Roger A. Clemens

Interest in probiotics—the use of live microbial agents for health maintenance and disease prevention or treatment—has exploded over the past several years, and the scientific evidence supporting their use is compelling. The safe use of probiotic organisms is founded on centuries of consumption of fermented foods and beverages, such as yogurt and kefir. The GRAS status of the organisms should be based on the scientific evidence—human trials, animal models, and in-vitro studies—and surveillance of the probiotics market.

In September 2000, the Food and Drug Administration’s Food Advisory Committee (FAC) met to consider safety and potential health effects of probiotics. The meeting focused on application of the current scientific knowledge in evaluating safety and efficacy of probiotic use in human foods. Nearly 200 human clinical trials involving approximately 8,000 subjects and more than 20 different species of probiotic organisms have been reported in the literature since 1961. During these years, the scientific nomenclature and methods of characterization of these strains have changed, and even the definition of probiotics has been modified. Thus, the FAC was charged to identify primary elements in identifying probiotic organisms, and to develop terms that would provide a clear and concise definition of probiotics.

Indications of safety in the published studies include the virtual absence of reported adverse events, even among those infants and adults diagnosed with acute or chronic disease. However, insufficient information exists to recognize probiotic strains as safe in products to be fed to severely immunocompromised infants and young children.

Thus, the FAC must consider additional scientific factors for assessing safety and applications of probiotics. For example, are there (a) special populations, such as infants, pregnant women, and the immunocompromised, that may be of higher morbidity risk than the general population, (b) novel organisms to be considered for novel applications, or (c) food matrices that influence the stability and functionality of the selected probiotic strains?

Several nutritional, health, and therapeutic effects have been ascribed to probiotics. These include improvement of nutritional quality of food, metabolic stimuli of vitamin synthesis and enzyme production, stabilization of gut microflora and competitive exclusion of enteric pathogens, and enhancement of innate host defenses by production of antimicrobial substances. Probiotic bacteria, alone or as part of a fermented milk product, may improve lactose malabsorption and apparent intolerance. Streptococcus thermophilus and Lactobacillus bulgaricus commonly used to make yogurt produce lactase and can digest lactose in the intestinal lumen. Ultimately, this may be the health claim that appeals to consumers and is accepted by the regulatory agencies.

The FAC must identify and examine the scientific elements that are common in considering potential health effects. Are there additional approaches and methods that should be considered in evaluating proposed health benefits associated with probiotics?

A significant percentage of the probiotic literature focuses on the management of diarrheal disease. Positive outcomes reported with the ingestion and “adequate dose” of probiotics include shortened duration of acute diarrheal disease, particularly of viral etiology, improved secretory immune response to infectious agents, and reduced risk of diarrheal illness with regular consumption of these organisms.

Despite the evidence for potential claims, the mechanism of action of these nonpathogenic bacteria needs further clarification. Clearly, the mechanism is probably multifaceted, and may include adherence to intestinal mucosa, lower luminal or microenvironment pH, and production of volatile fatty acids and antimicrobials. Therefore, the maintenance of probiotics in the gastrointestinal tract may be essential.

The FAC further asked whether viability (capability of resuscitation) of probiotics is essential to demonstrate a beneficial effect. If so, what is the appropriate dose of each organism, and when should viability be demonstrated? Should viability at a specified cfu/g be demonstrated in the finished product at the end of its projected shelf life, or should viability be verified on the basis of recovery of probiotics from stool samples?

Since the introduction of specific nonpathogenic bacteria into the diets of infants, children, and adults constitutes a new approach to promote health benefits in the emerging functional foods category, the food and supplement industries must be prepared to:
Provide evidence of appropriate organism identification using molecular techniques.

• Provide data on the genetic stability of the probiotic organism(s).

Document fermentation process control and ingredient standardization so as not to (a) alter organism stability or functionality and (b) introduce potential allergenic ingredients.

Demonstrate organism stability and functionality throughout product distribution.

Indicate the presence/absence of plasmids; if present, indicate their function.

Indicate evidence on potential antibiotic resistance by the strain of interest.

Provide evidence on modes of action, either as a single organism or as a probiotic cocktail, such as Bifidobacteria plus Streptococcus.

• Provide evidence that the organisms do not present a negative effect on morbidity, nutrient absorption, or immunocompetence, or introduce potential allergens.

The FAC will continue to evaluate the data presented during the September meeting and will likely convene another meeting before submitting recommendations to FDA. If probiotics is an important facet of the food industry’s strategy in the introduction of functional foods, it is incumbent that the industry invest in scientifically based evidence, as outlined above.

Contributing Editor