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Unraveling Mechanisms of Action of Probiotics

Philip M. Sherman, Juan C. Ossa and Kathene Johnson-Henry
Nutr Clin Pract 2009 24: 10
DOI: 10.1177/0884533608329231

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Invited Review
Unraveling Mechanisms of Action
of Probiotics
Philip M. Sherman, MD, FRCPC; Juan C. Ossa, MD;
and Kathene Johnson-Henry, BSc
Financial disclosure: Research efforts in the laboratory of the authors are supported by a Fay Shapiro-Cutler Research Grant-in-Aid
from the Crohn’s and Colitis Foundation of Canada and by Institut Rosell-Lallemand, Inc (Montreal, Quebec, Canada). PMS is the
recipient of a Canada Research Chair in Gastrointestinal Disease.
Probiotics are defined as living organisms that, when adminis-
tered in sufficient numbers, are of benefit to the host. Current
evidence indicates that varying probiotic strains mediate their
effects by a variety of different effects that are dependent on the
dosage employed as well as the route and frequency of delivery.
Some probiotics act in the lumen of the gut by elaborating anti-
bacterial molecules such as bacteriocins; others enhance the
mucosal barrier by increasing the production of innate immune
molecules, including goblet cell–derived mucins and trefoil fac-
tors and defensins produced by intestinal Paneth cells; and
other probiotics mediate their beneficial effects by promoting
adaptive immune responses (secretory immune globulin A,
T
he World Health Organization defines probiotics as
live organisms (bacteria, yeast) that, when ingested
in sufficient amounts, have a beneficial effect on
the overall health of the host.1 An array of products is cur-
rently sold to consumers,2 but availability varies from
country to country. In fact, there are concerns about
batch-to-batch consistency in viable numbers of organ-
isms present in many of the probiotics now available in the
marketplace. Current enthusiasm for implementing the
use of probiotics has been hampered, at least in part, by
concerns about precisely how the various organisms pur-
ported as probiotic agents mediate their beneficial effects.
A wide array of strains employed and a bewildering com-
plexity of proposed mechanisms of action have raised a
certain level of skepticism in the biomedical research com-
munity as a whole. Nevertheless, recent advances in the
field are helping to sort out facts from fiction.3,4
Multiple randomized, controlled clinical trials and
meta-analyses demonstrate that probiotics elicit beneficial
From the Research Institute, Hospital for Sick Children,
University of Toronto, Toronto, Ontario, Canada.
Address correspondence to: Philip M. Sherman, MD, FRCPC,
Gastroenterology and Nutrition, Room 8409, Hospital for Sick
Children, 555 University Avenue, Toronto, Ontario, M5G 1X8,
Canada; e-mail: philip.sherman@sickkids.ca.
10
Downloaded from ncp.sagepub.com at Scientific library of Moscow State University on January 6, 2014
Nutrition in Clinical Practice
Volume 24 Number 1
February/March 2009 10-14
© 2009 American Society for
Parenteral and Enteral Nutrition
10.1177/0884533608329231
http://ncp.sagepub.com
hosted at
http://online.sagepub.com
regulatory T cells, interleukin-10). Some probiotics have the
capacity to activate receptors in the enteric nervous system, which
could be used to promote pain relief in the setting of visceral
hyperalgesia. Future development of the effective use of probi-
otics in treating various gastroenterological disorders in human
participants should take advantage of this new knowledge. The
creation of novel formulations of probiotics could be directed to
effectively target certain mechanisms of actions that are altered
in specific disease states. (Nutr Clin Pract. 2009;24:10-14)
Keywords: lactobacillus; probiotics; intestines; diarrhea;
mucins; defensins; tight junctions
effects in a variety of conditions involving the gastrointesti-
nal (GI) tract.5 Figure 1 summarizes potential mechanisms
of action of probiotics. As considered in greater detail
below, it is now apparent that not all probiotic strains exert
the same mechanisms of action. The separations consid-
ered below are somewhat artificial in nature but are simply
presented as a conceptual framework by which to consider
just how probiotic agents might work. Certainly, some pro-
biotic agents will have multiple activities and can affect
various stages that are considered in the figure.
Lumenal Effects
Enhancing the Microbial Flora:
Creating a Balance
Probiotics possess the ability to transiently colonize the GI
tract, increase the concentration of beneficial microbes,
and thereby create a balance in the gut microbiota to the
ultimate benefit of the host. A front line of defense against
the adverse effects of pathogens is provided by probiotics
that exert a direct antimicrobial effect. For instance, some
probiotic strains elaborate antibacterial products referred to
as bacteriocins. These antimicrobial factors inhibit the
growth and virulence of enteric bacterial pathogens. Isogenic
mutants deficient in the gene coding for bacteriocin are less
 Actions of Probiotics / Sherman et al 11

Figure 1. Schematic depiction of potential mechanisms of action by which probiotics can promote GI health. Probiotics (PB) and
surface-layer proteins (slp) competitively exclude microbial pathogens from mucosal surfaces. Tight junction proteins, such as zona
occludins (ZO)-1 and claudin1, remain intact and thereby prevent both uptake of intact macromolecules and translocation of viable
organisms to mesenteric lymph nodes. Probiotic strains possess the ability to modulate signal transduction pathways to block activation
and translocation to the nucleus of the transcription factor, nuclear factor-kappa B (NF-κB), interferon-γ (IFNγ), and mitogen-activated
protein kinases (MAPK). Through a cascade of signaling events, probiotics can enhance production and secretion of anti-inflammatory
cytokines, including interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) by a subset of immune cells, referred to as T reg-
ulatory cells (Tregs). Humoral immune system responses to probiotics include enhanced production of immune globulins, including
secretory immunoglobin A (sIgA). Innate immune responses to probiotics include increased mucin and trefoil factor production by
goblet cells (G) and enhanced production of antibacterial defensins by Paneth cells (PC) and intestinal epithelia. DC, dendritic cell;
P, pathogen; TC, T lymphocyte.

effective as probiotics, at least when tested in a mouse
model of invasive Listeria monoctyogenes infection.6 Lactic
acid–producing probiotics may also exert antimicrobial
effects on pathogenic organisms by reducing the local pH
of the microenvironment in the gut lumen. Such specula-
tion is supported by in vitro studies demonstrating that co-
culture of Lactobacillus species with pathogens results in
reduced growth of the virulent organism in a pH-dependent
manner.7
Quorum sensing refers to the mechanisms by which
single-cell organisms communicate with each other.8 It
has been suggested that some strains of probiotics may
influence gene expression of microbial pathogens and
thereby reduce their virulence potential. For instance,
secreted factors from Lactobacillus acidophilus (strain La-5)
affect virulence gene expression by enterohemorrhagic
Escherichia coli of the serotype O157:H7.9 The probiotic
reduces the secretion of autoinducer-2 molecules by the
pathogenic E. coli, which results in reduced expression of
genes contained in the locus of enterocyte effacement
(LEE) pathogenicity island that is critical for mediating
intimate bacterial binding to host cell surfaces—the so-
called attaching and effacing lesion.10
Colonization Resistance
Although some probiotic strains have the ability to secrete
factors that affect the luminal microbiotia, other probiotics

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12 Nutrition in Clinical Practice / Vol. 24, No. 1, February/March 2009
interact with epithelial cells lining the GI tract to prevent
the binding and downstream effects of enteric pathogens.
Probiotics, such as Lactobacillus helveticus (strain
R0052), possess relatively hydrophobic cell surface prop-
erties and therefore are able to bind nonspecifically to
host cell surfaces, including the apical microvillus mem-
brane of epithelial cells.11 An attribute of this probiotic
strain is that it possesses a thick surface-layer protein,
which has the ability to adhere to the surface of epithelial
cells and reduce the effects of bacterial enteropathogens.11
As a result, probiotics and nonviable products derived
from certain probiotic strains can obscure receptor bind-
ing sites to prevent pathogens from binding and invading
the infected host.
Probiotics may also compete for a limited niche in
the complex microbiota of the large bowel, thereby exclud-
ing a site for replication by pathogens.12 This mechanism
of action is often referred to as colonization resistance.
Saccharomyces boulardii also has the potential to indi-
rectly block the attachment of enterohemorrhagic E. coli,
serotype O157:H7, to mucosal surfaces by binding
directly to the pathogen.13
Mucosal Effects
Probiotics, such as Lactobacillus plantarum (strain 299v),
have the capacity to enhance the production and secretion
of mucins (MUC2 and MUC3) from human intestinal (HT-
29) epithelial cells.14 Probiotic mixtures also increase
MUC2 gene expression and mucin protein secretion in rat
colon.15 The enhanced mucus layer overlying the epithelial
lining of the gut can serve as an antibacterial shield that pre-
vents the binding of enteric pathogens, such as enteropath-
ogenic E. coli,16 to mucosal surfaces and increase clearance
of the pathogen from the GI tract.17 Trefoil factors are anti-
bacterial peptides, which are also secreted from mucin-
producing cells in response to various noxious stimuli,
including microbial pathogens. These trefoil factors appear
to act in concert with mucins to reduce binding of pathogens
to the epithelial cell surface.18
Paneth cells are located near the base of the crypt cell
compartment in the distal small intestine. These special-
ized cells produce antibacterial cationic peptides referred
to as defensins (and cryptdins, in mice). At least some
probiotics enhance release of defensins from intestinal
epithelia, which may explain, at lease in part, the benefi-
cial effects of probiotics in the setting of acute infectious
enteritis.19 For instance, the probiotics Lactobacillus fermen-
tum and E. coli (strain Nissle 1917) each stimulate, in both
a time- and dose-dependent manner, human β-defensin
mRNA expression and protein secretion in intestinal
(Caco2) epithelial cells grown in tissue culture.20
In addition to promoting the production of antibac-
terial substances, probiotics also have a direct effect on
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enhancing the integrity of the epithelial barrier, which
serves as the surface lining of the GI tract.21,22 Probiotics
may do so by preventing changes in tight junction pro-
teins (such as occludins and claudins) and by enhancing
the electrical resistance of tight junctions contained in
the apical junction complexes between adjacent polarized
epithelia, which occur in a protein kinase C and mitogen-
activated protein (MAP) kinase-dependent fashion.23
Reduced programmed cell death (apoptosis) also appears
to enhance barrier resistance to injurious agents, including
proinflammatory cytokines.24 Decreased apoptosis may
serve to maintain epithelial barrier integrity and resist-
ance to injurious agents, including enteric pathogens, by
reducing breaks in the mucosal barrier.
Extending Findings to Relevant Animal
Models of Intestinal Injury
The protective effects of probiotics on intestinal function
in vitro have been confirmed in some in vivo studies by
using the Citrobacter rodentium infection of mice as a model
of bacterial-induced infectious colitis.25 Complementary
studies in rodent models of stress-induced intestinal
barrier dysfunction, including use of water avoidance,26
physical restraint,27 and maternal separation of rat pups,28
also demonstrate the benefit of probiotics in enhancing
epithelial cell barrier integrity, including a reduction in
both the uptake of intact macromolecules (including, for
example, fluorescein-tagged dextran, horseradish peroxi-
dase, and chromium-labeled EDTA) and the translocation
of viable bacteria from the intestinal lumen to mesenteric
lymph nodes.
Submucosal Effects
Through bacterial-epithelial cell cross-talk, probiotics are
able to affect both innate and adaptive arms of the host
immune system.29 For instance, some probiotic strains
have the ability to promote the differentiation of B cells
into plasma cells and increase the production of secretory
immunoglobulin A.30 Polymeric IgA sticks to the mucus
layer overlying the gut epithelium and binds to patho-
genic microorganisms, thereby reducing their ability to
gain access and bind to the microvillus membrane glyco-
calyx of enterocytes and colonocytes.
Probiotics can also prevent activation of the proin-
flammatory nuclear transcription factor, nuclear factor-
kappa B (NF-κB).31,32 This results in decreased secretion
of the chemokine interleukin (IL)-8, which is a potent
neutrophil chemoattractant. Probiotics and nonpathogenic
organisms prevent NF-κB translocation from the cytosol
to the nucleus by blocking phosphorylation and subse-
quent degradation by ubiquitination of I-κB.33 Although

some probiotics are able to inhibit activation of this
nuclear transcription factor, there are also reports that
other strains of probiotics are able to activate NF-κB and
increase levels of the proinflammatory cytokine IL-6.3
These discrepancies serve to emphasize further the
strain-specific effects of probiotics on the host.
Certain T cell immune responses are also affected by
probiotics. For instance, using adoptive transfer of
CD4+CD45RBhi T lymphocytes from healthy mice into
SCID (severe combined immunodeficiency) mice as a
reproducible model of colitis, the yeast probiotic S.
boulardii was shown to reduce intestinal inflammation.34
The mechanism of action relates to a yeast-related secre-
tion product, which reduces the trafficking of T helper-1
cells, producing the proinflammatory cytokine interferon-γ
from mesenteric lymph nodes to the inflamed colon. In
a model of hapten-induced colitis in mice, probiotics
(VSL #3) reduced the severity of a second induction of
intestinal inflammation, which was associated with the
presence of regulatory T cells expressing transforming
growth factor (TGF)-β.35 In another study, the subset
of regulatory T cells expressing CD4 and Foxp3 was
increased following challenge with Lactococcus lactis.36
These biological effects are mediated by TGF-β and the
anti-inflammatory cytokine IL-10.
It has also been demonstrated that varying probiotic
strains can have different effects on the secretion of anti-
inflammatory (eg, IL-10) and proinflammatory (eg, IL-12)
cytokines by immune cells. The relative secretion profiles
are reported to predict the ability of the probiotic strains to
have an impact on disease outcome—for instance, in
experimental models of hapten-induced colitis in mice.37 In
humans with irritable bowel syndrome (IBS), participants
randomized to treatment with Bifodobacterium infantis
(strain 35624) resulted in an improvement in clinical
symptoms in association with a normalization of the ratio
of IL-10:IL-12 secretion by peripheral blood mononuclear
cells. By contrast, another probiotic, Lactobacillus salivar-
ius (strain UCC4331), had less effect on abdominal symp-
toms and had no discernable effect on the abnormally low
ratio of IL-10:IL-12 in patients with IBS.38 These observa-
tions serve to highlight the strain-specific effects of various
agents proposed for use as probiotics.
Impact of Probiotics on the
Enteric Nervous System
A recent interesting and novel study provides compelling
evidence that some probiotics also have the capacity to
activate specific opioid and cannibinoid receptors in the
gut.39 Such strains could prove particularly useful as
agents in settings where visceral pain is a prominent man-
ifestation of disease—for instance, in patients with IBS
and chronic inflammatory bowel diseases.
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Actions of Probiotics / Sherman et al 13
Conclusions
There has been an explosion in our knowledge related to
how probiotics exert their beneficial effects. Current evi-
dence suggests that we should remain cautiously optimistic
about the increasingly widespread use of these agents as
therapeutics. However, there is also reason to pause and
reflect on the potential for adverse effects when using
viable organisms. For instance, the results of a prospective,
randomized trial in humans with severe acute pancreatitis
described a 2.5-fold increased relative risk of death among
those entered into the probiotic treatment arm of the
study.40 Although the precise mechanisms accounting for
this adverse outcome are not known, the authors of the
report suggest that reduced splanchnic blood flow in
severely ill patients cared for in an intensive care unit set-
ting may impair clearance of the large numbers of viable
bacteria employed as a probiotic agent. Relative tissue
hypoxia and impaired gut barrier function both could
increase the risk of bacterial translocation. Evidence of
bowel ischemia in 9 patients treated with probiotics,
including 8 who died, vs none of the patients in the placebo
group supports such considerations. Accordingly, even
though probiotics generally can be considered safe for use
in human participants,41 enthusiasm for testing probiotics
in high dosages, in combination regimens, and in extremely
ill patients must be tempered with the potential for causing
harm. As a result, initial animal studies and subsequent
applications to humans must be conducted with rigor
employing the best available research methodologies.
Ongoing studies should continue to rely on comple-
mentary experimental approaches, including reductionist
systems employing eukaryotic cells grown in tissue cul-
ture and relevant animal models of human disease.
Increasing evidence demonstrates that probiotics have
multiple mechanisms of action that are related to effects
in the lumen of the gut, the integrity of the mucosal bar-
rier, and both innate and adaptive immune host
responses. However, such effects are not likely to be
caused by all probiotics strains tested. Thus, strain selec-
tion and consideration of the merits of using combina-
tions of probiotics may well provide a strategy in the
future to develop targeted interventions.
Acknowledgments
We thank Ms Aleah Henry for the production of the fig-
ure employed in this work.
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