Probiotics are live microorganisms, which when administered in adequate amounts, confer a health benefit on the host. The main features of this definition are that the microbe must be alive when administered and must have undergone controlled evaluation to document health benefits in the target host. Subcategories of the general term probiotic include probiotic drugs (intended to cure, treat or prevent disease), probiotic foods (e.g., foods, food ingredients and dietary supplements), direct-fed microbials (e.g., for animal use) and designer probiotics (genetically modified probiotics). Currently, there is no legal definition of the term probiotic.
 
Common Myths & Misconceptions
Common misconceptions among consumers, manufacturers, marketers and scientific fraternity include 1) the understanding of the benefits of probiotics and the associated mechanisms; 2) the proper dosage required to achieve a beneficial effect; and 3) the constituents of a probiotic. By definition the term probiotic encompasses only live microbes from any source (human, animal or environmental) so long as they are safe for their intended use and have documented health effects.
 
Probiotics in theory can be composed of any live microbe. A large number of probiotics hail from the Lactobacillus or Bifidobacterium genera. Also popular is Saccharomyces boulardii (a yeast). Less commonly used are strains of Escherichia coli or Bacillus coagulans. One category of microbe that is typically not considered to be a probiotic is a virus. Live viruses have been administered as vaccines, but such use is generally considered to be outside the realm of probiotics.
 
A functional distinction must be made between a probiotic and a live, active culture. Fermented foods, especially fermented dairy products, frequently contain live, active cultures; but these are not probiotics, as they are generally tested only for food fermentation properties and not health benefits, which is an essential part of the definition of a probiotic. 
 
Dosages required to achieve beneficial effects are commonly reported to be on the order of 1–10 billion CFU (colony-forming units)/day. However, effective doses are sometimes greater or less than this recommended amount.
 
The concept of gut microbial balancing is another confusing area. Some evidence suggests that certain probiotic strains can stabilize the gut microbiota in response to specific stress or health conditions (e.g., antibiotic therapy). But long-term convincing clinical evidence is still missing. 
 
Challenges
An important challenge facing the probiotic industry today is to understand the extent to which different factors influence probiotic physiology, ranging from production vessel, product itself and within human gut. The effects manufacturing, product matrix and the host have on the physiology and functionality of probiotic organisms are not well understood. Controlled research in humans is required to determine the bioequivalency of specific probiotics under varied conditions and to clear up confusion between regulators, consumers and physicians.
 
Perhaps the most important challenge facing this industry is the validation of health benefit claims for probiotics. Intense mechanisms are in place to seek approval for health benefit claims with domestic and international regulatory bodies; however, no probiotics have currently been approved for health benefit claims. While human trials studying the health benefits of probiotics rely upon human disease endpoints, validated biomarkers for specific benefits will be required to gain regulatory approval.
 
Appropriate model systems for studying the efficacy of probiotics are important in the development of probiotics for use in humans. Several in vitro and in vivo models are currently in use. The utility of these in vitro systems is limited, and these systems are perhaps most useful as screening tools to evaluate a variety of interventions for development of probiotics for human use. Controlled human studies are essential in order to make a claim of probiotic benefit.
 
The Way Forward
Orally administered probiotics may be marketed as dietary supplements, conventional foods, medical foods and drugs (biologics). At present, no probiotic product is licensed in the U.S. or in Europe as a biological drug product for use in the treatment, prevention, cure, mitigation or diagnosis of a specific human disease.
 
Individuals or companies who wish to study the use of probiotics for the treatment of a disease must follow a regulatory pathway similar to that followed for live vaccines to prevent infectious diseases. This pathway begins with an Investigational New Drug (IND) application before studies in humans can begin.
 
Two recent meta-analyses including the systematic review published by Goldenberg group in The Cochrane Library 2013, Issue 5 have summarized the results of previous trials, detecting large reductions in the risk of antibiotic-associated diarrhea (AAD) in general and Clostridium difficile infections in particular. These impressive effect sizes are motivating many healthcare institutions to consider routine probiotic co-administration with antibiotic treatments. Within a few weeks of the Cochrane publication, Stephen Allen and colleagues questioned the usefulness of routine probiotics in The Lancet (“Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial”). This is a large (more than 3,000 patients) and rigorous negative study, and we must judge whether it can tip the balance of probiotic evidence.
 
Dilip Ghosh, PhD, FACN, is director of nutriConnect, based in Sydney, Australia. He can be reached at [email protected].au; www.nutriconnect.com.au.

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The ideas and opinions expressed in this article are those of the author and do not necessarily reflect views held by Nutraceuticals World.