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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
dose, confer a benefit of health on the receiver, non-
viable microbes have also been regarded as probiotics
probiotics. These “beneficial microbes” are most fre- because in certain circumstances they exhibit bene-
quently Lactobacillus or Bifidobacterium species; how- ficial effects equal to live bacteria. Prebiotic is the
ever, a range of lactic acid bacteria (LAB) and non- term given to food supplements that are generally
pathogenic Escherichia coli have also been identified nondigestible and stimulate the growth and/or activ-
as having health benefits. Furthermore, although the ity of probiotic bacteria, and a preparation containing
Food and Agriculture Organization/World Health both prebiotics and probiotics is referred to as a
Organization currently define probiotics as live micro- synbiotic.
organisms that when administered in appropriate Significant attention has been focused on the role
of probiotics in GI development, immune adaptation,
Manuscript received July 21, 2010; revision accepted September 13, and attenuation of GI inflammatory diseases. How-
Affiliations: From the Brain-Body Institute and Department of ever, there is steadily increasing evidence that orally
Medicine, McMaster University, Hamilton, ON, Canada. delivered probiotics are able to regulate immune
Correspondence to: Paul Forsythe, PhD, The Brain-Body Insti- responses outside the GI tract, including the respira-
tute, St. Joseph’s Healthcare, 50 Charlton Ave E, T3303, Hamilton,
ON, L8N 4A6, Canada; e-mail: tory mucosa. What follows is an outline of our current
© 2011 American College of Chest Physicians. Reproduction knowledge of the potential benefits and underlying
of this article is prohibited without written permission from the mechanisms of action of probiotic bacteria in relation
American College of Chest Physicians (
site/misc/reprints.xhtml). to the respiratory tract with a focus on modulation of
DOI: 10.1378/chest.10-1861 allergic responses and protection against infections. CHEST / 139 / 4 / APRIL, 2011 901

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

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suppression,”18 and in vivo transfer studies demon- treated control subjects, only following airway chal-
strate that Tregs can create a regulatory milieu that lenge in sensitized mice.
promotes the outgrowth of new populations of Tregs However, despite growing evidence supporting
with antigen specificities distinct from those of the an association between the antiinflammatory effects
original population.18 In this way, certain LAB may of LAB and an ability to induce Treg, a causal rela-
induce Tregs in the gut-associated lymphoid tissue tionship has yet to be clearly established. Tregs are
(GALT) that can spread to the airways in response to believed to be involved principally in the resolution
immune challenge and inflammation (Fig 1). This of established inflammation,14 and whereas adoptive
is supported by the finding that oral treatment with transfer of Tregs from LAB-fed and helminth-infected
L reuteri results in an increase in Tregs in the drain- mice can suppress airway inflammation,15,16 more
ing lymph nodes of the lung, relative to vehicle- 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. CHEST / 139 / 4 / APRIL, 2011 903

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LAB-induced Tregs contribute to protection against against bacterial and viral infections in the GI and
an allergic airway response. respiratory systems.24 Administration of probiotics
has been associated with lower incidence of ventilator-
Dendritic Cells: Key Translators associated pneumonia,25 reduced respiratory infections
of Microbial Signals in healthy and hospitalized children,26,27 and reduced
duration of common cold infection.28 It should be
It is an attractive concept that by controlling the noted that in addition to causing morbidity and mor-
maturation and function of dendritic cells (DCs), tality directly there is good evidence that respiratory
mucosal immune responses can be modulated. Given infections, particularly viral infections, are a contrib-
that DCs are pivotal in early bacterial recognition uting factor not only to the exacerbation of asthma,
and can induce a range of Treg subtypes, there has, but also to development of the disease.29 Indeed, it
understandably, been great interest in interactions has been suggested that the focus of potential benefi-
between commensal organisms and DCs. cial effects of probiotics in asthma should be directed
Consequently it is becoming apparent that although at identifying organisms capable of reducing viral infec-
Tregs may be major effectors of immune regulation tions in early life.30
mediated by probiotics, the functional changes in DCs In mouse studies, intranasal administration of
following interaction with the bacteria is critical in LAB protects against respiratory pathogens.31-33 How-
orchestrating these responses. Specifically, the ability ever, direct exposure of the probiotic organism to the
to induce IL-10 production by DCs, suggesting a airway mucosa is not required, and LAB can protect
regulatory phenotype, seems to be key to the immu- host animals from airway infection through an inter-
noregulatory action of many probiotics.19 Recently, action with GALT, such as Peyer patch cells, and indi-
Kwon et al20 confirmed that regulatory DCs express- rect enhancement of respiratory immunity (Fig 1).34
ing high levels of IL-10, transforming growth factor-b, The protective effects of both intranasal and oral pro-
COX-2, and indoleamine 2,3-dioxygenase (IDO) drive biotics are generally associated with upregulation of
the generation of CD41Foxp31 Tregs following natural killer (NK) cell and/or macrophage activity in
administration of a mixed-strain probiotic prepara- the airway mucosa.32,33
tion in mice. The enzyme IDO is the rate-limiting NK cells are the main components of host-nonspecific
step in the conversion of tryptophan to immunoac- cell-mediated immunity, recognizing and helping to
tive kynurenines. DC expressing IDO contribute to control a wide range of pathogens, including viruses,
the generation and maintenance of peripheral toler- bacteria, and intercellular parasites. NK cells are acti-
ance by depleting autoreactive T cells and by inducing vated by IL-12 that is produced by antigen-presenting
Treg responses.21 Hayashi et al22 observed that the cells, such as macrophages, DCs, and Langerhans cells.
ability of bacterial DNA-derived CpG motifs to atten- Here again, data suggest that the dialog between
uate the allergic airway response was dependent on DCs and bacteria is key to controlling the immune
increased IDO activity in the lung, whereas the anti- effects of LAB beyond the GI tract. Koizumi et al35
inflammatory effects of L reuteri in the airway of demonstrated that feeding mice with Lactobacillus
OVA-sensitized and -challenged mice is associated pentosus significantly enhances NK activity of spleen
with increased systemic, but not localized lung, IDO cells and induced NK1.1-positive NK and NK T cells
activity.11 Significantly, the maintenance of a clini- to produce interferon (IFN)-g. The increase in IFN-g
cally unresponsive state following aeroallergen expo- production did not occur through direct action of
sure in atopic individuals has been associated with L pentosus on NK cells but was dependent on IL-12
increased IDO activity and IL-10 production.23 Over- produced by CD11c1 DCs following a toll-like
all it appears that the ability of certain microbes to receptor (TLR) 2- and/or TLR4-dependent interac-
promote IDO activity, in addition to IL-10 expres- tion between the DC and LAB. Strains of LAB differ
sion by DCs, may be important in the generation of a greatly in their ability to induce high levels of IL-12
regulatory immune response and the establishment in human DCs and consequently DC-dependent
of tolerance. IFN-g production by NK cells.36
Alveolar macrophages provide the first line of
Probiotics and Lung Infection defense against organisms that reach the lower air-
ways. In addition to their phagocytic function, alve-
The increase in antibiotic resistance and need for olar macrophages can synthesize and release various
new and improved strategies to tackle infectious protein and lipid mediators on contact with patho-
disease have led to an examination of the therapeutic gens or pathogenic substances. LAB have been well
potential of commensal induced modulation of the characterized in terms of an ability to induce cyto-
mucosal immune response. Consequently, it has been kine production following contact with mononuclear
discovered that certain LAB do have protective effects phagocytes.37,38 The ability of orally administered L casei

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to dose-dependently enhance the phagocytic activity could contribute to protection against respiratory path-
of alveolar macrophages39,40 likely contributes to the ogens if administered directly to the site of infection.
accelerated recovery of the innate immune response
and improved outcomes following Streptococcus Challenges to Probiotic-Based Therapies
pneumoniae respiratory infection in malnourished
mice41 and in young mice infected with Pseudomonas It is likely that the antiinflammatory efficacy of
aeruginosa.40 Here again, the suggestion is that stim- a probiotic results from a combination of signaling
ulation of the GALT leads to a general enhancement pathways activated as a result of a specific pattern of
or priming of the innate immune response in the microbe-derived ligands interacting with the corre-
airway. However, recently Lactobacillus salivarius sponding receptors on host cells (Fig 2). Little is known,
and L fermentum strains were shown to enhance however, concerning the nature of the probiotic-host
both natural and acquired immune responses, as cell interactions, or how these interactions could be
evidenced by activation of NK cells and the expan- manipulated to obtain stronger regulatory responses.
sion of Tregs,42 whereas Bifidobacterium infantis can Factors to be considered include localization of par-
induce Foxp31 T cells that protect mice against ticular bacteria in the GI tract and strain-specific cell
Salmonella typhimurium infection.43 Therefore, it is wall components and metabolic products.
likely both branches of the immune system contrib- Although animal studies have provided clear evi-
ute to LAB-induced protection against respiratory dence that certain LAB can have profound immu-
pathogens. In addition, a number of LAB can produce noregulatory effects and regulate immune responses
antibacterial compounds,44 including Lactobacillus beyond the GI tract, the fact remains that the results of
plantarum, which can inhibit the induction of virulence clinical trials have been highly variable. With particular
factors and thus the pathogenicity of P aerogenosa,45 regard to asthma there have been no beneficial effects
suggesting that intrinsic antibacterial effects of LAB 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. CHEST / 139 / 4 / APRIL, 2011 905

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display a range of immune effects and therapeutic of effective probiotic strains or a clear understanding
efficacies in specific disease states or model systems. of their mechanism of action, testing of probiotic-
However, strain differences are unlikely to explain based treatment will remain highly empirical, and as
all of the observed variability, as in clinical tests such the outcome of clinical trials will continue to be
the same strains have produced conflicting results.8 variable and may serve to obfuscate the true potential
Kuitunen et al46 reported that probiotic supple- of microbial-based therapies for respiratory disorders.
mentation of pregnant mothers and their offspring
conferred protection from allergic disease only to Acknowledgments
cesarean-delivered children, suggesting that probi-
Financial/nonfinancial disclosures: The author has reported
otic treatment may be beneficial only in subpopula- to CHEST that no potential conflicts of interest exist with any
tions of patients (ie, those with abnormal or dis- companies/organizations whose products or services may be dis-
rupted gut microbiota). It is also clear that the cussed in this article.
immunoregulatory actions of certain LAB can be inhib-
ited in the presence of other strains. L reuteri, a poor References
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