Current Pharmaceutical Design - Volume 11, Issue 1, 2005

The functionality of dietary components, beyond provision of inherent nutritional benefits, has in relatively recent times become the focus of both lay and scientific interest. The imagination of the public has been captured by the concept that diet has a significant impact on health. The belief that one's quality of life can be enhanced through manipulation of patterns of food intake has resulted in “prebiotic” and, most especially, “probiotic” becoming common or garden household terms, no longer scientific jargon. In the scientific and medical literature, and in company portfolios, prebiotic and probiotic products are regularly associated with claims of prophylactic and therapeutic efficacy. These claims most commonly cite abilities to “balance” gut flora or to provide protection against infections, allergies, inflammatory bowel disease, irritable bowel syndrome, hypercholesterolemia, hypertension, or colon cancer. The agents capable of mediating these effects are diverse and comprise non-digestible oligosaccharides, beneficial bacteria or fungi, and combinations of these. In many cases, these claims may not be supported by clinical evidence. However, there are notable exceptions where some of the best known lactobacilli strains (and consortia of bacterial and / or fungal strains) have shown significant potential in rigorously-performed clinical assessments. It is clear that the diversity of prebiotic substances, probiotic microbes, and the influences that they may respectively exert mean that any health-enhancement claims must be supported by experimental and clinical data. The future of functional food ingredients as alternatives, or adjuncts, to existing and emerging lifestyle and medical practice requires the adoption of this principle of evidence-based legitimacy. The early adopters of this principle are now emerging as the innovative (if sometimes market-led) providers of high-credence functional foods capable of nourishment and, where designated, protection and / or treatment of specific issues in healthcare in a newly defined “near pharma” market sector. In Chapter One, Prof. O'Sullivan et al. [1] detail the emergence of probiotics as medical therapies while highlighting the necessity for randomised, double-blinded, placebo controlled clinical studies for validation of claims. Dr. Reid [2] expands on this theme by describing appropriate guidelines for the identification, characterization, manufacture, and clinical assessment of probiotic products in disease states suitable for their use. Chapter Three provides an informed synopsis by Prof. von Wright [3] of the regulatory environment in which European functional food industry operates. This summary also discusses how the European “take” on bioactive functional ingredients may differ from elsewhere. In Chapter Four, Dr. Michael Callanan [4] addresses the core technologies in the rapidly growing area of genomics, and their application to the molecular characterisation of probiotic bacteria and host-microbe interactions, while in Chapter Five Dr. Crittenden et al. [5] highlight the considerable levels of prebiotic- and probiotic-based academic and industry activity in Australia, New Zealand and the Asia-Pacific Region. In Chapter Six, Drs. Kullen and Bettler [6] detail the benefits of including prebiotic and probiotic agents in infant formula and in Chapter Seven Dr. Tuohy et al. [7] discuss approaches adopted in the evaluation of prebiotic efficacy.

There is considerable clinical interest in the utility of probiotic therapy - the feeding of (live) non-pathogenic bacteria, originally derived from the alimentary tract, for disease treatment or health promotion. The microflora of the gastrointestinal tract is essential for mucosal protection, for immune education and for metabolism of fecal residue. Physiological disturbances of these processes, when they occur, result from: i) alteration of a microbial ecosystem, originally conserved by evolution; ii) reduced consumption of microorganisms; iii) invasion of pathogens; or iv) modern interventions. Recent data support the use of proven probiotic organisms in prevention and treatment of flora-related gastrointestinal disorders including inflammatory bowel disease, infectious and antibiotic related diarrheas, and postresection disorders including pouchitis. Therapeutic activity of probiotic bacteria can be due to competition with pathogens for nutrients and mucosal adherence, production of antimicrobial substances, and modulation of mucosal immune functions. Although a promising treatment, controlled clinical trials are necessary to validate the benefit of probiotics

Probiotics, defined as ''Live microorganisms which when administered in adequate amounts confer a health benefit on the host'' have many attributes including the lack of adverse side effects associated with their use. While probiotics have proven benefits, the optimism associated with their use is counterbalanced by the fact that many so-called 'probiotic' products are unreliable in content and unproven clinically. Therefore much remains to be done to gain the acceptance of the broader medical community. Recognition of the obvious product inequality and the lack of any regulatory guidelines lead to the development of Operating Standards in 2002 (FAO / WHO), that would ensure product safety, reliability and a level playing field for all companies producing probiotic products. The guidelines constitute a set of parameters required for a product / strain to be termed 'probiotic' and also the clinically relevant steps to be followed to move probiotics closer to being embraced by the medical community. These include i) implementation of Guidelines for use of probiotics; ii) phase I, II and III clinical trials to prove health benefits that are as good as or better than standard prevention or treatments for a particular condition or disease; iii) Good Manufacturing Practice and production of high quality products; iv) studies to identify mechanism of action in vivo; v) informative / precise labelling; vi) development of probiotic organisms that can carry vaccines to hosts and / or anti- viral probiotics; vii) expansion of proven strains to benefit the oral cavity, nasopharynx, respiratory tract, stomach, vagina, bladder and skin as well as for cancer, allergies and recovery from surgery / injury.

This article reviews pertinent legislation regulating the safety of probiotics within the European Union (EU). Currently available probiotic organisms and known issues regarding their safety are briefly summarised. While most of the species and genera, particularly lactobacilli and bifidobacteria are apparently safe, certain micro-organisms may be problematic; particularly the enterococci, which are associated with nosocomial infections and harbour transmissible antibiotic resistance determinants. At present, probiotic human foods are not governed under specific EU regulatory frameworks, although the Novel Food Regulation EU 258 / 97, could be relevant in some specific cases. However, microbial feed additives (regulated by Council Directive 70 / 254 / EEC and in accordance with guidelines of the Scientific Committee on Animal Nutrition (SCAN)) are subjected to detailed safety assessment with the intention of ensuring that they are innocuous to target animals, users and consumers. Particular attention is focused on the presence of transmissible antibiotic resistance markers, and to the potential for production of harmful metabolites. The guidelines do not differentiate between species and strains with long histories of safe use and other micro-organisms. This has caused some concern regarding overregulation, if the same principles are to be applied to probiotics or starter cultures intended for human food use. Accordingly, SCAN has launched an initiative towards a “Qualified Perception of Safety” (QPS) concept, which would allow strains with established safety status to enter the market without extensive testing requirements. It is likely that the European Food Safety Authority (EFSA) will play a central role in the regulation of both human and animal probiotics.

Recent advances in DNA sequencing has made it possible to accurately decipher the entire genetic complement of a probiotic bacterium. Increases in sequencing capabilities have been enhanced through improved computer software that can annotate, or identify, the majority of genes encoded by the sequence. The availability of annotated genome sequence will be important in defining the capabilities of the individual strains of probiotic bacteria. It will also form the platform for microarray and proteomic technologies that allow real-time analysis of RNA and protein expression in the bacterial cell. Investigation of probiotic organisms with these new and potentially powerful tools will facilitate the development of the bacteria as therapeutic agents, and provide the mechanisms to produce advanced probiotic strains. This paper addresses the core technologies in the rapidly growing area of genomics, and their application to the molecular characterisation of probiotic bacteria and host-microbe interactions.

Although the epicentres of probiotic research in the past decade have been Japan and Europe, researchers in the Asia-Pacific region have actively contributed to the growing understanding of the intestinal microbial ecosystem, and interactions between gut bacteria, diet and health of the human host. A number of new probiotic strains have been developed in the region that have been demonstrated to have beneficial impacts on health in animal and human trials, including improved protection against intestinal pathogens and modulation of the immune system. Probiotics targeted to animals, including aquaculture, feature heavily in many Asian countries. Developments in probiotic technologies have included microencapsulation techniques, antimicrobial production in fermented meats, and synbiotic combinations. In particular, the impact of resistant starch on the intestinal environment and fermentation by intestinal bacteria has been intensively studied and new probiotic strains selected specifically for synbiotic combinations with resistant starch. This paper provides an overview of probiotic research within Australia, New Zealand and a number of Asian countries, and lists scientists in the Asia-Pacific region involved in various aspects of probiotic research and development.

A number of studies involving the feeding of probiotics and prebiotics to infants have been published over the last decade. These studies have examined a wide range of health outcomes, including growth and safety, prophylaxis and alleviation of diarrheal disease, reduction in atopic disease, reduction in necrotizing enterocolitis, and reduction in infection of the preterm infant. In addition, these studies have described microbiological alterations observed in response to probiotic and prebiotic feeding. Collectively, the reports demonstrate that probiotics show considerable promise in addressing several health outcomes of significance to both formula-fed and breastfed infants. As quantitative and qualitative differences appear to exist between the microfloras of human-milk fed and formula-fed infants, recent innovations to infant formula have involved the inclusion of probiotics and prebiotics as a means of making the flora of the formula fed infant more similar to that of the breastfed infant. To date, only a few probiotic- and prebiotic-containing infant formulas have been marketed, but as new safety and efficacy data emerge and the regulatory climate becomes more favourable, the number of products is expected to grow.

There is increasing awareness that the human gut microflora plays a critical role in maintaining host health, both within the gastrointestinal tract and, through the absorption of metabolites, systemically. An 'optimal' gut microflora establishes an efficient barrier to the invasion and colonisation of the gut by pathogenic bacteria, produces a range of metabolic substrates which in turn are utilized by the host (e.g. vitamins and short chain fatty acids) and stimulates the immune system in a non-inflammatory manner. Although little is known about the individual species of bacteria responsible for these beneficial activities, it is generally accepted that the bifidobacteria and lactobacilli constitute important components of the beneficial gut microflora. A number of diet-based microflora management tools have been developed and refined over recent decades including probiotic, prebiotic and synbiotic approaches. Each aims to stimulate numbers and / or activities of the bifidobacteria and lactobacilli within the gut microflora. The aim of this article is to examine how prebiotics are being applied to the improvement of human health and to review the scientific evidence supporting their use.