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k
ie
Available online at www.sciencedirect.com
including probiotics on the shelves in the supermarket
as well as in the pharmacy. A recent global probiotic
market analysis estimated a 7% annual growth, boosted
mainly by a rising request from the Asian and European
consumer, with a 48 billion dollars forecast in the next five
years (Global Industry Analysis Report 2012). This
amount also includes probiotics for animal feed. This
acceleration is likely to be tightly linked to both scientific
and regulatory developments, which, together, should
govern health claim substantiation. Recent observations,
for encapsulation. Within the Bacillus genus, the species
B. cereus, B. subtilis, B. clausii, B. licheniformis and B.
coagulans are mainly used in probiotic applications, albeit
often in animal applications. Although it requires a case
by case evaluation, some bacilli are considered non-
pathogenic and safe for animal and human consumption
[6]. The current research efforts, especially in the field of
microbiota analysis and host–microbe interaction, will
lead to the proposal of new potential probiotics, as the
functional importance of many non-lactic acid bacteria
Current Opinion in Microbiology 2013, 16:284–292 www.sciencedirect.com
Probiotics from research to mar
risks and challenges
Benoit Foligne´1,2,3,4,5, Catherine Dan
Probiotic foods can affect large parts of the population, while
therapeutic applications have a less wide scope. While
commercialization routes and regulatory requirements differ for
both applications, both will need good scientific support. Today,
probiotics are mainly used for gastrointestinal applications, their
use can easily be extended to skin, oral and vaginal health. While
most probiotics currently belong to food-grade species, the
future may offer new functional microorganisms in food and
pharma. This review discusses the crosstalk between probiotic
producers, regulatory people, medical care and healthcare
workers, and the scientific community.
Addresses
1 Institut Pasteur de Lille, Lactic acid Bacteria & Mucosal Immunity,
Center for Infection and Immunity of Lille, 1, rue du Pr Calmette, BP 245,
F-59019 Lille, France
2 Univ Lille Nord de France, F-59000 Lille, France
3 CNRS, UMR 8204, F-59021 Lille, France
4 Institut National de la Sante´ et de la Recherche Me´dicale, U1019, F-
59019 Lille, France
Corresponding author: Pot, Bruno (bruno.pot@ibl.fr)
5 Both these authors contributed equally to this work.
Current Opinion in Microbiology 2013, 16:284–292
This review comes from a themed issue on Ecology and industrial
microbiology
Edited by Jerry M Wells and Philippe Langella
For a complete overview see the Issue and the Editorial
Available online 15th July 2013
1369-5274/$ – see front matter, # 2013 Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.mib.2013.06.008
Introduction
The scientific concept of probiotics has paralleled their
industrial production and commercialization for over a
century. Increasing market interest in promoting health
in a natural way has intensified research in this area. This
has led to an overwhelming number of new products
et: the possibilities,
l1,2,3,4,5 and Bruno Pot1,2,3,4
however, show that there is a need for harmonization of
scientific developments and regulatory processes [1��].
The current rationale for the use of probiotics is largely
based on scientific and clinical research, but industrial
constraints and strictly regulated market conditions may
limit the number of well-documented products available.
The aim of this paper is to give a concise view on current
aspects of probiotics, including the industrial and regu-
latory perspectives which are very likely to determine the
future place of probiotics in the scientific community as
well as in the economic and consumer space.
Current context of industrial probiotics
Strains and their production
While a substantial number of microbial species have
been reported to exhibit potential probiotic properties,
established after in vitro and preclinical research and/or
after full-scale clinical trials [2], only the most documen-
ted and robust strains may make it to the market. Most
current probiotics are lactic acid bacteria, belonging to the
genera Lactobacillus and Bifidobacterium, with a smaller
number of leuconostocs, pediococci, lactococci, entero-
cocci and streptococci. A non-exhaustive list of the
species (but not strains) marketed as probiotics is shown
in Box 1. This list also includes an increasing number of
non-lactic acid bacteria and yeasts, including strains from
Bacillus, Clostridium, Propionibacterium and the Gram
negative Escherichia coli. Although the use of some Bacillus
or Clostridium spp. may appear controversial from a safety
point of view [3], the technological advantage of using
spores in comparison to the more vulnerable vegetative
cells, explains the increased research interest [4] and the
commercial development for these species [5]. Indeed,
spore-forming bacteria may offer many interesting advan-
tages compared to non-sporeformers, as they are heat-
stable, resistant to low pH and to other deleterious
conditions such as gastric acid and bile secretions in
the intestinal environment. Moreover, spores allow long
term storage of preparations without refrigeration or need
Probiotics from an industrial perspective Foligne´, Daniel and Pot 285
Box 1 Overview of the main organisms marketed as probiotics
in industry.
Bifidobacterium species
B. adolescentis, B. animalis, B. animalis subsp. lactis, B. bifidum,
B. breve, B. longum subsp. infantis, B. longum subsp. longum.
Lactobacillus species
Lactobacillus acidophilus, L. casei, L. ‘caucasicus’ = L. kefiri, L.
crispatus, L. delbrueckii subsp. delbrueckii L. delbrueckii subsp.
bulgaricus, L. delbrueckii subsp. lactis, L. helveticus, L. fermen-
tum, L. gallinarum, L. gasseri, L. johnsonii, L. leichmanii = del-
brueckii subsp. lactis, L. paracasei, L. plantarum, L. reuteri, L.
rhamnosus, L. sakei, L. salivarius, L. sporogenes = Bacillus
coagulans.
Other Lactic acid bacteria
Enterococcus faecalis, E. faecium,
Lactococcus lactis,
Leuconostoc mesenteroides,
Pediococcus acidilactici, P. pentosaceus,
will become clearer and mechanisms by which commen-
sals interact with the host will be clarified (e.g. butyrate
producing Faecalibacterium prausnitzii and Roseburia spp.
[7]; oxalate utilization by Oxalobacter formigines [8]).
Within this large variety of species, large differences are
seen among strains belonging to the same species, as they
may exhibit distinct phenotypes and properties that can
lead to various clinical effects [9]. Research-based evi-
dence largely confirms that mechanisms of probiotic
activity are diverse and are strain specific rather than
conserved within a species or genus [10��,11]. Con-
sequently documented health effects cannot be extrapo-
lated from one strain to another, not even within the same
species. Still we can see a widespread generalization of
mechanisms in communications to consumers and even to
health professionals [1��]. The observed diversity in
terms of activity profiles and underlying mechanisms also
renders comparative studies, especially meta-analysis of
clinical trials, very difficult as they cover different strains
or blends of strains, at different concentrations, in differ-
ent target populations. Furthermore, most studies do not
Streptococcus salivarius, S. macedonicus, S. mitis, S. sanguis, S
thermophilus.
Bacillus species
Bacillus cereus, B. clausii, B. coagulans, B. licheniformis, B.
mesentericus, B. subtillis.
Other bacteria
Clostridium butyricum,
Escherichia coli,
Propionibacterium freudenreichii,
Saccharomyces cerevisiae subsp. cerevisiae, Saccharomyces
cerevisiae subsp. boulardii.
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compareeffects with other benchmark probiotic strains in
the market.
Strain specificity extends beyond the functionality aspect,
as the choice of a candidate probiotic strain also depends
on several technological properties, for example, related
to its large scale manufacturing and to the possibility to
guarantee an optimal shelf life under less easily controlled
storage conditions [12��]. Although more frequently man-
aged by encapsulation, survival of the bacterium inside
the host and preservation of dedicated properties remain
an issue [13]. Process optimization and product design
will need to take into account cell viability and probiotic
functionality and stringent quality control of the fermen-
tation (culture medium or food matrix, pH, carbon source
composition, temperature and duration of fermentation)
and post-fermentation processing (spray-drying, lyophi-
lization, homogenization, blending and high-pressure
tableting, packaging, etc.). Sub-lethal stress during pro-
duction can be useful to improve resistance of probiotics
in foods and food additives [14]. This downstream pro-
cessing, moreover, contributes to a more consistent pro-
duction and helps to maintain expected properties. After
production, however, shelf life monitoring remains
necessary, guaranteeing viability of the intended levels
over the claimed time period.
Encapsulation is frequently being used as a mean to
improve survival of the strains after production, as well
as to increase viability during passage though the gastro-
intestinal tract. While microencapsulation appears to be a
promising technology for both aspects, the impact on the
final probiotic properties of the matrix is often unclear
[15]. This is less of an issue for strains which are more
recently brought to the market and for which clinical
research was based on the encapsulated formulation, but
needs attention for strains with older clinical evidence
and which are only now being brought to the market in an
encapsulated form.
Moreover, a recent in vivo human study underlines that,
for example, the growth phase at harvest may determine
efficacy [16]. Van Baarlen et al. showed that adjuvant
associated molecular responses were only elicited with
stationary growth phase cells of Lactobacillus plantarum,
whereas cells harvested from the logarithmic growth
phase had no effect.
Strains and their applications
Today, the practical use of food and supplements, in-
cluding probiotics, is driven by ‘soft’ health effects and
promotion of well-being [17] rather than the treatment of
disease symptoms. Beyond gut well-being and immuno-
logical effects [18,19], the overall claims range from low-
ering cholesterol, hypertension or postmenopausal
symptoms to improving oral health by the prevention
of halitosis and dental caries [20]. In dermatology,
Current Opinion in Microbiology 2013, 16:284–292
excellent example is the ongoing discussion on probiotics
and obesity. While a number of animal experiments with
non-human probiotics have increased growth efficacy in,
for example, poultry [34], it has never been shown that
established probiotic strains consumed by humans will
increase bodyweight. On the contrary, Delzenne and
Reid indicated that an improvement of the intestinal
barrier function through the modification of the micro-
biota will decrease lipopolysaccharide infiltration, reduce
inflammatory parameters in the fat tissue and so the
chances to develop obesity and insulin resistance [35].
The regulatory aspect
Where the approval of a drug is fairly well defined, the
substantiation needed for a health claim benefit for a food
or food supplement is not as obvious. Regulatory frame-
works for probiotics, or functional foods in a wider con-
text, are different in different parts of the world. The
Panel on Dietetic Products, Nutrition, and Allergies
(NDA) of the European Food Safety Authority (EFSA)
rejected all but one of over 300 health claims on the
benefits of probiotic bacteria. As a consequence, in
Europe not a single probiotic product, food or food
supplement, can mention the health benefits of the
strains it includes. Even the word ‘probiotic’ is currently
286 Ecology and industrial microbiology
probiotic-based treatments of atopic dermatitis and
eczema are widely studied [21]. New indications include
control of hair loss [22] and acne [23,24], using oral or
topical probiotics. Recently, the microbiota, through the
gut–brain connection, was suggested to play a crucial role
in the pathophysiology of mood and anxiety disorders
[25], sustaining possible interventions with probiotic
formulas in animals [26] and humans [27]. The role of
probiotics in pain was also documented using rats [28,29].
Recent results open completely new therapeutic strat-
egies against, for example, toxicity of heavy metals, as
Zhai et al. showed that a L. plantarum strain can protect
mice against acute cadmium toxicity [30,31�].
Clearly, the application range for probiotics is not only
very wide, it also suffers from variable degrees of scientific
substantiation. The availability as food, food supplement
or drug, is amplifying the challenges for the consumer or
the health care worker in choosing the right product, for
the right application and the right person. To date, the
prescribed use of probiotics represents only a marginal
fraction of the total probiotic consumption, while most
products are purchased by the general population in
regular food shops and pharmacies. As such they mostly
serve a prophylactic or health supporting, much more
than a therapeutic purpose. Still the number of clinical
applications with probiotics is expanding quickly.
With probiotics, the frontier between nutrition, pharma
and cosmetics is often unclear [32]. An overview of the
product types currently on the market is shown in Box 2.
Some of them can legitimately be called probiotics (live
microorganisms with a proven health benefit), because
they are supported by scientific evidence and have a
proven track record of safety and functionality. Others,
often the newer types of products, may have a realistic
future, as far as viability is optimized and guaranteed [33]
and the proof of clinical efficacy is available or under
construction. However, the use of probiotic-carrying pro-
ducts like pizzas or teas is very questionable, considering
that heating and cooking will kill the bacteria. The so-
called benefits of ‘cosmeceuticals’, marketed for rejuve-
nation or skin care, also lack good scientific proof and
‘health benefits’ conferred by ‘probiotic’ body lotions or
shampoos are obviously also in need of some scientific
substantiation. The probiotic mattresses ‘hampering the
development of mites, allergens and bad bacteria and
neutralizing bad smells’ is an excellent example of how
marketers can damage a concept that for many of its
aspects has been carefully documented with years of
research, and illustrates how communication on probiotics
remains difficult and sensitive to uncontrollable trends.
While debates and controversies inside the scientific
community are generally stimulating further research,
there is a risk that lay people may find it difficult to
position these controversies in the right context. An
Current Opinion in Microbiology 2013, 16:284–292 
Box 2 Different types of foods, food supplements, pharma
products, cosmetics and other commercial products with
probiotics (or so-called ‘probiotics’) on the market.
Naturally fermented products
Cheese, fermented milk, yogurt, butter
Not fermented food products
Bread, biscuits, cereals/chewing gums, coffee, cookies, chocolates,
chocolate bars, frozen yogurt, granola bars, honey, ice cream, ice
tea, juices, muffins, pizzas, royal jelly, tea Breast milk, soy milk
Food Supplement products
Dietary supplements provided as powders, (chewable) tablets, pills,
capsules, straws (sticks)Registered Pharmaceutical products
Tablets, pills, capsules, vaginal suppositories
Cosmetics and Hygiene
Aftershave, anti-aging serum, face and body lotion, hydrating cream,
toothpaste, sanitary napkins, tampons, shampoo, douche gel, oral
care gums
Others
Household cleaner (floor & carpet), mattress, mattress protector,
industrial wastewater treatment, bioremediation efforts, odor control
solutions
Animal applications
Digestive supplements and oral care for pets, grass protector (dog
urine neutralizer), fish care products, Food supplements for
commercial farm animals (poultry, pigs, horses, etc.)
no longer allowed, as its definition by an earlier FAO/
WHO panel [36] implies a health benefit. This dramatic
restriction is in contrast with the increasing knowledge
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Probiotics from an industrial perspective Foligne´, Daniel and Pot 287
and medical interest in probiotics. Explanations for the
rejection of health claims may be found in the NDA
review process, which was not very well explained at the
time dossiers were submitted and in the lack of com-
munication between the producers and EFSA. This situ-
ation has also worried the scientific community which is
concerned as claims supported by solid scientific evi-
dence have also been rejected [37��]. This situation might
also discourage producers to invest in further research that
could substantiate the health benefits of the strains or
products.
While in Europe the NDA rejected a claim [38] based on
a high quality study published in the British Medical
Journal [39] and describing a probiotic able to reduce
Clostridium difficile toxin levels in the gut, limiting the risk
of acute diarrhea in patients receiving antibiotics, Health
Canada recently approved a patented probiotic formula to
treat C. difficile infections in hospitalized patients. This
decision follows a recent meta-analysis study on the
subject [40].
In the US, the so-called ‘structure/function’ claims do not
need approval, but must be substantiated by proper scien-
tific studies. While the nature of the studies needed is not
well defined, regulatory authorities in the USA have
increased their scrutiny of structure/function claims,
demanding that the claims meet regulatory standards for
substantiation [1��]. It seems a pity that these frameworks
are different worldwide, as they affect research and com-
munication strategies, and determine product manufactur-
ing and product labeling [1��].
The Japanese FOSHU (Foods for Specific Health Use)
regulation was already established in 1993. The Ministry
of Health, Labor and Welfare approves foods or ingre-
dients that bear enough scientific evidence for health
claim substantiation. When approved, a FOSHU label
can be used on the product. Although Japan has one of the
biggest functional food markets world-wide, there are
relatively few products submitted for FOSHU approval.
A major difference with, for example, the European
situation is that in Japan an active, approved ingredient,
shown to be present in the product, allows a producer to
put the FOSHU label. In Europe a clinical trial with the
final product, not with the ingredient, is a prerequisite.
In India, there is no real regulatory framework for pro-
biotics. In an initiative from the Indian Council of
Medical Research, guidelines were formulated for the
evaluation of probiotic foods, their strains, efficacy and
health claim labeling [41].
The Chinese regulation, until recently, was probably one
of the most tolerant systems. However, since the publi-
cation in 2009 of the Food Safety Law, which approved 27
health claims (some of which only supported by in vitro
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and animal data), 9 of them (on ‘improved sleep’ and
‘relieves fatigue’) have been redrawn by the Chinese
State Food and Drug Administration because human
clinical data were lacking. The explicit need for human
clinical intervention studies resembles the European
approach, but in contrast to the European setting, animal
studies are still allowed for claims where human test
methods are not yet available.
Given the weaknesses mentioned above, however, there
is no doubt that a tight regulatory framework is necessary,
permitting the removal from the market of products that
have health claims but lack scientific proof. Therefore, a
trustful and discerning interplay is necessary between the
legislator, the scientists and the food and pharmaceutical
industry, allowing a food product with good scientific
substantiation to be marketed as such. This authorization
will depend on well-controlled clinical trials and mechan-
istic studies according to rigorously defined criteria and
using appropriate (physiological) end points (Figure 1a).
This is especially important as probiotics over the last
decade gained substantial attention and popularity and
have the real potential to reduce, on a large scale, health
care costs in the future [42,43�]. If the probiotic field does
not want to become victim of its own success, and wants
to maintain its credibility and attract attention from
politicians and regulators, it will need to deal with the
websites, advertisements and commercials that abuse the
concept merely for a pure commercial benefit (Figure 1b).
One of the ways to deal with this challenge is to further
fortify developments in research and, for example, pro-
vide verifiable evidence based on validated biomarkers
for the different strains and products.
Innovative approaches that will provide an
emerging market with new possibilities and
challenges
In recent years, the genomes of several probiotic species
have been sequenced, thus paving the way to the appli-
cation of ‘omics’ technologies to the investigation of
probiotic activities. Proteomics has contributed substan-
tially to the study of the molecular mechanisms under-
lying probiotic effects [44]. Moreover, advances in
computing and high-throughput sequencing technologies
enabled wider metagenomic surveys such as the Meta-
HIT or the Human Microbiome Project, which provided
detailed insight in the human microbiome composition,
in health or disease. Mechanistic studies, employing
gnotobiotic-specific or disease-specific models, are now
offering tools to test working hypothesis and solve the
mechanistic questions of probiotic functionality. The
resulting knowledge about the human microbiome, its
composition across multiple body sites and its local func-
tion and variability, has started the gradual understanding
of the extreme complexity of the commensal host–
microbe and microbe–microbe interactions as well as
the comprehension of the role of the billions of bacteria
Current Opinion in Microbiology 2013, 16:284–292
288 Ecology and industrial microbiology
atio
Figure 1
Individual 
variation of
the
microbiome
Genetic
profile of
the host
Good
quality
clinical
trials
Dosage &
frequency
of intake
Microbio-
logical and
immuno-
logical
profiling
Bacterial stability
Storage
condi-
tions
Strain
proper-
ties
(a)
Manufac
turing
proper-
ties
Functional
analysis-
mechanism
of action
In vitro and
preclinical
studies −
safety
profile
(a) Factors influencing the success of an industrial probiotic strain evalu
in health and disease. The next step will be the explora-
tion of this accumulated knowledge in potential diagnos-
tic or therapeutic tools [45].
The association of certain diseases with a dysbiosis of the
microbiota, may indicate possibilities for probiotic
therapy. An intriguing example is the association between
increased relative abundances of Faecalibacterium praus-
nitzii and extended remission periods in patients with
Crohn’s disease. F. prausnitzii was subsequently shown to
elicit strong anti-inflammatory responses suggesting that
the organisms could be used to counterbalancethe dys-
biosis in patients with Crohn’s disease [46]. Similarly,
Eeckhaut et al. showed that patients with IBD have lower
fecal counts of a butyrate-producing bacterium, Butyri-
coccus pullicaecorum, and that this bacterium attenuates
colitis in rats [47�]. These bacteria are conceptually
attractive as new probiotics in patients with IBD. Finally,
the involvement of representatives of the spore-forming
Clostridium clusters IV and XIV in the induction of
tolerance (TReg cell regulatory) responses in the colon,
may suggest a therapeutic potential in the treatment of
diseases that are associated with loss of tolerance [48�].
Interestingly, these groups of potential new probiotic
species are long term-residents of a community and
should be capable of modulating the microbiota com-
munity structure and function in ways that short-term
residents could not [49]. It remains to be investigated
credibility for probiotic products.
Current Opinion in Microbiology 2013, 16:284–292 
(b)
Objectivity
Seriousness
Rigor
Independency
Transparency
Deontology
Ethics
Adapted
application
Scientific
Evidence
and 
support
Legislative
approval
Consumer
education
Sincere
connection
with media
Safety &
quality
monitoring
Appropriate
advertising
Current Opinion in Microbiology
n (modified from [63,64]). (b) Factors critical to the industry in eliciting
though whether long term-residents will have the same
impact as trespassing bacteria, for example, on the
immune system.
Another challenge will be the use of probiotic prep-
arations composed of multiple species [50]. Most existing
probiotic products consist of only one or a few strains and
most of the simple consortia appear to have been
assembled without too much scientific reasoning. At
the other end of the complexity spectrum, fecal trans-
plants consist of intact, highly complex communities of
hundreds of species [51]. Although already used in a
clinical context, the safety issues remain largely unsolved.
Could probiotics occupy the middle of the spectrum:
larger communities of well characterized, safe strains?
Several studies suggested this will indeed be the case.
A model community of 10 sequenced human gut bacteria
was introduced into gnotobiotic mice, and changes in
species abundance and microbial gene expression were
measured and to some extent predicted in response to a
varying diet [52]. More recently, a synthetic human stool
mixture composed of 33 different bacterial strains, was
developed and used to treat successfully two patients
with severe C. difficile infection [53�]. Finally, more ambi-
tiously, a defined mixture of 50+ species could be chosen
to mimic the healthy state of one of the common ‘enter-
otypes’ [54] and used as a simplified fecal transplant in a
capsule.
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immunomodulatory effects to the host [60,61��]. Such
products fall under the general term ‘pharmabiotics’
which encompass non-viable microbes and health-pro-
moting substances (Box 3). While most of the above has
focused on the gut as a major target for probiotics, all
principles of selecting, designing and testing ‘functional
strains’ can be extended to the skin, oral, vaginal and
upper respiratory tract communities.
Conclusions
Probiotics have a brilliant future. Applications will be
both in the food domain, affecting large parts of the
population, as well as in very specific disease situations,
where they can play a true therapeutic role for a limited
number of patients. Success, however, will depend on a
number of, mostly interlinked, conditions. Good quality
research will be required to find the safest and most
functional strains and to identify the optimal target popu-
lation, the optimal dose and mode of administration. This
concept was recently highlighted in a study from van
Baarlen et al., stating that the success rate of probiotic
Probiotics from an industrial perspective Foligne´, Daniel and Pot 289
considered as ‘probiotics’ and could be a safer alternative in
severely immunodeficient subjects who may be at risk from
treatment with live bacteria.
� Taverniti and Guglielmetti proposed the new term ‘paraprobiotic’
or ‘ghost probiotic’ to indicate the use of inactivated microbial
cells or cell fractions which can confer a health benefit to the
consumer [61��]. The prefix ‘para’ has been chosen because of its
meaning ‘alongside of’ or ‘atypical’, which can simultaneously
indicate similarity to and difference from the traditional probiotic
definition. However, the paraprobiotic concept excludes purified
molecules of microbial origin or pure microbial cell products.
There is a strong interest in unraveling the molecular
mechanisms involved in industrial robustness, cognate
stress resistance and health-promoting phenotypes of
food bacteria. The patho-biotechnology concept seeks
to attain this goal, ultimately leading to the development
of improved probiotic strains [55]. This strategy, which
involves the construction of mutant or recombinant pro-
biotics, can be divided into three distinct approaches. (i)
Delivery: engineering technological robustness; (ii) Sur-
vival: improved competitiveness in the gastrointestinal
tract (or on other mucosa), and (iii) Efficacy: improved
therapeutic/prophylactic qualities. The first tackles the
issue of probiotic storage and delivery by cloning and
expressing specific stress survival mechanisms, thus coun-
tering reductions in probiotic numbers which generally
occur during manufacture and storage in the delivery
matrix. This approach involves the construction of
mutant strains, over or under-producing relevant stress
factors and regulators. The second approach aims to
improve host persistence by expression of host-specific
survival strategies such as the ability to cope with bile in
the GIT context, thereby positively affecting the thera-
peutic efficacy of the probiotic [55]. The final approach
involves the development of the so-called ‘designer pro-
biotics’, strains which have been engineered to produce
specific therapeutic molecules which can be delivered to
the mucosal sites (such as the GIT) to prevent and treat
diseases [56,57]. This led to the concept of ‘biodrugs’
based on the oral administration of live recombinant
microorganisms for the prevention and treatment of var-
ious diseases.
Despite their obvious clinical potential, the industrial
application of genetically engineered bacteria is still
hampered by legal issues and by a rather negative general
public opinion; at least when food is concerned. Within
the pharmaceutical industry, however, the application of
GMOs (genetically modified organisms) appears much
more acceptable, provided that specific containment
strategies are implemented which prevent the release
of GMOs into the environment and guarantee the use
of food-grade markers only [58].
As an alternative, adaptive evolution can also be used to
modulate phenotypic characteristics of bacteria. It was
used to increase the growth rate of bacteria, or adapt them
to growth under special conditions [59]. Such naturally
adapted strains are not considered to be genetically
modified and can thus be applied in food application
without legislative constraints.
Probiotic effects, as per definition, are allocated to bac-
teria that are still alive at the time they reach the small or
large intestine, suggesting a need for metabolic activity of
the strain administered. However, it has been shown that
culture supernatants of bacteria, non-viable microbial
cells (intact or broken) or crude cell extracts also confer
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Box 3 New directions in the field of health-promoting products:
postbiotics, paraprobiotics and ghost probiotics.
� Tsilingri and Rescigno proposed the use of purified and well-
characterized ‘postbiotic’ components as a safer alternative for
clinicalapplications, especially in chronic inflammatory conditions
[60]. They considered as ‘postbiotic’ any factor resulting from the
metabolic activity of a probiotic or any released molecule, capable
of conferring beneficial effects to the host in a direct or indirect
way. Examples of postbiotics include food metabolic products like
short chain fatty acids, saccharides such as polysaccharide A,
secreted molecules such as lactocepin [65�] and the p40 molecule
[66��], degradation products [10��] as well as other less well-
characterized molecules.
� The probiotic paradox (or is it the probiotic advantage?) is that
both live and dead cells can generate beneficial biological
responses [61��,67]. Killed/inactivated ‘probiotic’ cells may be
sufficient to generate a biological response: bacterial components
such as cell wall components (wall teichoic acids, lipoteichoic
acid, capsular polysaccharides), cytoplasmic extracts and surface
layer proteins have been shown to exert immunomodulating
effects [61��]. Products based on dead cells or microbial cell
extracts would be relatively easy to standardize and would have a
long shelf-life. Also the use of killed/inactivated cells or microbial
cell extracts would permit a wider range of microorganisms to be
interventions can be improved by a more reliable charac-
terization of the target population [62]. Probiotic research,
however, will need to be accepted by the regulatory
Current Opinion in Microbiology 2013, 16:284–292
290 Ecology and industrial microbiology
authorities and by the medical community who has been
rather skeptical about their use in a routine clinical
setting.
The real challenge will be the introduction of the newer
generation of probiotic strains and mixtures, probiotic
metabolites or designer strains. Accumulated knowledge
generated by the introduction of high throughput sequen-
cing, advanced bioinformatics, and specialized in vitro
and in vivo models, will allow a better understanding of
underlying mechanisms. This will improve selection of
new strains and, whenever necessary, will stimulate the
construction of designer strains for a safer or more effi-
cient solution.
Regulators will need to do what they are expected to do:
eliminate products which do not fit the definition or that
contain unsubstantiated health/benefit claims from the
market and provide a workable application procedure,
allowing food and pharma products to obtain the recog-
nition they deserve, based on the research performed.
Both legal frameworks will differ considerably, as foods
are intended to maintain normal body functions or to
reduce the risk of disease in a very broad target population
of healthy and sub-healthy people, while pharma pro-
ducts should provide a primary therapeutic solution in a
specific disease situation. The inherent safety of
traditional probiotics remains an advantage in this phar-
maceutical context. Legal frameworks will have to con-
sider the need for adapted quality control measures for
products on the market. Currently, for example, the
European Medicines Agency is not routinely dealing with
live microorganisms. The newer types of probiotic-
derived strains that are currently being developed will
require even more specialized approaches.
Since regulatory frameworks do affect research
approaches, communication strategies, product manufac-
turing and product labels [1��], communication between
producers, consumers, researchers, regulatory authorities,
politicians and health care workers may need to be
optimized. While it is essential to prohibit all false claims
and prevent misleading information being distributed to
the public, the possibility to communicate positively on
proven health benefits is necessary to promote the use of
probiotics in a number of conditions that have the poten-
tial to reduce substantially the health care cost for society.
Each safe dietary approach that can reduce a specific
morbidity in the population deserves to be promoted.
Key to this reasoning is how to prove a health benefit.
There is no consensus today on how to conduct mean-
ingful studies to show that health is improved — or, even
more challenging, maintained — in a healthy person?
[1��]. The answer to this question could lie in the identi-
fication of biomarkers for health which are then moni-
tored for a larger population. A significant improvement of
Current Opinion in Microbiology 2013, 16:284–292 
the biomarkers, measured over the entire population,
might then be considered as proof of functionality. Lastly,
the current probiotic interest from consumers, scientists,
and healthcare workers will only increase as more and
better information is becoming available.
Acknowledgements
BF, CD and BP like to thank the French Association Nationale de
Recherche (ANR), section ‘Contaminants Ecosyste`mes Sante´’ for the
research grant ‘Me´lodie-Reˆve’, number ANR 2009-CESA-16. BP is
indebted to the Institut Pasteur de Lille (IPL) for staff support.
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