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Pharmacological Research
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Article history:
Received 5 November 2009
Received in revised form 7 January 2010
Accepted 8 January 2010
Keywords:
Microbiota
Intestinal ora
Prebiotics
Probiotics
Diarrhea
Enteric infections
Inammatory bowel disease
Irritable bowel syndrome
Lactobacilli
Bidobacteria
a b s t r a c t
A new era in medical science has dawned with the realization of the critical role of the forgotten organ,
the enteric microbiota, in generating a variety of functions which sustain health and, when disrupted,
lead to disease. Central to this benecial interaction between the microbiota and man is the manner in
which the bacteria contained within the gut talk to the immune system and, in particular, the immune
system that is so widespread within the gut itself, the gut-associated (or mucosa-associated) lymphoid
system. Into this landscape come two new players: probiotics and prebiotics. While many products
have masqueraded as probiotics, only those which truly and reproducibly contain live organisms and
which have been shown, in high quality human studies, to confer a health benet can actually claim this
title. Several human disease states have beneted from the use of probiotics, most notably, diarrheal
illnesses, some inammatory bowel diseases, certain infectious disorders and, most recently, irritable
bowel syndrome. Prebiotics promote the growth of good bacteria and, while a variety of health benets
have been attributed to their use, prebiotics have been subjected to few large scale clinical trials.
2010 Elsevier Ltd. All rights reserved.
Contents
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the survival of live organisms over the time and in the conditions
specied on the label. Whether or not these same products can
provide the health benets that they claim can only be deduced
from a critical assessment of the medical literature. Fortunately,
more and higher quality clinical trials are being performed and can
guide the consumer on the optimal product for a given condition.
This latter point is critically important: no two probiotics are the
same! Even within the same species different strains may have
vastly different and even contrasting effects. Although probiotics
have been proposed for use in inammatory, infectious, neoplastic
and allergic disorders, the ideal probiotic strain for many of these
indications has yet to be dened, though progress continues in this
area. While probiotic cocktails have also been advocated to maximize effect, it needs to be noted that some probiotic combinations
have been shown to prove antagonistic, rather than synergistic, in
certain situations.
Right now the consumer nds it impossible to assess the validity of the many claims made for probiotics. This dilemma stems, in
large part, from the manner in which they are regulated. Despite
the fact that probiotics are advocated for the management of disease, they are regulated, in most jurisdictions, in a manner which
is more akin to a food than a pharmaceutical. This situation may
change very soon as agencies in both the US and in Europe are
currently re-evaluating the status of these products. Deliberations
by the European Food Safety Authority on health claims for probiotics pursuant to European Union Regulation 1924/2006 [17] will
undoubtedly set a much higher standard for all health claims relating to nutritional products, including probiotics.
One of the areas of most active research pertains to the mechanism of action of probiotics [7]. The interaction between a probiotic
strain or cocktail of strains/species must be examined in the context of those interactions that normally take place between the
microbiota and the host, as well as between individual components of the microbiota. How does the host differentiate between
friend and foe? What interactions between the constituents of the
microbiota favour the growth of some bacteria but not others?
The complexities of microbiotahost and microbemicrobe interactions continue to be unraveled. With regard to the former, the
important roles of pattern recognition receptors [PRRs; such as
Toll-like receptors (TLRs)], signaling pathways, immune responses
and the secretion of anti-microbial peptides, such as defensins and
chemokines by the epithelium, all appear to play important roles
[3,18,19]. While some probiotic strains may well be autochthonous
to the consumer, many may well be allochthonous. Clearly, the ability of the latter to survive transit through the intestine is a critical
factor in determining their potential for a health-beneting role;
where the administered species acts and in what niche it prospers are issues that have been scarcely studied in man? The more
widespread application of molecular technologies is beginning to
address these issues. Administered probiotics appear to be able,
if only transiently and for the duration of their administration, to
inuence the composition and function of the intestinal microbiota
[2022]. It appears plausible to suggest that effects which are primarily metabolic in nature should occur primarily in that site of
greatest microbial metabolic activity, the colon, whereas probiotic effects that are mediated through immune engagement should
take place in those areas where immune tissue is most dense, the
distal small intestine. Using novel reporter systems the location
of niche environments for administered probiotics are beginning
to be dened in animal models [23]. While it is undoubted that
many of the factors, such as secretion of anti-microbial peptides,
quorum sensing, possession of certain metabolic pathways, competition for resources, bacterial motility and adherence properties,
to name but a few [20,24], which have been identied as relevant to competition within the microbiota, are directly relevant
to the survival and proliferation of an administered probiotic,
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5. Safety of probiotics
Many different species and strains and preparations of probiotics have been used for decades and by millions of healthy and
diseased individuals, yet denitive data on safety is scanty. In a
careful and critical review in 2006, Boyle et al. concluded that
although probiotics have an excellent overall safety record, they
should be used with caution in certain patient groupsparticularly
neonates born prematurely or with immune deciency [62]. They
reviewed case reports of instances of abscesses and endocarditis in relation to probiotic use; in many instances the probiotic
cultured from the infected tissue was most likely an innocent contaminant rather than the real pathogen. Fears that live probiotic
organisms might translocate across the gut and lead to systemic
sepsis have also been allayed by the absence of such reports from
studies among patients with inammatory bowel disease and other
situations where the intestinal barrier may be compromised. Two
notes of caution must be mentioned. The rst relates to reports of
septicemia occurring among infants with short bowel syndrome
[63,64] and the second to instances of increased mortality among
patients with severe acute pancreatitis who had been administered
a probiotic cocktail through a naso-enteric tube. These deaths were
associated, not with sepsis, but with intestinal ischemia whose etiology remains unclear [65].
EFSA recently addressed this issue in their report on QPS (qualied presumption of safety of micro-organisms in food and feed) and
concluded that the QPS designation could be applied only to microorganisms which are identiable at the strain level and where there
is a history of apparent safe use [66]. In the future, molecular tech-
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