| Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 11, Number 1, 2005
Contents
Prebiotics and Probiotics: Delivering Therapeutics
as Dietary Components
Executive Editor: Colum Dunne
Editorial Pp.1-2
Colum Dunne
Probiotics: An Emerging Therapy Pp.3-10
G.C. O'Sullivan, P. Kelly, S. O'Halloran, C. Collins,
J.K. Collins, C. Dunne and F. Shanahan
[Abstract]
The Importance of Guidelines in the Development
and Application of Probiotics Pp.11-16
Gregor Reid
[Abstract]
Regulating the Safety of Probiotics – The
European Approach Pp.17-23
Atte von Wright
[Abstract]
Mining the Probiotic Genome: Advanced Strategies,
Enhanced Benefits, Perceived Obstacles Pp.25-36
Michael Callanan
[Abstract]
Probiotic Research in Australia, New Zealand and
the Asia-Pacific Region Pp.37-53
R. Crittenden, A.R. Bird, P. Gopal, A. Henriksson, Y.K.
Lee and M.J. Playne
[Abstract]
The Delivery of Probiotics and Prebiotics to Infants
Pp.55-74
M.J. Kullen and J. Bettler
[Abstract]
Modulation of the Human Gut Microflora Towards
Improved Health Using Prebiotics – Assessment of Efficacy
Pp.75-90
K.M. Tuohy, G.C.M. Rouzaud, W.M. Bruck and G.R. Gibson
[Abstract]
Abstracts
[Back to top]
Editorial
Colum Dunne
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 characterization 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.
Colum Dunne, B.Sc., Ph.D.
General Manager
Cork Cancer Research Centre
BioSciences Institute & Mercy University Hospital
University College
Cork
Ireland
[Back to top]
Probiotics: An Emerging Therapy
G.C. O'Sullivan, P. Kelly, S. O'Halloran, C.
Collins, J.K. Collins, C. Dunne and F. Shanahan
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
[Back to top]
The Importance of Guidelines in the Development and Application
of Probiotics
Gregor Reid
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.
[Back to top]
Regulating the Safety of Probiotics – The European Approach
Atte von Wright
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.
[Back to top]
Mining the Probiotic Genome: Advanced Strategies, Enhanced
Benefits, Perceived Obstacles
Michael Callanan
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.
[Back to top]
Probiotic Research in Australia, New Zealand and the
Asia-Pacific Region
R. Crittenden, A.R. Bird, P. Gopal, A. Henriksson,
Y.K. Lee and M.J. Playne
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.
[Back to top]
The Delivery of Probiotics and Prebiotics to Infants
M.J. Kullen and J. Bettler
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.
[Back to top]
Modulation of the Human Gut Microflora Towards Improved Health
Using Prebiotics – Assessment of Efficacy
K.M. Tuohy, G.C.M. Rouzaud, W.M. Bruck and G.R.
Gibson
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.
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