CHEST Translating Basic Research Into Clinical Practice

Probiotics and Lung Diseases

Paul Forsythe, PhD

Increasing awareness of the role of intestinal commensal bacteria in the development and mod-
ulation of the immune system has led to great interest in the therapeutic potential of probiotics
and other bacteria-based strategies for a range of immune-related disorders. Studies in animal
models have identified strong immunomodulatory effects of many nonpathogenic bacteria and
provided evidence that intestinal microbes can activate a common mucosal immune response and,
thus, influence sites distant to the intestine, including the respiratory tract. Respiratory effects of
probiotics in animal models have included attenuating allergic airway responses and protecting
against respiratory pathogens. Dendritic cells appear central to directing the beneficial immune
response to probiotic bacteria and in translating microbial signals from the innate to the adaptive
immune system, whereas regulatory T cells are emerging as potentially key effectors of probiotic-
mediated responses, particularly in the reduction of allergic inflammation. Despite progress in
basic research, clinical trials of probiotics in allergy/asthma and respiratory infection have been
highly variable at best, leading to an undermining of confidence in this potential therapeutic
strategy. It is clear that there is still much to learn regarding the determinants of the diverse
immune responses elicited by different bacterial strains. A deeper knowledge of the interactions
between administered probiotics and the existing microbiota, together with an understanding
of how the dialogue between microbes and the innate immune system is translated into ben-
eficial/protective responses, will be required before we can achieve clinically effective bacteria-
based strategies that maintain and promote respiratory health. CHEST 2011; 139(4):901–908

Abbreviations: DC 5 dendritic cell; GALT 5 gut-associated lymphoid tissue; IDO 5 indoleamine 2,3-dioxygenase;
IFN 5 interferon; LAB 5 lactic acid bacteria; NK 5 natural killer; OVA 5 ovalbumin; Th 5 T helper; TLR 5 toll-like
receptor; Treg 5 regulatory T cell

Nonpathogenic bacteria that promote beneficial

health effects when ingested have been termed
probiotics. These “beneficial microbes” are most fre-
quently Lactobacillus or Bifidobacterium species; how-
ever, a range of lactic acid bacteria (LAB) and non-
pathogenic Escherichia coli have also been identified
as having health benefits. Furthermore, although the
Food and Agriculture Organization/World Health
Organization currently define probiotics as live micro-
organisms that when administered in appropriate
Manuscript received July 21, 2010; revision accepted September 13,
2010.
Affiliations: From the Brain-Body Institute and Department of
Medicine, McMaster University, Hamilton, ON, Canada.
Correspondence to: Paul Forsythe, PhD, The Brain-Body Insti-
tute, St. Joseph’s Healthcare, 50 Charlton Ave E, T3303, Hamilton,
ON, L8N 4A6, Canada; e-mail: forsytp@mcmaster.ca
© 2011 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians (http://www.chestpubs.org/
site/misc/reprints.xhtml).
DOI: 10.1378/chest.10-1861
dose, confer a benefit of health on the receiver, non-
viable microbes have also been regarded as probiotics
because in certain circumstances they exhibit bene-
ficial effects equal to live bacteria. Prebiotic is the
term given to food supplements that are generally
nondigestible and stimulate the growth and/or activ-
ity of probiotic bacteria, and a preparation containing
both prebiotics and probiotics is referred to as a
synbiotic.
Significant attention has been focused on the role
of probiotics in GI development, immune adaptation,
and attenuation of GI inflammatory diseases. How-
ever, there is steadily increasing evidence that orally
delivered probiotics are able to regulate immune
responses outside the GI tract, including the respira-
tory mucosa. What follows is an outline of our current
knowledge of the potential benefits and underlying
mechanisms of action of probiotic bacteria in relation
to the respiratory tract with a focus on modulation of
allergic responses and protection against infections.

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 Allergy and Asthma
The microflora hypothesis proposes that pertur-
bations in the GI microbiota, because of antibiotic
use and dietary differences in industrialized coun-
tries, have disrupted the normal microbiota-mediated
mechanisms of immunologic tolerance in the mucosa
leading to an increase in the incidence of allergic
disease, including asthma.1 Proof of principal has
been provided in murine models, wherein antibiotic
administration causes altered intestinal flora, impaired
barrier function, diminished T helper (Th)1 immune
responses, and enhanced allergic airway responses.2
The hypothesis is further supported by epidemiologic
data from various regions of the world that link varia-
tions in GI microbiota, in particular a reduction in
lactobacilli and bifidobacteria, with increased inci-
dence of allergy and asthma.3,4 Data also suggest that
a balanced microbiota plays a positive role in main-
taining mucosal immunologic tolerance long after
postnatal development.5 The fact that this immuno-
modulation is mediated by harmless commensals has
led to efforts to determine whether probiotic treat-
ment could be of benefit in allergic disorders.
Resulting clinical trials have indicated that feeding
mothers with LAB, such as Lactobacillus rhamnosus
GG and Lactobacillus fermentum, in the prenatal
and early postnatal period may be effective in the
treatment and prevention of early atopic disease in
children.6,7 However, there have also been a number
of clinical trials showing no effect of the same probi-
otic strains on the incidence or severity of allergic dis-
ease.8 It should also be noted that, to date, there have
been no studies of children at high risk for devel-
oping allergy that have shown significant beneficial
effects of probiotics on the incidence of asthma.8
However, there is evidence in animal models indi-
cating that oral administration of certain LAB can
modulate allergic responses in the respiratory tract.9-12
These beneficial effects are strain specific and the
observed efficacy is also likely influenced by the
antigen sensitization and challenge protocols used
in the animal model. The differential response to
LAB in asthma models is further emphasized by at
least one study demonstrating enhanced allergic air-
way inflammation following neonatal treatment of
mice with Lactobacillus casei.13 Although the exact
mechanism(s) behind the antiallergic action of these
bacteria remain obscure, several potential compo-
nents of this response have been highlighted.
Asthma is a T lymphocyte-mediated inflammatory
disease, and it has been suggested that the common
mucosal immune system is involved, with activated
T lymphocytes migrating from one mucosal site to
another. In keeping with this, the beneficial effect of
probiotic organisms appears to be strongly associated
902
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with changes in the balance of T-cell responses that
lead to a reduction in Th2 activity. In particular, there
is growing evidence from a range of model systems
that the ability to induce regulatory T cell (Treg)
classes that attenuate both Th1 and Th2 responses
may be a critical element in the antiinflammatory
action of many probiotic organisms.
Tregs: Effectors of the Antiallergic
Response?
Diverse populations of Tregs play an important role
in regulating Th2 responses to allergen and maintain-
ing functional tolerance. Tregs can be detected at
sites of inflammation, and in many situations, their
ability to migrate to and remain in inflamed tissue is
important for their function in vivo. In rodent asthma
models, CD41CD251Foxp31 Tregs are recruited into
the lungs and draining lymph nodes and can suppress
allergen-induced airway eosinophilia, mucous hyper-
secretion, and hyperresponsiveness.14,15
Attenuation of the allergic airway response fol-
lowing oral treatment of mice with Lactobacillus reuteri
is associated with a significant increase in the pro-
portion of functional CD41CD251Foxp31 regulatory
cells in the spleen and mediastinal lymph nodes.16
Indeed, CD41CD251 transferred from L reuteri-fed
nonsensitized mice can attenuate the allergic airway
response in ovalbumin (OVA)-sensitized animals.
L rhamnosus GG has also been shown to reduce the
murine allergic airway response, with associated
increases in Foxp31 T cells, but only when the bacte-
ria are administered in the neonatal period.9,10 This
led to the suggestion that probiotic intervention
might be successful primarily in the initial stage of
intestinal colonization, a time point that is believed
to be crucial for the maturation and balance of the
immune system. However, as described previously, it
is clear that certain strains of LAB can have profound
immunoregulatory and antiallergic effects when admin-
istered to adult mice. Interestingly, Lyons et al17 dem-
onstrated that one particular strain of Bifidobacterium
induced Tregs only when fed to mice in the perinatal
period, whereas another strain was able to induce
Tregs in both adult and neonatal mice. Only this sec-
ond strain attenuated the allergic airway response
in adult OVA-sensitized mice. This suggests that a
combination of bacterial strain-specific characteris-
tics and host-specific processes, such as immunologic
maturity, mucosal lymphoid antigen sampling, and
gut barrier integrity, may be important for the induc-
tion of host regulatory responses.
LAB can induce a regulatory response that does
not require prior exposure of Tregs to a specific
allergen.16 Once activated, Tregs can suppress effector
T cells in an antigen-nonspecific way called “bystander
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suppression,”18 and in vivo transfer studies demon-
strate that Tregs can create a regulatory milieu that
promotes the outgrowth of new populations of Tregs
with antigen specificities distinct from those of the
original population.18 In this way, certain LAB may
induce Tregs in the gut-associated lymphoid tissue
(GALT) that can spread to the airways in response to
immune challenge and inflammation (Fig 1). This
is supported by the finding that oral treatment with
L reuteri results in an increase in Tregs in the drain-
ing lymph nodes of the lung, relative to vehicle-
treated control subjects, only following airway chal-
lenge in sensitized mice.
However, despite growing evidence supporting
an association between the antiinflammatory effects
of LAB and an ability to induce Treg, a causal rela-
tionship has yet to be clearly established. Tregs are
believed to be involved principally in the resolution
of established inflammation,14 and whereas adoptive
transfer of Tregs from LAB-fed and helminth-infected
mice can suppress airway inflammation,15,16 more
research is required to determine the extent to which

Figure 1. Proposed gut-lung axis of probiotic action. Microbes in the intestine are sampled by DCs either directly from the lumen or
following translocation through M cells to the GALT. A combination of signals from the microbes results in phenotypic changes in the DCs
and the production of Th1 type and/or regulatory mediators. IL-12 promotes Th1 cells and activation and IFN-g production by NK cells.
Regulatory cytokines such as IL-10, TGF-b, and the activation of IDO and subsequent production of immunoactive KYNs promotes
Tregs and depletes Th2 cells. Following immune challenge in the airway, cells activated in the GALT and MLN traffic to the respiratory
mucosa where they promote protective and antiinflammatory responses. AHR 5 airway hyperresponsiveness; BALT 5 bronchus-associated
lymphoid tissue; DC 5 dendritic cell; GALT 5 gut-associated lymphoid tissue; IDO 5 indolamine 2,3 dioxygenase; IFN 5 interferon;
Kyn 5 kynurenine; MLN 5 mesenteric lymph node; NK 5 natural killer; TGF 5 transforming growth factor; Th 5 T helper; Treg 5 regulatory
T cell.

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LAB-induced Tregs contribute to protection against
an allergic airway response.
Dendritic Cells: Key Translators
of Microbial Signals
It is an attractive concept that by controlling the
maturation and function of dendritic cells (DCs),
mucosal immune responses can be modulated. Given
that DCs are pivotal in early bacterial recognition
and can induce a range of Treg subtypes, there has,
understandably, been great interest in interactions
between commensal organisms and DCs.
Consequently it is becoming apparent that although
Tregs may be major effectors of immune regulation
mediated by probiotics, the functional changes in DCs
following interaction with the bacteria is critical in
orchestrating these responses. Specifically, the ability
to induce IL-10 production by DCs, suggesting a
regulatory phenotype, seems to be key to the immu-
noregulatory action of many probiotics.19 Recently,
Kwon et al20 confirmed that regulatory DCs express-
ing high levels of IL-10, transforming growth factor-b,
COX-2, and indoleamine 2,3-dioxygenase (IDO) drive
the generation of CD41Foxp31 Tregs following
administration of a mixed-strain probiotic prepara-
tion in mice. The enzyme IDO is the rate-limiting
step in the conversion of tryptophan to immunoac-
tive kynurenines. DC expressing IDO contribute to
the generation and maintenance of peripheral toler-
ance by depleting autoreactive T cells and by inducing
Treg responses.21 Hayashi et al22 observed that the
ability of bacterial DNA-derived CpG motifs to atten-
uate the allergic airway response was dependent on
increased IDO activity in the lung, whereas the anti-
inflammatory effects of L reuteri in the airway of
OVA-sensitized and -challenged mice is associated
with increased systemic, but not localized lung, IDO
activity.11 Significantly, the maintenance of a clini-
cally unresponsive state following aeroallergen expo-
sure in atopic individuals has been associated with
increased IDO activity and IL-10 production.23 Over-
all it appears that the ability of certain microbes to
promote IDO activity, in addition to IL-10 expres-
sion by DCs, may be important in the generation of a
regulatory immune response and the establishment
of tolerance.
Probiotics and Lung Infection
The increase in antibiotic resistance and need for
new and improved strategies to tackle infectious
disease have led to an examination of the therapeutic
potential of commensal induced modulation of the
mucosal immune response. Consequently, it has been
discovered that certain LAB do have protective effects
904
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against bacterial and viral infections in the GI and
respiratory systems.24 Administration of probiotics
has been associated with lower incidence of ventilator-
associated pneumonia,25 reduced respiratory infections
in healthy and hospitalized children,26,27 and reduced
duration of common cold infection.28 It should be
noted that in addition to causing morbidity and mor-
tality directly there is good evidence that respiratory
infections, particularly viral infections, are a contrib-
uting factor not only to the exacerbation of asthma,
but also to development of the disease.29 Indeed, it
has been suggested that the focus of potential benefi-
cial effects of probiotics in asthma should be directed
at identifying organisms capable of reducing viral infec-
tions in early life.30
In mouse studies, intranasal administration of
LAB protects against respiratory pathogens.31-33 How-
ever, direct exposure of the probiotic organism to the
airway mucosa is not required, and LAB can protect
host animals from airway infection through an inter-
action with GALT, such as Peyer patch cells, and indi-
rect enhancement of respiratory immunity (Fig 1).34
The protective effects of both intranasal and oral pro-
biotics are generally associated with upregulation of
natural killer (NK) cell and/or macrophage activity in
the airway mucosa.32,33
NK cells are the main components of host-nonspecific
cell-mediated immunity, recognizing and helping to
control a wide range of pathogens, including viruses,
bacteria, and intercellular parasites. NK cells are acti-
vated by IL-12 that is produced by antigen-presenting
cells, such as macrophages, DCs, and Langerhans cells.
Here again, data suggest that the dialog between
DCs and bacteria is key to controlling the immune
effects of LAB beyond the GI tract. Koizumi et al35
demonstrated that feeding mice with Lactobacillus
pentosus significantly enhances NK activity of spleen
cells and induced NK1.1-positive NK and NK T cells
to produce interferon (IFN)-g. The increase in IFN-g
production did not occur through direct action of
L pentosus on NK cells but was dependent on IL-12
produced by CD11c1 DCs following a toll-like
receptor (TLR) 2- and/or TLR4-dependent interac-
tion between the DC and LAB. Strains of LAB differ
greatly in their ability to induce high levels of IL-12
in human DCs and consequently DC-dependent
IFN-g production by NK cells.36
Alveolar macrophages provide the first line of
defense against organisms that reach the lower air-
ways. In addition to their phagocytic function, alve-
olar macrophages can synthesize and release various
protein and lipid mediators on contact with patho-
gens or pathogenic substances. LAB have been well
characterized in terms of an ability to induce cyto-
kine production following contact with mononuclear
phagocytes.37,38 The ability of orally administered L casei
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to dose-dependently enhance the phagocytic activity
of alveolar macrophages39,40 likely contributes to the
accelerated recovery of the innate immune response
and improved outcomes following Streptococcus
pneumoniae respiratory infection in malnourished
mice41 and in young mice infected with Pseudomonas
aeruginosa.40 Here again, the suggestion is that stim-
ulation of the GALT leads to a general enhancement
or priming of the innate immune response in the
airway. However, recently Lactobacillus salivarius
and L fermentum strains were shown to enhance
both natural and acquired immune responses, as
evidenced by activation of NK cells and the expan-
sion of Tregs,42 whereas Bifidobacterium infantis can
induce Foxp31 T cells that protect mice against
Salmonella typhimurium infection.43 Therefore, it is
likely both branches of the immune system contrib-
ute to LAB-induced protection against respiratory
pathogens. In addition, a number of LAB can produce
antibacterial compounds,44 including Lactobacillus
plantarum, which can inhibit the induction of virulence
factors and thus the pathogenicity of P aerogenosa,45
suggesting that intrinsic antibacterial effects of LAB
could contribute to protection against respiratory path-
ogens if administered directly to the site of infection.
Challenges to Probiotic-Based Therapies
It is likely that the antiinflammatory efficacy of
a probiotic results from a combination of signaling
pathways activated as a result of a specific pattern of
microbe-derived ligands interacting with the corre-
sponding receptors on host cells (Fig 2). Little is known,
however, concerning the nature of the probiotic-host
cell interactions, or how these interactions could be
manipulated to obtain stronger regulatory responses.
Factors to be considered include localization of par-
ticular bacteria in the GI tract and strain-specific cell
wall components and metabolic products.
Although animal studies have provided clear evi-
dence that certain LAB can have profound immu-
noregulatory effects and regulate immune responses
beyond the GI tract, the fact remains that the results of
clinical trials have been highly variable. With particular
regard to asthma there have been no beneficial effects
reported. It is clear that candidate probiotic strains

Figure 2. The probiotic-DC dialogue. Probiotic bacteria can interact with DCs via various surface molecules, which act to signal through
microbe-associated molecular pattern (MAMP) receptors such as TLRs that can be extracellular or associated with endosomes such as
TLR-9, and lectins, including the C-type lectin DC-SIGN. Important MAMPs include LTAs, PGNs, LPSs, and a range of CPSs including
PSA. In addition to cell surface components, secreted products of bacteria may also influence DCs, including AHLs, part of the quorum
sensing system of gram-negative bacteria. It is likely that specific combinations of signals instigated by these interactions determine the
response of DCs and thus the immunoregulatory capacity of individual bacterial strains. 1ve 5 gram-positive bacteria; −ve 5 gram-negative
bacteria; AHL 5 acyl-homoserine lactone; CPS 5 cell wall-associated polysaccharide; DC-SIGN 5 DC-specific intercellular adhesion mol-
ecule 3-grabbing non-integrin; LPS 5 lipopolysaccharide; LTA 5 lipoteichoic acid; PGN 5 peptidoglycan; PSA 5 polysaccharide A;
TLR 5 toll-like receptor. See Figure 1 legend for expansion of the other abbreviation.

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display a range of immune effects and therapeutic
efficacies in specific disease states or model systems.
However, strain differences are unlikely to explain
all of the observed variability, as in clinical tests
the same strains have produced conflicting results.8
Kuitunen et al46 reported that probiotic supple-
mentation of pregnant mothers and their offspring
conferred protection from allergic disease only to
cesarean-delivered children, suggesting that probi-
otic treatment may be beneficial only in subpopula-
tions of patients (ie, those with abnormal or dis-
rupted gut microbiota). It is also clear that the
immunoregulatory actions of certain LAB can be inhib-
ited in the presence of other strains. L reuteri, a poor
inducer of IL-12 from murine DCs, inhibits IL-12, IL-6,
and TNF-a induction by the otherwise strong cyto-
kine inducer L casei,47 whereas both Bifidobacterium
bifidum and L reuteri can inhibit Lactobacillus
acidophilus-induced IL-12 production by DCs and
accordingly abrogate IFN-g production by NK cells.36
This suggests that the benefits of mixed strain pro-
biotic preparations may actually be less than the
sum of their parts. How the existing commensal LAB
and other bacteria composing the host microbiota
might influence immunomodulatory action of a single
orally administered strain is also unknown. Other
factors that have not been fully explored and may
influence therapeutic efficacy include the fact that
the immune response to candidate probiotics may
depend on the growth phase of the bacteria.48 Fur-
thermore, there has also been little examination of
the immunomodulatory effects of long-term exposure
to probiotics, and one study in mice suggests that
some of the extraintestinal immune effects may be
lost with sustained treatment.49
Conclusions
For the reasons outlined previously, the therapeutic
efficacy of live probiotic strains may be limited. How-
ever, alternative approaches may be developed. To
date a number of microbial cell wall components,
including polysaccharides50 and lipoteichoic acids,51
as well as potential secreted products,52 have been
identified as being critical to the immunoregulatory
effects of certain bacteria and/or to mimic the effect
of whole organisms, including the ability to attenuate
the allergic airway response in mice22,53 (Fig 2). Such
research may lead to the development of therapies
that effectively deliver critical triggers to the innate
immune system in such a way as to mimic the immu-
noregulatory effects of whole probiotic organisms
while bypassing some of the strain- and host-specific
factors that might hinder the efficacy of live bacteria.
Regardless of the approach taken, it is clear that
without the identification of the critical characteristics
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of effective probiotic strains or a clear understanding
of their mechanism of action, testing of probiotic-
based treatment will remain highly empirical, and as
such the outcome of clinical trials will continue to be
variable and may serve to obfuscate the true potential
of microbial-based therapies for respiratory disorders.
Acknowledgments
Financial/nonfinancial disclosures: The author has reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be dis-
cussed in this article.
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