Europeans and Asians, in particular, have long known about the health benefits of pre- and probiotics. Now, manufacturers are eyeing the fertile North American market for product penetration. Gregor Reid, PhD, tells how science is the backbone of this growth sector.
The famous words of New York Tribune editor Horace Greeley, "Go West, young man," are most appropriate for today's manufacturers of probiotics. After many years of popularity in eastern Europe and Japan, makers of probiotic drinks, in just six years, have created a $350 million market in western Europe.
North Americans are just now learning about the probiotic approach to intestinal health, and manufacturers and distributors are scoping out the world's great marketplace: the North American free-trade zone.
The basic notion behind probiotics is pretty straightforward: restore the depleted ecology of the intestine with new, healthful bacteria. More than 100 years after Elie Metchnikoff, as director of the Pasteur Institute, identified the benefits of Lactobacillus bacteria, the concept has been expanded to define health benefits far beyond the gut.
Indeed, the Food and Agriculture Organisation of the United Nations (FAO) and the World Health Organisation (WHO), following a request from member nations, prepared a report and a set of guidelines for use of probiotics in the new millennium.1,2 They now define probiotics as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host." Several aspects of this definition are critical to future growth of the field.
Defining The Field
First, with respect to product contents, it is critical that probiotics be living at the time of use, and the viable colony-forming unit count must be at the level proven to confer a health benefit in humans or animals. No longer is it sufficient to state a viable count at the time of manufacture. The consumer needs to know the count at time of use. Consumers have no way of knowing how a product is handled prior to its purchase or how many organisms are alive when they use it.
In a yoghurt format, likely 107,8 probiotic organisms (added after the yoghurt is made) could be delivered per dose, although in capsule or other freeze-dried format more than 109 can be delivered per dose. Few dosage studies have been undertaken, but one showed that a physiological effect on the vaginal flora following oral intake required at least 108 live Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 per daily dose.3 In terms of gut health, at least 109 of L. rhamnosus GG or L. reuteri (apparently strain SD 2112) appear to be required to reduce the duration of rotaviral diarrhoea in children, yet even at this dose the effect against bacterial gastroenteritis is questionable.4,5
Probiotics have long been promoted as improving the host intestinal microbial balance, thereby leading to improved general health. However, no study has actually tested this theory, and indeed, general health is difficult to measure. Companies such as Yakult, whose probiotic beverage product reaches 24 million people per day, would be well placed to undertake a large study to determine benefits of their product in healthy people vs. nonusers of probiotics.
For this reason, in part, current conceptions of probiotic benefits must be based on target- and site-specific effects of clearly defined strains. Although this may be due to differences in adhesion and immunological effects,6 no clinical studies have proven the precise mode of action. Nevertheless, just as E. coli 0157: H7 causes gastroenteritis and not urinary tract infection, and type 1 and P fimbriated E. coli cause the latter and not the former, so too Lactobacilli strains differ in the effects on the gut and urogenital tract even when they belong to the same species.7,8,9
The FAO/WHO Expert Consultation lists benefits that had substantial support from peer-reviewed publication of human studies.1 Essentially, these are to prevent and reduce the duration of diarrhoea, prevent onset of atopic dermatitis, and prevent urogenital infections. Promising data exist on suppressing Helicobacter pylori stomach infections, reducing the risk of certain cancers, modulating mucosal immunity, and lowering serum cholesterol and oxaluria. Remediation of irritable bowel syndrome and inflammatory bowel disease is possible, but it is too early to define the probiotic organisms that can be effective. Studies currently under way might achieve this. In all likelihood, this will require a multispecies probiotic approach. In that case, the formulation must be reproducible, with the role of each constituent known and documented.
The host microflora is often badly disrupted when patients are seriously ill or hospitalised. In a series of studies, an L. plantarum 299 strain was shown to minimise surgical complications. Researchers in a double-blind, placebo-controlled study of 45 London patients with severe acute pancreatitis found significantly reduced pancreatic sepsis as well as reduced number of surgical interventions after supplementing with L. plantarum 299.10 Similarly, a prospective, randomised, placebo-controlled study of 95 patients in Germany found L. plantarum 299 reduced bacterial translocation and minimised the incidence of infections after liver transplantation, leading researchers to speculate that supplementation should begin while patients are on the waiting list for transplantation.11 A small group of German surgery patients experienced reduced post-surgical infections upon taking an enteral solution containing oat fibre and either live or heat-killed L. plantarum 299. The only difference between the two probiotics groups was the live group received antibiotics for a significantly shorter time.12 Given the enormous morbidity, mortality and economic impact associated with hospitalisation and certain surgical procedures, probiotic use could become a vital component of patient management in the future.
Of critical importance, the microorganisms claimed as probiotics must be defined using standard molecular techniques. Many producers will need specialised labs to do this work, but can then properly name the organisms on product labels. For example, some products claim to contain L. sporogenes, when this organism does not even exist and lactobacilli do not form spores.13 Another known example is that L. acidophilus strains may actually be L. crispatus, L. gasseri, L. johnsonii, L. gallinarum or L. amylovorus because subtle differences have been found in their DNA homology.14 Indeed, L. helveticus, L. iners and L. amylolyticus are all phenotypically highly similar to the seven strains in the L. acidophilus group.15
The organisms must then be given a designated number or identity, such as L. rhamnosus GG. No two organisms are identical, and companies that make loose claims based on some generic link to L. acidophilus or historical studies performed on other organisms such as L. rhamnosus GG are only confusing consumers and health professionals. If a company has a promising strain of L. rhamnosus, it has to prove that it has similar properties to those published for LGG, especially if claims are being made based on areas where LGG has shown great promise, such as diarrhoea prevention and treatment as stated above, and down-regulation of the milk-induced inflammatory response in milk-hypersensitive subjects.16
Upon reading these comments, representatives of smaller companies may feel the anxiety of not having the funds necessary to conduct extensive clinical trials, but how can any company ethically sell an untested product? Human (or livestock, if that is the target population) trials need not be extensive, but they must be more than testimonials that do not take into account the potential placebo effects. The FAO/WHO Guidelines provide an outline of what will be required.2
The greatest potential for market growth of probiotics, estimated to be a staggering $120 million per month,18 will be achieved through broader buy-in from physicians, pharmacists and other professional health caregivers. This can happen only through valid scientific and clinical verification. In an era when well-educated consumers, especially baby boomer women, are learning about health through the Internet, probiotic producers must not underestimate the potential for market demand and the need for solid scientific reckoning of their product.
Exposure to oxygen, light, temperature changes and humidity, as well as stomach acidity, can easily degrade and destroy probiotic microorganisms. The biggest challenge is delivering the promised number of cells to the intestine. A number of innovations address this issue.
It is important to note that room temperature in northern Sweden in February is not the same as in Italy in July. Thus, manufacturers should consider climactic variations across regions when establishing a product's shelf life. Tests for bacterial survival, while useful in accelerated lab tests that reach 40°C (104°F) or higher, are best determined following one to two years in use.
It is noteworthy to mention that benefits from these stabilisation techniques remain to be clinically demonstrated.
Foods You Can Use
For reasons ranging from obesity epidemics to escalating health care budgets, from pharmaceutical side effects to antibiotic overuse in both humans and livestock, the opportunities for probiotics have never been greater. Probiotics and functional foods have the potential within 20 years to significantly influence the health of humanity.
Amongst the new generation of products are those designed for the lunch-pack market, many of which are packaged with children in mind. Combine a milk-based probiotic drink like Yakult or Actimel (due for a North American launch within two years), probiotic cheeses such as the ones being developed at TEAGASC in Ireland21 or Bio-Cheese in Australia using L. rhamnosus HN001; almonds, organic fruits, and slices of free-range, drug-free chicken on sugar-free, multi-grain flax bread, and you have the seeds of a healthy lunch.
As Stig Bengmark, MD, a surgeon and developer of Probi's L. plantarum 299V, rightly noted, Palaeolithic humans ate significantly less salt, sugar and fat than we do, and they consumed far more beneficial bacteria.22 As a society, we have paid little attention nutritionally to this latter ingredient, and it would behoove the food and pharmaceutical industries to catch the trend early on.
We have more bacterial cells in our body than human cells, yet we do not purposely nurture these microbes. On the contrary, we use so many antiseptics, preservatives, pesticides, herbicides, antibiotics and disinfectants that only the drug-resistant pathogens tend to thrive. It is no wonder that there are so many cases of post-antibiotic yeast infections and Clostridium difficile gastroenteritis.
Opportunities And Threats
The FAO/WHO and subsequent Codex initiatives should finally bring a semblance of standardisation and quality to the probiotic field. Likewise, scientific advances will produce new products, while consumer education and demands will support expansive business opportunities. The greater challenge is in determining when probiotics should be taken.
Clearly, one key stage for establishing the commensal microflora is at birth and the subsequent first months of life when the immune system is developing. Manipulating the intestinal microflora of the infant may have long-term benefits if the flora of the adult is determined by events in this critical period of gut colonisation, particularly the days after birth and during weaning when flora composition diversifies.23
In addition to the ethical issues of purposely colonising every baby at birth, many practical problems arise. Which flora is appropriate for which person? What roles do genetics and receptor-site availability play? If the body is designed to select certain strains, as appears to be the case in the oral cavity, then it may be impossible to significantly modify the gut flora, even following select probiotic use at birth. It would be useful to have additional studies that show how probiotics at birth can, for instance, prevent atopic dermatitis.24
It may be 20 years or more before we have the capability of designing an ideal method of optimising health from birth. For this reason, we need to forge ahead with research into this field. In premature, low-birth-weight babies, the development of necrotising enterocolitis is so devastating that we should reassess our clinical practices. Studies have shown the incidence can be cut in half when physicians administer the species L. acidophilus and Bifidobacterium infantis.25
A second challenge will be at the regulatory level. The US Food and Drug Administration, for example, does not know how best to handle probiotics and has developed a bureaucratic system fearful of errors rather than one that is open to new concepts. If probiotics are not foods and not drugs, what are they? If probiotic foods have been shown to have functional health benefits, why can't medical disease-based claims be made without drug designation and 10 years of research and development? Perhaps DSHEA needs to be amended to address this shortcoming.
In the past five years, there have been more than 800 peer-reviewed articles on probiotics, in contrast to 85 papers the previous 25 years. Scientific excellence, quality manufacturing, honest marketing, vision and flexibility in funding and regulatory agencies, and progressive consumer education will ensure that pre-and probiotics flourish and find their appropriate place in health restoration and maintenance.
Gregor Reid, PhD, MBA, is director of the Canadian Research and Development Centre for Probiotics at Lawson Health Research Institute and professor at the University of Western Ontario, London, Canada. He is the inventor of several pending and issued patents describing the use of probiotics, and is a principal in Urex Biotech Inc, a Canadian probiotics and functional foods company. [email protected]
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2. FAO/WHO. Guidelines for the evaluation of probiotics in food. Food and Agriculture Organization of the United Nations and World Health Organization Working Group Report, 2002. http://www.fao.org/es/ESN/Probio/probio.htm.
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