INTRODUCTION
The popularity of probiotics has expanded
exponentially recently, but along with their
increased use, debate rages on how probiotics
should be regulated and whether probiotics
should be considered as a medical food,
drug or a food supplement. In the USA, probiotics
are typically available as dietary supplements
and thus are limited to ‘structure
or function’ health claims and, unlike prescription
drugs, are not permitted to claim
to ‘treat’ or ‘cure’ disease. In Europe and
the UK, probiotics are allowed to have health
or function claims. These claims are
required to be supported by well-conducted
human trials in the targeted population or in
healthy volunteers, but the European Food
Safety Authority (EFSA) has rejected >80%
of claims submitted to them.1–3 In many
cases, scientific substantiation of a specific
health claim was judged insufficient or based
on an indirect effect.4 One such functional
claim made for probiotic products is they
correct dysbiosis (or the disruption of bacterial
and fungal species after antibiotics or
other disruptive exposures) and thus may be beneficial to maintain health. Probiotics are active
during this susceptible window from the time of the disruptive
event to the time when normal microbiota is
restored. A wide variety of mechanisms-of-action have
been documented for probiotics (ranging from blocking
pathogen attachment sites, destruction of the pathogen
by bacteriocins or proteases that degrade toxins, to regulation
of the immune system),5 6 and while clinical evidence
supports efficacy of some probiotic strains, the
evidence linking these mechanisms-of-action to a specific
health or function claims is not as clear.
A classic example of the consequence of dysbiosis is
antibiotic-associated diarrhoea (AAD).7 8 While antibiotics
may be effective in the elimination of pathogenic
organisms, a common, unintended effect is the killing
or inhibition of beneficial microbes due to shared susceptibility
to the antibiotic. One of the many functions
for normal microbiota is the ability to resist infection by
pathogenic organisms, termed ‘colonisation resistance’.
9 10 The loss of a subpopulation of the normal
microbiota, for example, can lead to the loss of the
ability to break down fibres and starches into absorbable
short chain fatty acids, resulting in high level of
undigested carbohydrates, which can trigger diarrhoea.
11 Disruption of the normal microbiota has been
shown to lead to higher rates of infections in other body
systems other than the intestinal tract including the
skin,12 13 vagina,14 15 respiratory tract,16 17 and in the
buccal cavity.18–20
The major challenge to establishing a cause and
effect for the improvement of dysbiosis by probiotics is
a lack of a standard definition of ‘normal’ microbiota.
There is substantial inter-individual variation of the
species of microbes present at different body niches,
which also varies by age, geographic area and health
status of the host. In addition, a complete accounting
of the microbiota is currently impossible, as there are
no assays to detect all of >1013–1014 organisms in the
intestines and standard microbial culturing methods
miss 75–95% of these organisms.21 22 The development
of metagenomics (cataloguing individual and diseasespecific
bacterial gene profiles) and the creation of the
international Human Microbiome Project ushered in a
new era for our understanding of the complexity of
these interactions within the body.23 24 This paradigm
shift from culturing to metagenomic analysis has
expanded our ability to document shifts in microbial
populations to an unparalleled degree, but the interpretation
of these shifts continues to be under
debate.25–28 With the advent of these newer metagenomic
tools, the role of probiotics in the restoration of
normal microbiota is being revisited.29
In light of new guidance documents and recommendations,
the goal of this systematic review is to determine
how claims for the restoration of the normal microbiota
and the correction of dysbiosis have been studied using
well-designed trials and which probiotic strains have
evidence-based data to support these claims.