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Probiotics marketing races ahead of the science

Even as consumers embrace the concept of probiotics, there are serious challenges associated with their emergence into prime time. Bug guru Mary Ellen Sanders, PhD, says that products today are expected to be identified to the strain level and substantiated by well-controlled, published, strain-specific human studies. Are yours?

Probiotics have become almost a household word. Ten years ago the idea that bacteria could be good for you just didn't register in mainstream America. Today — with successful products such as Activia Yogurt and the Align dietary supplement — and the advertising that accompanies them — the concept of probiotics has arrived in the consciousness of US consumers. This reality intersects with a scientific undertaking called the human microbiome project. This $115 million research initiative funded by the US National Institutes of Health aims to identify and characterize the microbes associated with humans, and to determine their role in health and disease. This is a global research priority, and one that will provide an invaluable scientific foundation for further developments in the probiotic field. It's an exciting time for probiotics.

But even as consumers embrace the concept of probiotics, there are serious challenges associated with their emergence into prime time. Probiotics once flew below the regulatory radar (a 1990 Office of Dietary Supplements survey of 3,000 dietary-supplements products did not include a single probiotic product), but recently the FDA and FTC have targeted probiotic companies through warning letters and initiation of investigations into claims, respectively. A marketplace once characterized by undefined products touting claims rooted in unsubstantiated hypotheses, products today are expected to be identified to the strain level and substantiated by well-controlled, published, strain-specific human studies.

And these issues are not unique to the United States. Europe, Canada, India and other regions globally are specifically addressing issues surrounding the science and marketing of probiotic products. For example, in Europe, where all claims related to health benefits of foods must be approved by the European Food Safety Authority, close to 100 claims for probiotic health benefits have been denied.

This situation has caused a bit of a tumult among researchers, regulatory authorities and companies marketing the products. Over the past 20 years, the pace of mechanistic and clinical research on probiotics has accelerated greatly. According to the PubMed bibliographic database, the number of human clinical trials on probiotics published in the past 10 years has increased 20-fold. However, translating this emerging science into health-benefit claims that are meaningful to the consumer, accurately reflect the science, and satisfy regulatory authorities is a challenging undertaking with high stakes.

US regulatory situation

In the US, the word "probiotic" has no legal definition. The scientific definition — "live micro-organisms, which when administered in adequate amount confer a health benefit on the host" ( — although well-accepted among scientists, is not necessarily applied to the commercial use of the term.

Probiotics in the US are marketed as foods, food ingredients or dietary supplements. There are no approved probiotic drugs in the United States. Therefore, no products can legally be characterized as having a role in the cure, treatment, prevention, mitigation or diagnosis of disease. Foods and dietary supplements can be labeled with two types of health benefit claims relevant to probiotics. One is a structure/function claim, which relates the probiotic to the normal structure or function of the human body. The other is a health claim, which relates consumption of the probiotic to the reduction of risk of disease, and which must be approved by the FDA or an authoritative body. Currently, there are no approved health claims for probiotics — only structure/function claims are used to communicate benefits. Typically, these claims address issues such as improvement of the gut microflora, digestive health or immune health.

Such claims are sometimes viewed as "unregulated," but these claims are required by the FDA to be "truthful and not misleading" and by the FTC to be supported by "competent and reliable scientific evidence." However, inadequate enforcement has led to a market situation with products bearing unsubstantiated health benefit claims.

The logical ramifications of this regulatory framework are beginning to be felt in the probiotic industry. When you look at the myriad of studies that have been conducted on probiotics, it is apparent that many of them are conducted using endpoints that would be viewed by the FDA to be drug-use endpoints. For example, a 2010 study tested a fermented milk's ability to reduce incidence of common infectious diseases in healthy children in day care centers. Even though this study documents a decreased incidence rate for common infectious diseases (CIDs) in the active group by 19 percent compared to control group, use of the product used in this study to prevent CIDs in day care children would be considered a drug use.

A similar interpretation would apply to numerous other studies in the probiotic field, including a 2009 study that showed probiotics reduced symptoms of colds and flu in Chinese children,5 a 2007 study that showed that probiotics reduced diarrheal illness among young children attending daycare centers,6 not to mention a 2008 study that showed that probiotic prevented eczema in at-risk infants,7 or another recent 2010 study that showed probiotics decreased the risk of gastrointestinal and respiratory infections and episodes of vomiting and diarrhea among hospitalized children.8

The upshot is that even if you have the data to prove it, the FDA does not allow any statements on a food or dietary supplement that would communicate benefits on reducing the risk of chronic diseases (colds, flu, gastrointestinal infections) or managing symptoms in people who are not healthy (in-patients or people with a diagnosed condition such as IBS).

Furthermore, a recent FDA warning letter sent to Nestlé regarding their BOOST Kid Essentials Nutritionally Complete Drink product warned against using published clinical studies that demonstrate probiotic effectiveness on an FDA-deemed "disease use" to market a food or supplement.

For example, Nestlé cited an article that documented lower incidence of fever and diarrhea, and fewer clinic visits, absences from child care and antibiotic prescriptions among healthy day care children taking Bifidobacterium lactis Bb-12, the probiotic in BOOST Kid Essentials.9 Citing such studies was seen by the FDA as making unapproved drug claims for the product, even though it is exactly this type of research that would support the value of consuming this product. Other papers Nestlé was warned about citing were review papers that addressed the use of probiotics in the prevention of different diseases.

So it seems companies are chastised for not having studies supporting health benefits of their products, but then are warned to not use well-conducted, peer-reviewed research if such research looks at clinical endpoints viewed by the FDA to be drug-use endpoints.

What's a company to do?

Food and dietary supplement companies are limited in what claims they can make and what science they can use to substantiate claims. According to a guidance document issued by the FDA, claims are evaluated based on:

  1. the meaning of the claim being made
  2. the relationship of the evidence to the claim
  3. the quality of the evidence
  4. the totality of the evidence.


Science supporting any claims must use valid, scientific approaches, with randomized, double-blinded, placebo controlled trials at the top of the hierarchy. The product tested in any studies used to support a claim should match the intended conditions of use with regard to formulation, route of administration and product intake parameters. The populations studied in this efficacy research must be currently healthy (or at-risk) individuals, but must be representative of the target population. Of course, when designing a trial, if broad inclusion criteria are used, study results will have more variation, but narrow inclusion criteria may be criticized for not representing the target population.

The most difficult issue to determine is what endpoint to study. Studies could evaluate either clinical endpoints or biomarker endpoints. As demonstrated above, many clinical endpoints would be deemed drug studies by the FDA, and therefore could not be used to substantiate the health benefits of a food or dietary supplement. But validated biomarker endpoints useful for probiotic research are rare. For example, studies on movement of immune biomarkers would be challenged by the scientific community for lack of knowledge of how the types and magnitudes of changes in these biomarkers can be related to a health outcome.

Everyone involved in this issue, including regulatory authorities, surely want efficacy studies to measure something that is physiologically meaningful with outcomes that demonstrate magnitudes of effects that are both statistically significant but biologically relevant to health. How to accomplish this is the current question.

Logical conclusions

So when your doctor tells you to eat a yogurt if you have trouble tolerating an antibiotic or if you are susceptible to vaginal infections, he cannot base this recommendation on communications by companies that their yogurt has been tested and shown to have this effect. In addition, a clinical researcher cannot conduct a publicly funded study to test these effects of probiotics. A recent NIH-funded proposal to evaluate a probiotic yogurt on antibiotic-associated side effects in otherwise healthy children was blocked by FDA's Center for Biologics Evaluation and Research, which demanded that an Investigational New Drug application be on file before the research could proceed.10 Since it is unlikely a yogurt company will be interested in selling a drug, this requirement was cumbersome, obstructionist and of questionable value considering more than a dozen clinical trials on the effect of probiotics on pediatric antibiotic-associated diarrhea are already in the published literature.

In the U.S., a dietary supplement or a food cannot make any claims about keeping you healthy if by health you mean prevention of any acute diseases such as cold, flu, diarrhea, irritable bowel syndrome or antibiotic side effects.

As mentioned at the outset of this article, the field of probiotics is rapidly developing. There is still only limited evidence for specific strains, at specific doses, for specific populations, for specific endpoints.

Indications are promising and continued research (mechanistic, clinical and human microbiome) will certainly provide better guidance on how these substances can be useful to promote human health and manage disease. A very high standard of scientific evidence is being sought by regulatory authorities in the US and other regions globally, but this is a good thing. Significant scientific challenges exist when attempting to substantiate health effects for probiotic foods and supplements (Table 1), and researchers will need to tackle them.2

What we need to figure out in the U.S. is how to use the good quality data that demonstrate the value of probiotic foods/supplements to reduce the risk of acute conditions and provide safe, dietary management of health conditions. Do we need a new regulatory category — or reinterpretation of a current one — to allow such endpoints to be in the purview of foods or dietary supplements? Is a change in the regulatory framework needed to include foods in drug-dominated world of health benefits?

If deemed safe by scientific standards,3 it is hard to understand why foods or supplements can't be used to reduce the risk of a getting an acute disease, or why they can't be used for providing dietary support for certain health conditions such as antibiotic-associated diarrhea or reducing symptoms of IBS.

Probiotic strain selection

A probiotic strain should be identified by genus, species and strain. A number of tests are available to provide knowledge of the strains and their mechanism of action. In vitro testing should be substantiated by human trials. Among the currently used in vitro tests are:

  • Resistance to gastric acidity
  • Bile acid resistance
  • Adherence to mucus and/or human epithelial cell and cell lines
  • Antimicrobial activity against potentially pathogenic bacteria
  • Demonstrated Health Benefits


Probiotic strains used in foods and supplements should provide health benefits such as:

  • Colonization of the intestinal, respiratory and urogenital tracts
  • Cholesterol metabolism
  • Metabolism of lactose, the absorption of calcium and synthesis of vitamins
  • Reduction of yeast and vaginal infections
  • Reduction of digestive problems like constipation and diarrheal diseases

From: Selection Criteria for Probiotics, presented by S.K. Dash of EAS Laboratories at the International Association of Colon Therapists Meeting on June 18 in Eden Prairie, Minn.


Table 1: Some challenges in establishing causality between a probiotic and a health benefit

  • Few recognized biomarkers for many probiotic endpdoints
  • Impact of delivery vehicle and fermentation conditions on probiotic functionality not known.4
  • Mixed results (some positive, some negative studies)
  • Magnitude of effect may be small
  • Numerous confounders in nutritional studies, such as background diet or baseline microbiota composition
  • Choice of placebo
  • Choosing study populations
  • Effects in healthy people difficult to establish, but choosing patient population triggers drug status
  • Unknown criteria for responders/non-responders



Table 2. Let's make a health claim!

Say you're interested in using Bifidobacterium lactis Bb12 as your probiotic of choice for your immune-boosting product. It's a good choice, you're thinking. After all, there are nearly 5,000 published references citing the connection of probiotics and immunity. Can-do, right? Let's take a quick closer look at what you're really up against:
B lactis Bb12 "supports immune function in adults"

  • 4,904 published references
  • 806 human clinical trials
  • 113 human clinical trials with B lactis Bb12
  • 17 with immunity
  • 9 without any additional probiotics or prebiotics
  • 4 with at least 10(9) cfu/day
  • 0 in healthy adults*


(* all four remaining studies done with elderly or infants)


Probiotic and healthy beverages vie for consumer attention

This is a tale of two beverages. They were the best of drinks. They were in the worst of regulatory climates. Drinks are increasingly being seen as the delivery system of choice for functional ingredients. Two new launches come to mind. One is brought to you by Nestlé, called Kid Essentials. Its Nutrition Facts panel boasts 7 grams of protein and a veritable multivitamins' worth of vitamins and minerals, in the range of about 20 to 30 percent of the daily value. The downside: When you look at the ingredients panel, it reads: water, sugar, maltodextrin, fructose — so two out of the first four ingredients are sugar. In fact, 24 grams of sugar in all. Plus all of zero grams of fiber.

Nestle Boost Kid EssentialsNestlé's BOOST Kid Essentials drink packs a multivitamin punch and comes with a probiotic straw. But the claims the company made regarding the benefits of the probiotics got it into hot water with regulators.

Standing in the not-as-mainstream aisle (Nestlé has muscular connections in distribution) is Orgain. It has more than double the protein — 16 grams per 11-oz drink — and 13 grams sugar, plus 3 grams of fiber thrown in. It has 25 percent of the daily value of calcium, compared to 30 percent in Kids Essentials. Orgain also contains a cornucopia of vitamins and minerals, all formulated at 25 percent of the daily value.

It would be easy to declare Orgain the winner. Except.

Except that the Kids Essentials comes replete with a probiotic straw housing the probiotic strain Bifidobacterium lactis Bb-12.

OrgainOrgain competes with Kid Essentials. It has a similar amount of vitamins and more than double the protein. But it doesn't include the probiotics, losing, perhaps, some cachet, but skirting thereby the tricky marketing issues surrounding probiotic health claims.

Except that Nestlé conducted a human clinical trial using this probiotic. The trial documented lower incidence of fever and diarrhea, and fewer clinical visits, absences from child care and antibiotic prescriptions, among healthy day-care children taking the Boost Kids Essentials probiotic.

Parents will tell you that providing good nutrition to their kids is great. They'll also tell you that keeping their kids healthy and not missing school days from sickness trumps the generic 'good nutrition' especially since sickness can certainly be a marker of poor nutrition.

The US FDA didn't help the cause of Nestlé. That's because Nestlé took the published clinical study results to boast the drink's effectiveness. To which the FDA told Nestlé they were now making a "disease use" claim to market the drink, and told them to back off.

So it seems companies are chastised for not having studies supporting health benefits of their products, but then are warned to not use well-conducted, peer-reviewed research if such research looks at clinical endpoints viewed by the FDA to be drug-use endpoints.

Damned if you do, damned if you don't, you might say.


Select suppliers: probiotics and prebiotics

Orafti oligofructose from chicory root.

Oliggo-Fiber inulin can be incorporated into almost any food or beverage without affecting taste or texture. Inulin is recognized as a prebiotic ingredient that supports t healthful bacteria in the GI tract.

Cosucra Groupe Warcoing
Inulin and oligofructose from chicory root. 10% to 35% solubility, with a de-sugared variety available.

The world's biggest probiotics supplier, Danisco offers FloraFIT and HOWARU lines of probiotics that feature multiple strains for a variety of applications including beverages, confectionaries, desserts and supplements.

Embria Health Sciences
Known as an immune ingredient, EpiCor contains oligosaccharides that are clinically proven to be beneficial to gut health.

Friesland-Campina Domo
Vivinal GOS is a prebiotic lactose-derived galacto-oligosaccharide. Vivinal GOS is selectively fermented by the key beneficial probiotic bacteria in the colon.

The stability of Ganaden's BC30 probiotic enables it to be used in a variety of products, including chocolates launched recently with Italian chocolatier Agostini.

GTC Nutrition
NutrFlora NutraFlora short-chain fructooligosaccharides (scFOS) and Purimune prebiotic GOS is a highly pure prebiotic derived from lactose containing a minimum of 90% galactooligosaccharides (GOS).

Gum Technology Corporation
Coyote Brand Konjac glucomman fiber.

Improve USA, Inc.
Supplier of aloe vera gel products that are processed from the inner fillet and have been shown to aid in gastrointestinal disorders. Studies have shown the natural soothing effects of the aloe aid in calming the effects of an irritable bowel.

Researches and develops probiotics applications into foods and supplements. Company recently partnered with A. Lassonde Inc to launch in Canada a '10 fruits with Probiotics' fruit juice line, containing Lallemand's documented probiotic strain L. rhamnosus R0011, providing 1 billion cfu's per 250ml serving at the end of shelf-life.

Lonza, Inc.
FiberAid is a soluble prebiotic fiber with good digestive tolerance and technological properties. It is water soluble, stable against a wide pH and temperature range and forms low-viscosity solutions.

Morinaga Milk Industry
Offers Lactulose, produced by isomerizing lactose and used as a growth factor for Bifidobacterium.

National Enzyme Company
Features BioCore line of enzymes, which includes both broad-spectrum and action-specific products.

National Starch Food Innovation
Hi-maize resistant starch, Hi-maize whole grain corn flour, Nutriose soluble fiber.

Nebraska Cultures
An early leader in probiotic research and technology, Nebraska Cultures supplies a full range of custom-manufactured probiotic microorganisms.

Nutraceutix, Inc.
PrimeBiotix Bulk Probiotic Powders, Patented BIO-tract Delivery System Probiotic Caplets, Contract Manufacturing/Private Labeling.

Nut-trition Inc.
Almond Bran from ground almond skin. Adds insoluable fiber as well as almond sterols and essential minerals such as magnesium, calcium, phosphorus, and potassium.

Roquette America Inc.
NUTRIOSE range of soluble dietary fibres obtained from cereals. NUTRIOSE promotes healthy eating by improving nutrition profile of food while maintaining their original taste. Use NUTRIOSE to increase fiber content to contribute to recommended daily intake; decrease calories intake; bring specific nutritional benefits.

Lactospore (Bacillus coagulans, formerly known as Lactobacillus sporogenes) GRAS self affirmed probiotic. Its naturally encapsulated spore form offers stability at room temperature without refrigeration, amenability to a variety of processing conditions, and sustained activity.

Tate and Lyle
STA-LITE polydextrose, a soluble fiber with prebiotic properties, used as a low-calorie bulking agent. Used to provide body and texture in reduced-calorie, no-added-sugar and high-fiber foods Also SOLACTIS Galactofructose and PROMITOR Soluble Gluco Fibre and Resistant Starch.

UAS Laboratories
UAS Probiotic Blend #3, a premium probiotic blend containing proprietary superstrain, Lactobacillus acidophilus DDS®-1(50%), Bifidobacterium longum, Bifidobacterium bifidum and Bifidobacterium lactis (combined 50%) at a potency of 10 billion CFU/g, fortified with prebiotic FOS.



1. Sanders, M.E. 2009. How do we know when something called “probiotic” is really a probiotic? A guideline for consumers and healthcare professionals. Functional Food Rev 1:3-12.
2. Shane, A., et al. 2010. Guide to designing, conducting, publishing and communicating results of clinical studies involving probiotic applications in human participants. Gut Microbes 1: 1-11.
3. Sanders, M.E., et al. 2010. Assessment of probiotic safety for human use. Gut Microbes 1: 164-185.
4. Sanders, M.E. and Marco, M. 2010. Food formats for effective delivery of probiotics. Ann. Rev. Food Sci. Technol.  1:65–85.
5. Leyer GJ, Li S, Mubasher ME, Reifer C, Ouwehand AC. 2009. Probiotic effects on cold and influenza-like symptom incidence and duration in children. Pediatrics 124:e172-9.
6. Binns CW, Lee AH, Harding H, Gracey M, Barclay DV. 2007. CUPDAY study: pro/prebiotics reduce incidence of diarrhea in day care children. Acta Pædiatrica 96:1646–1650.
7. Wickens K, Black PN, Stanley TV, Mitchell E, Fitzharris P, Tannock GW, Purdie G, Crane J; Probiotic Study Group. 2008.  A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 122:788-94.
8. Hojsak I, Abdovic S, Szajewska H, Milosevic M, Krznaric Z, Kolacek S. 2010. Lactobacillus GG in the prevention of nosocomial gastrointestinal and respiratory tract infections. Pediatrics.125(5):e1171-7.
9. Weizman Z, Asli G, Alsheikh A. 2005. Effect of a probiotic infant formula on infections in child care centers: comparison of two probiotic agents. Pediatrics 115:5-9.

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