as acid and bile tolerance, antimicrobial production, and adherence ability to human intestinal cells should be performed, depending on the proposed health benefit. For in vivo testing, randomized double-blind placebo-controlled human trials should be undertaken to establish the efficacy of the probiotic product. With respect to measuring the health benefit in human studies, consideration should be given to clinically relevant outcomes in the population being studied. For diarrhea studies, this might be preventing death in some countries, whereas in others it might be prevention of a defined and statistically significant weight loss or decreased duration or faster recovery from illness.
Elucidation of mechanisms
The molecular mechanisms behind the health benefits of probiotics are not well understood. The mechanisms may vary from one probiotic to another and may be a combination of events, thus making this a complex area of investigation. Certain mechanisms are well defined, e.g., the ability of certain probiotics to alleviate the symptoms of lactose intolerance by the production of the specific enzyme (ß-galactosidase) that can hydrolyze the offending lactose into its component sugars. In vitro and in vivo experiments should be designed at the molecular level to elucidate the mechanisms of probiotic beneficial effects.
Safety considerations
In terms of safety of probiotics, a need for standardized assays to determine drug insensitivity or resistance profiles in lactobacilli and bifidobacteria was recognized. Furthermore, a need for research on potential for transmission of genetic elements to other intestinal/food borne microorganisms was recognized, given that insufficient information is available on situations in which these genetic elements could be mobilized, and it is not known if situations could arise where this could become a clinical problem. For safety assessment in humans, it was recognized that there is a need for guidelines to describe the minimum requirements, as will be discussed later in this article.
Government regulations differ among countries, and the status of probiotics as a component in food is currently not established on an international basis. For the most part, probiotics come under food and dietary supplements because most are delivered by mouth as foods and, as such, are allowed to make only general health claims.
It was recognized there is a need to accurately enumerate the probiotic bacteria in food products to include them on a label and that proper manufacture and handling procedures be employed to ensure maintenance of viability and probiotic activity through processing, handling, and storage of probiotic foods, including powdered milk products. Although not considered in great detail, the potential benefits of prebiotics were recognized with respect to probiotics in addition to their ability to stimulate indigenous beneficial bacteria in the host. Finally, it was recognized that a proper trace-back system is a necessary prerequisite for surveillance to monitor the health outcomes (and potential side effects) of long-term probiotic administration.
The conclusions of the Expert Consultation were these: Adequate scientific evidence exists for the derivation of health benefits from consuming food containing probiotics. Additional research data are needed to confirm health benefits in humans by applying a systematic approach and following the guidelines for the assessment of probiotics suggested in the report. Good evidence exists that specific strains of probiotics are safe for human use and able to confer some health benefits on the host, but such benefits cannot be extrapolated to other strains without experimentation. Health benefits include amelioration of gastrointestinal infections, certain bowel disorders, allergy, and urogenital infections. The application of probiotics to prevent and treat these disorders should be more widely considered by the medical community. There is emerging evidence that probiotics can be taken by healthy people as a means to prevent certain diseases and modulate host immunity. Regulatory status of probiotics is not established on an international basis, and regulatory procedures do not allow probiotic products to describe specific health benefits.
The recommendations were these: Potential probiotic strains must be identified by internationally accepted methods and named according to the International Code of Nomenclature and strainsmust be deposited in an internationally recognized culture collection. In order to be termed a probiotic, the microorganism must be able to confer defined health benefits on the host in the actual product vehicle. There is a need for refinement of in vitro and in vivo tests. There is a need for more statistically significant efficacy data in humans. Good manufacturing practices must be applied with quality assurance, shelf-life conditions established, and labeling made clear to include minimum dosage and verifiable health claims. The regulatory status of probiotics as a component in food has to be established on an international level. A regulatory framework should be established to better address probiotic issues, including efficacy, safety, labeling, fraud, and claims. Probiotic products shown to confer defined health benefits on the host should be permitted to describe these specific health benefits. Surveillance systems (trace-back, postmarketing) should be put in place to record and analyze adverse events associated with probiotics in food and monitor long-term health benefits. Probiotic products should be made more widely available, especially for relief work and to populations at high risk of morbidity and mortality. Further work is needed to address criteria and methodologies for probiotics.
The full FAO/WHO report of 2001 is available at the FAO website (2) (ftp://ftp.fao.org/es/esn/food/probio_report_en.pdf). The report provided FAO, WHO, and their member states with scientific advice in relation to the nutritional and safety assessment of probiotics, in particular powdered milk with live lactic acid bacteria; provided general guidance for the assessment of these probiotics; and addressed specific questions arising in relation to their pathogenicity, toxigenicity, allergenicity, or other specific features relevant to their nutritional properties or safety.
Working group
The need for guidelines for the evaluation of probiotics in food leading to the substantiation of health claims was highlighted following the Expert Consultation. Consequently, a Working Group was convened by FAO/WHO in London, Ontario, April 30 and May 1, 2002 to generate guidelines and recommend criteria and methodology for the evaluation of probiotics and to identify and define what data need to be available to substantiate health claims accurately. Dr. Maya Pineiro represented FAO, and Ben Embark represented WHO. The Working Group identified and outlined the minimum requirements needed for probiotic status and provided guidelines to meet this objective.
The report of the Working Group is on the FAO website (3): ftp://ftp.fao.org/es/esn/food/wgreport2.pdf.
It is recommended that the guidelines set out in the report be followed to claim that a food has a probiotic effect.
The minimium requirements needed for probiotic status include the assessment of strain identity, in vitro tests to screen potential probiotics, assessment of safety above all, and in vivo studies for substantation of effects.
It was recognized that it is necessary to know the genus and species of the probiotic strain, and strain identity is important to link a strain to a specific health effect as well as to enable accurate surveillance and epidemiological studies. Probiotic strains should be deposited in an internationally recognized culture collection. In vitro tests are critical to assess the safety of probiotic microbes and are also useful for functional characterization and to gain knowledge of the mechanism of the probiotic effect, as are animal studies. However, it was noted that currently available in vitro tests are not fully adequate to predict functionality of probiotic microorganisms in the human body and that probiotics for human use will require substantiation of efficacy with human trials.
In recognition of the importance of assuring safety, even among a group of bacteria that is generally recognized as safe, it was recommended that probiotic strains be characterized at a minimum with the following tests: 1) determination of antibiotic resistance patterns, 2) assessment of certain metabolic activities (d-lactate production, bile salt deconjugation), 3) assessment of side effects in humans, 4) epidemiological surveillance of adverse incidents in consumers, 5) testing for toxin production (if the strain under investigation belongs to a species that is a known mammalian toxin producer), and 6) testing for hemolytic activity if the strain under evaluation belongs to a species with known hemolytic potential.
Assessment of lack of infectivity by a probiotic strain in immunocompromised animals would add a measure of confidence in the safety of the probiotic.
Double-blind, randomized, placebo-controlled phase 2 (efficacy) studies should be undertaken with probiotic foods (where the placebo is the food carrier devoid of the test probiotic). Sample size needs to be calculated for specific endpoints, and statistically significant differences must apply to biologically relevant outcomes.
The principal outcomes of efficacy studies on probiotics should be proven benefits in human trials, such as statistically and biologically significant improvements in conditions, symptoms, signs, well-being, or quality of life; reduced risk of disease or longer time to next occurrence; or faster recovery from illness. It is recommended that the human trials be repeated by more than 1 center for confirmation of results, and results published in peer-reviewed scientific or medical journals. Where food is considered, no adverse effects related to probiotic administration should be experienced.
It was recommended that the following information be described on the label: genus, species, and strain designation; minimum viable numbers of each probiotic strain at end of shelf-life; the suggested serving size, which must deliver the effective dose of probiotics related to the health claim; health claim; and proper storage conditions.
The recommendations as set out in the report (3) are listed below:
Codex and health and nutrition claims
The Codex Alimentarius Commission was created in 1963 by FAO and WHO to develop food standards, guidelines, and related texts, such as codes of practice, under the Joint FAO/WHO Food Standards Program. At present it has 163 member countries. The main purposes of this Program are protecting health of the consumers, ensuring fair trade practices in the food trade, and promoting coordination of all food standards work undertaken by international governmental and nongovernmental organizations.
The probiotic results and recommendations of the Consultation and the Guidelines for the Evaluation of Probiotics in Foods have been presented to 2 Codex Committees, Codex Committee on Food Labeling (CCFL) and Codex Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU). The CCFL provides general standards for the labeling of prepackaged food, guidelines on nutrition labeling, and guidelines on the use of nutrition claims. The aims of the CCFL are to draft provisions on labeling applicable to all foods; to consider, amend, and endorse draft-specific provisions on labeling prepared by the Codex Committees; to study specific labeling problems assigned to it by the Codex Commission; and to study problems associated with the advertisement of food with particular reference to claims and misleading descriptions.
The aims of the CCNFSDU are to study specific nutritional problems and advise the Codex Alimentarius Commission on nutrition issues; to draft general provisions on nutritional aspects of all foods; to develop standards and related texts for food for special dietary use; and to consider, amend, and endorse provisions on nutritional aspects proposed for inclusion in Codex standards and related texts.
General guidelines on claims can apply to all food, but no food should be presented in a manner that is false, misleading, deceptive, or likely to create an erroneous impression regarding its character. Claims should be substantiated, and specific claims involve national legislation. Currently, no health claims are allowed on food labels for the prevention, alleviation, or treatment of diseases in most countries, and in most countries, only general claims are allowed on foods containing probiotics. The FAO/WHO Consultation and the Working Group Probiotic Guidelines recommended that specific health claims be allowed where sufficient scientific evidence is available (preferably supported by an independent third-party review by scientific experts). It is hoped that the Probiotic Guidelines will be incorporated or taken as example for the Codex draft being prepared on health and nutrition claims and as a scientific assessment of a novel food. Within this framework, it is hoped that the works of the probiotic groups will be used as a model for the Codex draft guidelines, for use of health and nutrition claims, and as specific reference for probiotics in the Codex draft to scientifically evaluate probiotics, and for the specific substantiation of health claims for probiotics.
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FOOTNOTES |
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2 Author disclosure: no relationships to disclose.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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1. Isolauri E, Juntunen M, Rautanen T, Sillanaukee P, Koivula T. A human Lactobacillus strain (Lactobacillus casei sp. strain GG) promotes recovery from acute diarrhoea in children. Pediatrics. 1991;88:90–7.
2. FAO/WHO. Report on Joint FAO/WHO Expert Consultation on Evaluation of Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria. 2001. ftp://ftp.fao.org/es/esn/food/probio_report_en.pdf.
3. FAO/WHO. Report of a Joint FAO/WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food. 2002. ftp://ftp.fao.org/es/esn/food/wgreport2.pdf.
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