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Pharmacological Research 61 (2010) 213218

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Review

Prebiotics and probiotics; modifying and mining the microbiota


Eamonn M.M. Quigley
Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

a r t i c l e i n f o a b s t r a c t

Article history: A new era in medical science has dawned with the realization of the critical role of the forgotten organ,
Received 5 November 2009 the enteric microbiota, in generating a variety of functions which sustain health and, when disrupted,
Received in revised form 7 January 2010 lead to disease. Central to this benecial interaction between the microbiota and man is the manner in
Accepted 8 January 2010
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
Keywords:
system. Into this landscape come two new players: probiotics and prebiotics. While many products
Microbiota
have masqueraded as probiotics, only those which truly and reproducibly contain live organisms and
Intestinal ora
Prebiotics
which have been shown, in high quality human studies, to confer a health benet can actually claim this
Probiotics title. Several human disease states have beneted from the use of probiotics, most notably, diarrheal
Diarrhea illnesses, some inammatory bowel diseases, certain infectious disorders and, most recently, irritable
Enteric infections bowel syndrome. Prebiotics promote the growth of good bacteria and, while a variety of health benets
Inammatory bowel disease have been attributed to their use, prebiotics have been subjected to few large scale clinical trials.
Irritable bowel syndrome 2010 Elsevier Ltd. All rights reserved.
Lactobacilli
Bidobacteria

Contents

1. The normal microbiota: an essential factor in health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213


2. The gut microbiota in disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
3. Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
4. Probiotics in digestive disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
5. Safety of probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
6. Prebiotics and synbiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

1. The normal microbiota: an essential factor in health been claimed that the composition of each individuals microbiota
is so distinctive that it could be used as an alternative to ngerprint-
The human gastrointestinal microora (now more usually ing. When disturbed, the microbiota has a remarkable capacity to
referred to as the microbiota) is a complex ecosystem of approx- restore itself and to return to exactly the same state as it was before
imately 300500 bacterial species comprising nearly two million [2].
genes (the microbiome). Indeed, the number of bacteria within Because of the normal motility of the intestine (peristalsis) and
the gut is about 10 times that of all of the cells in the human body. At the anti-microbial effects of gastric acid, the stomach and proxi-
birth, the entire intestinal tract is sterile; bacteria enter the gut with mal small intestine contain relatively small numbers of bacteria in
the rst feed [1]. Following infancy, the composition of the intesti- healthy subjects; jejunal cultures may not detect any bacteria in as
nal microbiota remains relatively constant thereafter. Indeed, it has many as 33%. The microbiology of the terminal ileum represents
a transition zone between the jejunum containing predominantly
facultative anaerobes and the dense population of anaerobes found
Alimentary Pharmabiotic Centre, Dept of Medicine, Clinical Sciences Building,
in the colon. Bacterial colony counts may be as high as 109 CFU/mL
Cork University Hospital, Cork, Ireland. Tel.: +353 21 490 1228;
in the terminal ileum immediately proximal to the ileocecal valve,
fax: +353 21 490 1289. with a predominance of Gram-negative organisms and anaerobes.
E-mail address: e.quigley@ucc.ie. On crossing into the colon, the bacterial concentration and variety

1043-6618/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.phrs.2010.01.004
214 E.M.M. Quigley / Pharmacological Research 61 (2010) 213218

of the enteric microbiota change dramatically. Concentrations as impaired and/or gastric acid secretion abolished, an environment
high as 1012 CFU/mL may be found; comprised mainly of anaerobes conducive to the proliferation, in the small intestine, of organisms
such as Bacteroides, Porphyromonas, Bidobacterium, Lactobacillus that are normally conned to the colon, results. Small intestinal
and Clostridium, with anaerobic bacteria outnumbering aerobic bacterial overgrowth can signicantly disturb both the digestion
bacteria by a factor of 1001000:1 [3]. The predominance of anaer- and absorption of food and the products of digestion [11]. Alter-
obes in the colon reects the fact that oxygen concentrations in the natively, the immunological interaction between the microbiota is
colon are very low; the microbiota has simply adapted to survive disturbed and the host may, for example, begin to recognize the
in this hostile environment! constituents of the normal microbiota, not as friend, but as foe and
It must be emphasized; however, that the true size and may mount an inappropriate inammatory response which may
diversity of the human microbiota are largely unknown. The ultimately lead to conditions such as inammatory bowel disease
application of modern technologies: genomics, metagenomics and [12]. Injury to the intestinal epithelium, regardless of cause, ren-
metabolomics, to the study of the colonic microbiota has the ders the gut wall leaky and permits luminal bacteria (in whole or
potential to expose the true diversity and metabolic prole of the in part) to gain access to the submucosal compartments or even
microbiota and the real extent of changes in disease [4]. Tech- to the systemic circulation with the associated potential to cause
niques based on 16S rDNA sequences have already revealed that the catastrophic sepsis. This mechanism is thought to account for many
diversity of the human microbiota is much greater than previously of the infections that occur in the critically ill patient in the inten-
thought and that the majority of bacterial sequences correspond to sive care unit, for example. Most recently, qualitative changes in
unculturable sequences and novel bacteria [5]. At any given level of the microbiota have been invoked in the pathogenesis of a global
the gut, the composition of the microbiota also demonstrates varia- epidemic: obesity [13]. It has been postulated that a shift in the
tion along its diameter with certain bacteria tending to be adherent composition of the microbiota towards a population where bacteria
to the mucosal surface while others predominate in the lumen; that are more avid extractors of absorbable nutrients thus deliver-
studies which rely on the analysis of the fecal microbiota alone may ing more calories to the host could play a major role in obesity [14].
miss the impact of an important population of organisms: those Indeed, gastric bypass surgery has been associated with a reversion
closely adherent to the mucosa [5]. In humans, the composition of of the microbiota towards normal [15].
the microbiota is also inuenced by age, diet and socio-economic
conditions and, above all, by the use of antibiotics.
3. Probiotics
The normal enteric bacterial microbiota inuences a variety of
intestinal functions and plays a key role in nutrition, in maintain-
Probiotics, derived from the Greek and meaning for life, are
ing the integrity of the epithelial barrier and in the development of
dened as live organisms that, when ingested in adequate amounts,
mucosal immunity [6]. Unabsorbed dietary sugars, such as lactose,
exert a health benet to the host. There are several commer-
and alcohols are salvaged by bacterial disaccaridases, converted
cially available supplements containing viable micro-organisms
into short-chain fatty acids (SCFAs) and used as an energy source
with probiotic properties. The most commonly used probiotics are
by the colonic mucosa. SCFAs promote the growth of intestinal
Lactobacilli, Bidobacteria and nonpathogenic yeasts. Although pro-
epithelial cells and control their proliferation and differentiation.
biotics have been proposed for use in inammatory, infectious,
Nutrients and vitamins, such as folate and vitamin K, are pro-
neoplastic and allergic disorders, the ideal probiotic strain, for use
duced by enteric bacteria. The relationship between the hosts
in any of these indications, has yet to be identied. The inter-
immune system and nonpathogenic constituents of the microbiota
pretation of available data on probiotics is further confounded by
is important in protecting the host from colonization by pathogenic
variability in strain selection, dose, delivery vehicle and evaluation
species. In this regard, intestinal bacteria produce a variety of
of viability and efcacy [16].
substances, ranging from relatively nonspecic fatty acids and per-
Probiotics were rst described by Metchnikoff in 1908 based on
oxides to highly specic bacteriocins, which can inhibit or kill other,
his observations on the longevity of individuals who lived in a cer-
potentially pathogenic, bacteria [7]. Bacterial metabolism of some
tain part of Bulgaria and which he attributed to their ingestion, on a
medications (such as sulfasalazine) within the intestinal lumen is
regular basis, of a fermented milk product. Over the years since then
essential for the release of their active moieties.
many products have appeared on health food store and supermar-
ket shelves throughout the world which include the term probiotic
in their label. Very few fulll the denition provided above:
2. The gut microbiota in disease

Just as we are only now beginning to understand the key role 1. They may not contain live organisms or have not been ade-
of the microbiota in health, it has only been in very recent years quately tested to ensure that the organisms will survive in the
that the true extent of the consequences of disturbances in the conditions (e.g. room temperature) or for the length of time
microbiota, or in the interaction between the microbiota and the (days, weeks, or months) that is claimed.
host, to health has been recognized [6,8]. Some of these are rela- 2. They may not confer health benet because, either, they have
tively obvious: for example, when many components of the normal never been tested on man or because what tests have been pre-
microbiota are eliminated or suppressed by a course of broad- formed have been inadequate or even negative.
spectrum antibiotics the stage is set for other organisms which may
be pathogenic to step in and cause disease. The classical example Other issues of quality control continue to complicate the pro-
of this is antibiotic-associated diarrhea and its deadliest manifes- biotic area. Does the product actually contain the organism and
tation, Clostridium difcile colitis. This potentially fatal disorder the dose of that organism that the label claims that it contains?
commonly occurs among the elderly or debilitated patient who has Unfortunately, when researchers have analyzed some store prod-
been hospitalized or lives in a nursing home and has just received a ucts, they have found, not only that organisms claimed to be alive
course of antibiotics [9]. Similar perturbations in the microbiota are were actually dead, but also that the product contained organisms
thought to be involved in a devastating form of intestinal inam- (including pathogens) that it was not supposed to contain.
mation that may occur in new-born and, especially, premature, Some probiotic companies have gone to considerable efforts to
infants: necrotizing enterocolitis [10]. In other situations, bacte- ensure that their products do contain the very organisms and in
ria may simply be where they should not be: if intestinal motility is the precise dose that are claimed. These products can guarantee
E.M.M. Quigley / Pharmacological Research 61 (2010) 213218 215

the survival of live organisms over the time and in the conditions very little direct research has been preformed on these issues in
specied on the label. Whether or not these same products can man.
provide the health benets that they claim can only be deduced If the probiotic survives its hazardous journey through the intes-
from a critical assessment of the medical literature. Fortunately, tine and manages to establish a niche within the microbiota how
more and higher quality clinical trials are being performed and can does it exert its health-beneting effects? For answers, we are,
guide the consumer on the optimal product for a given condition. again, largely reliant on animal work with some limited data from
This latter point is critically important: no two probiotics are the man. Possible modes of action revealed in such studies include
same! Even within the same species different strains may have competitive metabolic interactions with pathogens, production of
vastly different and even contrasting effects. Although probiotics chemical products (bacteriocins) that directly inhibit other bacte-
have been proposed for use in inammatory, infectious, neoplastic ria or viruses, inhibition of bacterial movement across the gut wall
and allergic disorders, the ideal probiotic strain for many of these (translocation), enhancement of mucosal barrier function, and sig-
indications has yet to be dened, though progress continues in this naling with the epithelium and immune system to modulate the
area. While probiotic cocktails have also been advocated to max- inammatory/immune response [7,16,2527]. Probiotics may also
imize effect, it needs to be noted that some probiotic combinations produce other chemicals, including neurotransmitters that are nor-
have been shown to prove antagonistic, rather than synergistic, in mally found in the bowel, that can modify other gut functions,
certain situations. such as motility [28,29] or sensation [30]. The whole area of the
Right now the consumer nds it impossible to assess the valid- production of biologically active products by probiotic organisms
ity of the many claims made for probiotics. This dilemma stems, in promises to be one of the most exciting areas of research in this
large part, from the manner in which they are regulated. Despite eld. It is evident that various probiotics have different potency
the fact that probiotics are advocated for the management of dis- in relation to any one of these actions; some are avid producers
ease, they are regulated, in most jurisdictions, in a manner which of anti-bacterial peptides and may become active participants in
is more akin to a food than a pharmaceutical. This situation may the ght against certain infections [31,32], while others are potent
change very soon as agencies in both the US and in Europe are anti-inammatory agents [7]. Other probiotics have been shown to
currently re-evaluating the status of these products. Deliberations enhance epithelial barrier function through direct effects on mucin
by the European Food Safety Authority on health claims for probi- expression, proteins of the cytoskeleton and intercellular tight
otics pursuant to European Union Regulation 1924/2006 [17] will junctions [33] and indirect effects emanating from interactions
undoubtedly set a much higher standard for all health claims relat- between the bacterium, the mucosa and the mucosa-associated
ing to nutritional products, including probiotics. lymphoid tissue [6]. The potent anti-inammatory effects of some
One of the areas of most active research pertains to the mecha- probiotics have clearly emphasized how the therapeutic poten-
nism of action of probiotics [7]. The interaction between a probiotic tial of these agents may extend beyond their ability to displace
strain or cocktail of strains/species must be examined in the con- other organisms and has led to their evaluation in inammatory
text of those interactions that normally take place between the bowel disease [34]. In an experimental animal (IL-10 knockout)
microbiota and the host, as well as between individual compo- model of colitis, for example, one group of researchers found that
nents of the microbiota. How does the host differentiate between both a lactobacillus and a bidobacterium produced a marked
friend and foe? What interactions between the constituents of the and parallel reduction in inammation in the colon and cecum
microbiota favour the growth of some bacteria but not others? and in the production of the pro-inammatory cytokines IFN-,
The complexities of microbiotahost and microbemicrobe inter- TNF-, and IL-12, while levels of the anti-inammatory cytokine
actions continue to be unraveled. With regard to the former, the TGF- were maintained [35]. Similar effects have been demon-
important roles of pattern recognition receptors [PRRs; such as strated for the probiotic cocktail VSL#3 (containing Bidobacterium
Toll-like receptors (TLRs)], signaling pathways, immune responses breve, Bidobacterium longum, Bidobacterium infantis, Lactobacillus
and the secretion of anti-microbial peptides, such as defensins and acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lac-
chemokines by the epithelium, all appear to play important roles tobacillus bulgaricus, Streptococcus thermophilus) in experimental
[3,18,19]. While some probiotic strains may well be autochthonous models of colitis; these anti-inammatory effects could, indeed, be
to the consumer, many may well be allochthonous. Clearly, the abil- transmitted by bacterial DNA alone [36]. What is very exciting is
ity of the latter to survive transit through the intestine is a critical the observation, again in an animal model, of the ability of orally
factor in determining their potential for a health-beneting role; administered probiotics to exert anti-inammatory effects at sites
where the administered species acts and in what niche it pros- well distant from the gut such as in an inamed joint [37].
pers are issues that have been scarcely studied in man? The more While the focus of this review will be on the gut and on digestive
widespread application of molecular technologies is beginning to disorders, the latter experiments illustrate the ability of strategies
address these issues. Administered probiotics appear to be able, that manipulate the microbiota to alter immune function at distal
if only transiently and for the duration of their administration, to sites and provide an experimental basis for clinical observations on
inuence the composition and function of the intestinal microbiota the efcacy of probiotic therapy in allergic disorders, for example.
[2022]. It appears plausible to suggest that effects which are pri- For many probiotics their mechanism(s) of action in a given disease
marily metabolic in nature should occur primarily in that site of state, or in health, is likely to be multifactorial.
greatest microbial metabolic activity, the colon, whereas probi-
otic effects that are mediated through immune engagement should
take place in those areas where immune tissue is most dense, the 4. Probiotics in digestive disorders
distal small intestine. Using novel reporter systems the location
of niche environments for administered probiotics are beginning While experimental observations suggest potential benets for
to be dened in animal models [23]. While it is undoubted that probiotics in a variety of gastrointestinal, pancreatic and liver dis-
many of the factors, such as secretion of anti-microbial peptides, orders, solid clinical data is conned to three main areas: infection,
quorum sensing, possession of certain metabolic pathways, com- inammatory bowel disease and irritable bowel syndrome [38,39].
petition for resources, bacterial motility and adherence properties, With regard to infectious diarrhea, there appear to be two main
to name but a few [20,24], which have been identied as rele- areas of efcacy for probiotics: rotavirus-associated diarrhea and
vant to competition within the microbiota, are directly relevant Clostridium difcile-related diarrhea. Several studies have reported
to the survival and proliferation of an administered probiotic, that probiotics may be effective in rotavirus-induced diarrhea,
216 E.M.M. Quigley / Pharmacological Research 61 (2010) 213218

resulting in a shortening of the duration of this illness which is cernible trends. Thus, a number of organisms, such as Lactobacillus
a scourge of day care centers and similar environments [40]. A GG, L. plantarum, L. acidophilus, L. paracasei, the probiotic cocktail
meta-analysis of nine double-blind, placebo-controlled trials, sug- VSL#3 and Bidobacterium animalis, have been shown to alleviate
gested that probiotics (Saccharomyces boulardii, L. acidophilus and individual IBS symptoms, such as bloating, atulence and consti-
L. bulgaricus, Enterococus fecium SF68, B. longum, and Lactobacillus pation, only a few products have been shown to affect pain and
GG) appear to be effective in preventing antibiotic-associated diar- global symptoms in IBS [4852]. Among these, B. infantis 35624
rhea [41]. The proteolytic digestion of toxin A and B molecules by has attracted particular attention [53]. In the rst study with this
protease may explain, at least in part, the protective effects of S. organism, superiority was shown over both Lactobacillus salivar-
boulardii on Clostridium difcile-induced diarrhea [42]. Others have ius and placebo for each of the cardinal symptoms of the irritable
shown that L. plantarum prevents recurrent episodes of Clostrid- bowel syndrome (abdominal pain/discomfort, distension/bloating
ium difcile-associated diarrhea and have even suggested that the and difcult defecation), as well as for a composite score [54]. A
administration non-toxigenic strains of C. difcile may prevent toxi- larger, 4-week duration, dose-ranging study of the same Bidobac-
genic, Clostridium difcile-associated diarrhea in 8797% of patients terium in over 360 community-based subjects with IBS conrmed
[43]. efcacy for this organism in a dose of 108 ; again, all of the primary
The rationale for the therapeutic use of probiotics in inam- symptoms of IBS were signicantly improved and a global assess-
matory bowel diseases and its complications, such as pouchitis ment of IBS symptoms at the end of therapy revealed a greater than
and postoperative recurrence of Crohns disease, is derived from 20% therapeutic gain for the effective dose of the probiotic over
the hypothesis that the endogenous intestinal microbiota plays a placebo [55]. Further large, long-term, randomized controlled trials
crucial role in the pathogenesis of these disorders [12]. of this bidobacterium and other strains are warranted in IBS and
Evidence from a number of controlled trials featuring a number detailed explorations of its mechanism(s) of action are indicated.
of probiotic organisms, including nonpathogenic Escherichia coli, S. Several factors, including a reduction in gas production [5658],
boulardii and a Bidobacterium have suggested efcacy for probi- changes in bile salt conjugation, an anti-bacterial or anti-viral effect
otics in maintaining remission in ulcerative colitis and in treating (in the case of post-infectious irritable bowel syndrome), the pro-
mild to moderate are-ups; other studies have been less favorable motion of motility [59], effects on mucus secretion or, even, an
[44]. anti-inammatory effect [54], could be relevant to the benets of
VSL#3, a probiotic cocktail containing eight different strains (B. specic probiotic strains in IBS.
breve, B. longum, B. infantis, L. acidophilus, L. plantarum, L. paracasei, Animal studies have demonstrated the ability of probiotic
L. bulgaricus, S. thermophilus), has proven effective in the primary organisms to modulate body weight and even modify fat content
prevention [45] and maintenance of remission [46] among patients and composition [60]; in man, changes in the microbiota have
with pouchitis, an ulcerative colitis variant that occurs in the neo- been associated with obesity and shown to normalize with weight
rectum in ulcerative colitis patients who have undergone a total loss [15,61]. However, until it is known whether these changes
colectomy and ileo-anal pouch procedure. In one study, remission in the microbiota play a primary role in pathogenesis of obesity
was maintained in 85% patients on VSL#3 compared to 6% in those and related disorders or are mere epiphenomena, the translation of
receiving placebo [46]. these intriguing observations into a component of the management
In contrast to these somewhat encouraging ndings in ulcer- strategy for obesity cannot be realized.
ative colitis, a review of the available literature on the use
of probiotics either in the management of acute illness or the
maintenance of remission in Crohns disease provides little encour- 5. Safety of probiotics
agement.
Reecting, perhaps, the paucity of truly disease-modifying ther- Many different species and strains and preparations of probi-
apies that are available to relieve the disorder, irritable bowel otics have been used for decades and by millions of healthy and
sufferers commonly have recourse to the use of complimentary and diseased individuals, yet denitive data on safety is scanty. In a
alternative medical remedies and practices [47]. Foremost among careful and critical review in 2006, Boyle et al. concluded that
such approaches have been various dietary manipulations, includ- although probiotics have an excellent overall safety record, they
ing exclusion diets, and a variety of dietary supplements. In Europe, should be used with caution in certain patient groupsparticularly
in particular, where several such products are advertised widely for neonates born prematurely or with immune deciency [62]. They
their general immune-boosting and health-enhancing proper- reviewed case reports of instances of abscesses and endocardi-
ties, probiotics have been widely used as dietary supplements by tis in relation to probiotic use; in many instances the probiotic
irritable bowel syndrome (IBS) patients. Recently, based on data cultured from the infected tissue was most likely an innocent con-
from the experimental laboratory, as well as some evidence from taminant rather than the real pathogen. Fears that live probiotic
clinical trials, the concept of probiotic use in IBS has begun to wend organisms might translocate across the gut and lead to systemic
its way into the realm of conventional medicine. While probiotics sepsis have also been allayed by the absence of such reports from
have been used on an empiric basis for some time in the manage- studies among patients with inammatory bowel disease and other
ment of IBS, several recent developments provide a more logical situations where the intestinal barrier may be compromised. Two
basis for their use in this context [48]. These include the clear notes of caution must be mentioned. The rst relates to reports of
recognition that IBS may be induced by bacterial gastro-enteritis septicemia occurring among infants with short bowel syndrome
(post-infectious IBS) and that qualitative changes in the micro- [63,64] and the second to instances of increased mortality among
biota, as well as immune dysfunction, may be prevalent in IBS, in patients with severe acute pancreatitis who had been administered
general. a probiotic cocktail through a naso-enteric tube. These deaths were
Up to the year 2000, a small number of studies evaluated associated, not with sepsis, but with intestinal ischemia whose eti-
the response of IBS to probiotic preparations and, while results ology remains unclear [65].
between studies were difcult to compare because of differences EFSA recently addressed this issue in their report on QPS (quali-
in study design, probiotic dose and strain, there was some, but by ed presumption of safety of micro-organisms in food and feed) and
no means consistent, evidence of symptom improvement. concluded that the QPS designation could be applied only to micro-
Further studies, since then, have assessed the response to a organisms which are identiable at the strain level and where there
number of well-characterized organisms and have produced dis- is a history of apparent safe use [66]. In the future, molecular tech-
E.M.M. Quigley / Pharmacological Research 61 (2010) 213218 217

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