Mediators of Inflammation

Volume 2013 (2013), Article ID 751068, 10 pages

http://dx.doi.org/10.1155/2013/751068

Review Article

Probiotics in the Management of Lung Diseases

Esmaeil Mortaz,1,2 Ian M. Adcock,³ Gert Folkerts,¹ Peter J. Barnes,³ Arjan Paul Vos,1,4 and Johan Garssen1,4

¹Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

²Chronic Respiratory Diseases Research Center and National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Department of Immunology, Shahid Beheshti University of Medical Sciences, Tehran, Iran

³Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK

⁴Danone Research Centre for Specialised Nutrition, Wageningen, The Netherlands

Received 1 December 2012; Revised 14 March 2013; Accepted 28 March 2013

Academic Editor: Alex Kleinjan

Copyright © 2013 Esmaeil Mortaz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The physiology and pathology of the respiratory and gastrointestinal tracts are closely related. This similarity between the two organs may underlie why dysfunction in one organ may induce illness in the other. For example, smoking is a major risk factor for COPD and IBD and increases the risk of developing Crohn’s disease. Probiotics have been defined as “live microorganisms which, when administered in adequate amounts, confer health benefits on the host.” In model systems probiotics regulate innate and inflammatory immune responses. Commonly used probiotics include lactic acid bacteria, particularly Lactobacillus, Bifidobacterium, and Saccharomyces, and these are often used as dietary supplements to provide a health benefit in gastrointestinal diseases including infections, inflammatory bowel disease, and colon cancer. In this respect, probiotics probably act as immunomodulatory agents and activators of host defence pathways which suggest that they could influence disease severity and incidence at sites distal to the gut. There is increasing evidence that orally delivered probiotics are able to regulate immune responses in the respiratory system. This review provides an overview of the possible role of probiotics and their mechanisms of action in the prevention and treatment of respiratory diseases.

1. Introduction

There is growing evidence as to how diet and nutrition influence the microbiome and interact with the immune system to ultimately improve human health, for example, fecal bacteriotherapy, whereby the microflora of a healthy patient is transplanted to a patient with ulcerative colitis (UC) [1]. This suggests that the composition of the microbiome has an important role in intestinal inflammation and that restoration of a “healthy microbiome” can promote remission of disease. Probiotic bacteria are already used to treat or prevent a wide range of human diseases, conditions, and syndromes including antibiotic-associated diarrhea [2, 3] and inflammatory bowel disease occurring as a consequence of surgical treatment [4]. In addition, they have been proposed to be of potential benefit in increasing numbers of therapeutic areas, particularly in the prevention or treatment of many different chronic inflammatory diseases [5]. Probiotics are characterized as “live organisms, which when applied in adequate amounts confer a health benefit to the host” [6, 7]. Recently, for example, probiotics have been shown to have beneficial effects in models of neuronal inflammation and pain. In particular, probiotics have been reported to decrease the perception of visceral pain induced by distension or inflammation [8, 9].

Emerging studies also indicate that dietary supplementation with probiotics could exert a wide range of beneficial effects on humans with respect to reduced infections and seasonal illness and in the attenuation of the perception of symptoms and disease duration [10–12]. Despite this, many aspects of the probiotic-host immune system crosstalk are still unknown.

Probiotics can exert pleiotropic effects, including a protective role in the intestinal tract where they exert direct antimicrobial effects by competing with local pathogens and indirectly by enhancing intestinal barrier functions [13]. In addition, probiotics have the ability to modulate the host’s local and systemic mucosal immune systems [14]. For example, probiotics can change the mucosal immune system towards a noninflammatory, tolerogenic pattern by increasing IL-10 levels [15]. Moreover, the induction of CD4⁺Foxp3⁺ regulatory cells by probiotics inhibits the production of proinflammatory cytokines and may skew T cells towards a T-helper (Th) 1 phenotype [16–19]. The precise cytokine profile depends upon the nature and strength of the stimulus and the strain of probiotic bacteria that was administered [20, 21]. Moreover, the method of growing and preparing probiotic bacteria for consumption can influence their biological activity. Finally, while probiotics are applied predominantly as living bacteria, bacterial lysates have also been described as having immunomodulatory and anti-inflammatory effects as well (see Table 1).

Table 1: Dietary supplementation with lactobacilli that have shown enhanced immune response and protection against respiratory tract pathogen challenge.

LAB treatments
Immune response
Authors

The immune stimulation induced by L. rhamnosus CRL1505 (Lr05) and L. rhamnosus CRL1506 (Lr06) on the resistance to infection with an intestinal pathogen (Salmonella typhimurium) and a respiratory pathogen (Streptococcus pneumoniae)
Both strains were able to improve resistance against the intestinal pathogen. Only Lr05 was able to induce a significant decrease in the number of S. pneumoniae in the lung, prevent its dissemination into the blood, and induce a significant increase in Th1 (INF-γ) and Th2 (IL-6, IL-4 and IL-10) cytokine levels in the bronchoalveolar lavages (BAL)
Salva et al. [55]

2 days before feeding of L. casei prior to pathogen challenge
Increased rate ofclearance of P. aeruginosa from the lungs increased phagocytic activity of alveolar macrophages, and increased levels of IgA in BAL fluid
Alvarez et al. [56]

Prefeeding of L. casei (Shirota strain) for 4 months prior to challenge
Reduced viral titre in nasal washings; increased NK activity of splenocytes and nasal tract mononuclear cells; increased IFNQ and TNFK production by mitogen-stimulated nasal lymphocytes
Hori et al. [57]

OVA-sensitized mice were orally administered with Bifidobacterium breve M-16V, B. infantis NumRes251, B. animalis NumRes252 and NumRes253, Lactobacillus plantarum waNumRes8, and L. rhamnosus NumRes6. After challenge by OVA inhalation in the lungs, the response to methacholine was measured

Pulmonary inflammation assessed by analyzing BALF for the presence of inflammatory cells and mediators
Of the panel of 6 strains, B. breve M-16V and L. plantarum NumRes8 inhibited (1) the response to methacholine, (2) reduced the number of eosinophils in the bronchoalveolar lavage fluid, and (3) reduced both OVA-specific IgE and (4) OVA-specific IgG1, whereas the other strains did not affect all these parameters simultaneously. B. breve M-16V but not L. plantarum NumRes8 reduced interleukin 4, interleukin 5, and interleukin 10 Furthermore, B. breve M-16V but not L. plantarum NumRes8 reduced acute allergic skin reactions to OVA
Hougee et al. [58]

In this regard, it is important to gain a better understanding of the immunomodulatory mechanisms underlying probiotic functions in order to improve the targeting of probiotic interventions by selecting the optimal strain(s). The fact that probiotic treatment can modulate immune responses in the lung [22] and, in particular, the encouraging indications that microbial stimulation of the gut can enhance the T regulatory response in the airway [23], emphasizes the therapeutic potential as well as the need for greater understanding of the mechanisms underlying effects of specific probiotic strains. In this regard, identification of the key immunoregulatory components of bacteria and/or their metabolism and confirming that results obtained in animal models translate into human models will be critical to the selection of strains and treatment strategies that are most likely to meet with success in preventing or treating human airways diseases such as asthma and COPD.

Most probiotics contain lactic acid-producing bacteria (LABs, e.g., Lactobacillus, Streptococcus, Bifidobacterium, and Enterococcus sp.) or nonpathogenic yeasts such as Saccharomyces boulardii [24, 25]. These products are advocated for the prevention and treatment of various medical conditions, including gastroenteritis, Clostridium-associated diarrhea, inflammatory bowel disease, food allergies, and dental cavities. These applications of LAB have been based on various hypothesized health-promoting attributes including antimutagenic activity [26], anticarcinogenic and -tumor effects [27–30], hypocholesterolemic properties [28], inhibition of intestinal and food-borne pathogens [29], and the promotion of T- and B-cell proliferation [31]. Thus, understanding the immunological mechanism of probiotic action is important in rationalising the impact of these agents in a variety of diseases. Many in vitro and in vivo studies have been conducted examining the effects of probiotics in disease models. Most in vitro studies have examined the effects of probiotics on the production of cytokines from human PBMCs in order to define the basis for their clinical benefit [32, 33]. However, translation of these results into in vivo effects in man in randomized controlled clinical trials will require better models of disease and understanding of probiotic function in order to enable the selection of optimal strains and prediction of clinical efficacy.

The microflora hypothesis proposes that antibiotic use and dietary differences in industrialized countries have resulted in perturbations of the gastrointestinal microbiota thereby disrupting the normal microbiota-mediated mechanisms of immunologic tolerance in the mucosa leading to an increase in the incidence of allergic diseases including asthma [34]. This hypothesis provides a rationale for the application of probiotics to aim for normalization of immunological balance and treatment of disease. Lactobacilli and Bifidobacteria strains are often employed as (potential) probiotics, many of which are useful microorganisms in dairy technology with a long-documented history of use in foods.

2. Immunomodulatory Effects of Probiotics

The mechanisms by which probiotic bacteria elicit their effects are not fully understood. The immune response to probiotics is generally thought to be strain dependent, with differences proposed to be due to the diverse protein and glycan/carbohydrate profiles present in their cell walls, the differing CpG content of their DNA, and possibly the metabolites and other molecules they excrete [35]. The beneficial effects of probiotics are thought to be based partly on their ability to differentially regulate the production of anti and proinflammatory cytokines and the balance between types of T cell responses such as Th1/Th2, Treg, and Th17 responses [36–38] (see Figure 1).

Figure 1: The putative immunomodulatory functions of probiotics on lung disease asthma and COPD. The immune and inflammatory drivers of allergic asthma (left side of figure) and of COPD (right side of figure) may be modified by strain-specific probiotics. The precise mechanisms by which gut-located probiotics can cause immunomodulation in the airway are unclear but may reflect changes in blood and local immune cells including T-cell subsets.

Probiotic treatment of infectious diarrhea in both adults and children appears efficacious, although evidence of their effectiveness in other diseases often remains to be confirmed in placebo-controlled randomized clinical trials [39–41]. In diarrhea both antipathogenic mechanisms on the microbiota level as well as immunomodulation of the host mechanisms may underlie the clinical benefit of probiotic therapy. At present it is unclear what the relative contribution of these different mechanisms is. Oral administration of Lactobacilli may modulate cytokine profiles not only at the intestinal level but also systemically [34]. To date, several LAB strains have been shown to enhance cell-mediated immune responses, including T-lymphocyte proliferation, mononuclear cell phagocytic capacity, and NK cell tumoricidal activity [42] (see Figure 1).

Additional medical applications have been proposed, although their true efficacy will depend upon the outcomes of future experimental and clinical studies. Indeed, despite the widespread advocacy of the clinical benefit of probiotics, evidence-based support for their use is limited and in need of continuing evaluation.

Current ideas center on the hypothesis that administration of probiotic bacteria to the airway mucosa is not required to treat airways disease. Thus, LAB can protect host animals from airway infection through an interaction with GALT such as those in Peyer’s Patches in the gut eliciting an indirect enhancement of respiratory immunity [43]. However, it has also been proposed that the protective effects of probiotics (both intranasal and oral) are associated with activation of proinflammatory NK cell and/or macrophages within the airway mucosa [43, 44]. In support of this, Koizumi et al. [45] showed that treating mice with Lactobacillus pentosus augmented the activity of NK cells within the spleen and stimulated NK1.1-positive NK and NK T cells to produce IFN-γ. The increase in IFN-γ production did not occur through direct action of Lactobacillus pentosus on NK cells but was dependent on IL-12 produced by CD11c⁺ DCs following a TLR2 and/or TLR4-dependent interaction between the DC and LAB [32, 46]. Strains of LAB differ greatly in their ability to induce high levels of IL-12 in human DCs and consequently DC-dependent IFN-γ production by NK cells [47].

The effect of probiotics on other inflammatory cells has also been described. For example, the involvement of Th17 and Treg cells in lung disease has become clear. Th17 cells are a subset of CD4⁺ T cells that produce the proinflammatory cytokine IL-17 [48]. Th17 cells have recently been shown to play a critical role in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease [48]. cells are considered to be the master regulators of the immune response in both humans and rodents. Defects in the transcription factor FoxP3, which defines the Treg lineage, result in multiple autoimmune diseases and atopy [49, 50] demonstrating the central role of FoxP3+ CD4 cells in immune homeostasis.

Karimi et al. have demonstrated that 9 days oral administration of Lactobacillus reuteri resulted in a significant increase in the percentage and total number of spleen CD4⁺ CD25⁺ FoxP3⁺ T cells [51]. In addition, increases in FoxP3 mRNA expression in peribronchial lymph nodes has been noted upon administration of Bifidobacterium lactis Bb12, LGG, and Lactobacillus casei DN114001 suggesting the induction of Treg cells by these strains [52]. In addition to enhancing Treg-cell numbers, LGG has shown effects in a number of Th2-, Th1-, and Th17-mediated disorders [53, 54].

3. Probiotics as a Therapeutic Approach in Prevention of Lung Diseases

3.1. Asthma and Allergic Reactions

The rise in allergic disease is becoming a major global health issue fast. Whilst this was first evident in the more developed countries of Australasia, Western Europe and North America where more than 40% of the population may be affected at some stage [59, 60], it is now becoming apparent in virtually all regions of the world undergoing industrial development and westernization [61]. International trends, therefore, provide some indication that environmental changes can affect immune function regardless of genetic background. However, recent evidence that non-Caucasian races may be even more susceptible to allergic disease [62, 63] has alarming implications for the most populous areas of the world undergoing rapid urbanization.

Although the exact mechanism(s) behind the antiallergic action of probiotics remain obscure, studies have highlighted several potential components of this response. The development of mucosal and systemic tolerance relies on immunosuppressive mechanisms orchestrated by Treg cells that attenuate both Th1 and Th2 responses, and there is accumulating evidence linking the immunomodulatory function of microbial components and/or commensal bacteria to the induction of Treg cells and their associated cytokines.

Extensive studies examining probiotic modulation of allergic reactions have been reported for atopic eczema with LGG as the probiotic [63–67]. However, clinical trials of probiotics in the treatment of eczema and other allergic diseases have yielded inconsistent results [68–72]. For example, two studies using LGG, with similar study designs, resulted in either a decrease in eczema [73, 74] or no clinical benefit [75].

Despite the inconsistent effects seen in some studies, several allergic diseases may be prevented with treatment of the intestinal flora with probiotics [76, 77] and probiotics have been proposed as being able to both prevent and treat several allergic diseases [78]. In a murine model of asthma, administration of Lactobacillus reuteri, LGG, and Bifidobacterium breve decreased airway hyperresponsiveness, the number of inflammatory cells in bronchoalveolar lavage (BAL) fluid, and inflammation of lung tissue [58, 79].

In addition to the prevention of experimental asthma, probiotics can prevent atopic dermatitis in infants and alleviate food allergy [80–82]. Recently, Donkor et al. reported that some probiotics induced significant amounts of proinflammatory cytokines, including IL-2, which is a critical cytokine for the clonal expansion of recently antigen-activated T cells and also in Treg homeostasis [32] (see Figure 1).

Specific bacterial strains have been shown to induce IL-10 producing Treg cells in vitro [82]. In vivo, effects on both regulatory and effector T cells by Lactobacillus casei DN114001 have been associated with decreased allergic skin inflammation. In addition, in vivo treatment with a preparation of heat-killed Mycobacterium vaccae can induce allergen-specific Treg ( IL-10⁺) cells that confer protection against allergic airway inflammation [83]. Furthermore, Feleszko and colleagues demonstrated that early-life treatment with LGG leads to an attenuated allergic airway response in adult animals that is associated with an increased T cell expression of Foxp3 [84], whereas Bifidobacterium infantis induces Foxp3⁺ T cells that protect mice against Salmonella typhimurium infection [85].

Interestingly, oral administration of Enterococcus faecalis FK-23 has recently been shown to suppress the asthmatic response and that this is associated with attenuation of Th17 cell development [86].

Overall, it is unlikely that LABs directly enter into the circulation and then into the lungs. By contrast, they are likely to have an immunomodulatory action affecting the function of immune cells that migrate into the lung. The precise mechanisms underlying the favorable effects of probiotics on the respiratory system are unclear, and several mechanisms have been proposed as a result of in vitro and in vivo animal experiments. In addition to modulation of the intestinal microbiota, probiotics improve the barrier function of the intestinal mucosa, reducing leakage of antigens through the mucosa and thereby the amount of allergen that the lung may be exposed to via the circulatory route. In addition, direct modulation of the immune system may occur through the induction of anti-inflammatory cytokines or through the increased production of secretory IgA or via activation of Treg cells and skewing of Th1, Th2, and Th17 cell activation or alterations in macrophage function resulting in reduced allergic responses. For example, Salva et al. showed that changes in the BAL cytokine profile occurred after LAB application and that these were associated with an increase in the number and activity of phagocytic cells and with increased levels of allergen-specific antibodies in serum and BAL [55].

3.2. Viral Infections and Asthma

Respiratory infections, particularly viral infections, directly affect morbidity and mortality and are indirectly a contributing factor not only to asthma exacerbations but also to the development of the disease [87]. It has been speculated that identifying probiotic organisms capable of reducing viral infections in early life, or in utero, may prevent the development of asthma [88]. As indicated above, emerging evidence supports the role of probiotics, for example, LGG and Lactobacillus casei strains Shirota (LcS) and DN114001, in the prevention and/or treatment of bacterial and viral infections in the gastrointestinal and respiratory systems including influenza [57, 89–93].

Respiratory pathogens are recognized by pattern recognition receptors (PRRs). For example, Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD-) like receptors, transcription factors, cytokines, and chemokines play essential roles in sensing perturbations in the health of the lungs. The expression of many PRRs is high in lung inflammatory cells such as neutrophils, monocytes, macrophages, and epithelial cells, and they are able to respond rapidly to increased levels of PAMPs and DAMPs which are associated with exacerbation of lung diseases. It is possible, therefore, that modulation of these responses induced by LAB may have an impact on immune cell activation in the lung.

In addition to oral delivery of probiotics, probiotic efficacy has been demonstrated following nasal challenge. Thus, Harata et al. reported that intranasal administration of LGG could protect mice from H1N1 influenza virus infection by regulating respiratory immune responses [94]. In addition, probiotic use has been associated with lower incidence of ventilator-associated pneumonia [95], reduced respiratory infections in healthy and hospitalized children [96, 97], and reduced duration of infection with the common cold [98].

3.3. Chronic Obstructive Pulmonary Disease (COPD)

COPD is currently the 4th biggest killer worldwide and is expected to be the third leading cause of death over the next 10 years [99]. Smoking is the most important lifestyle risk factor for pathogenesis of COPD [100] and lung cancer [101]. COPD and IBD share many epidemiological and clinical characteristics, as well as inflammatory pathologies [102–107]. The crosstalk between the pulmonary and intestinal mucosal in chronic inflammatory diseases such as COPD and IBD has recently been extensively reviewed [108].

The level of inflammation in the COPD airways is a strong correlate of disease severity in patients and is critically involved in disease development experimentally [109–111]. Attention has traditionally centered on the roles of macrophages and neutrophils in disease development [112]. However, lymphocytes have received increasing attention, and reports from many laboratories have provided insight into functions of T cells and NK cells in the pathogenesis of COPD [113–115].

COPD has been characterized by exacerbations of symptoms including increased dyspnea, enhanced sputum, enhanced inflammation, and decline in lung function [116, 117]. COPD exacerbations are psychologically destructive, since patients with exacerbations have a lower quality of life and decreased mobility, leading to increased depression [118]. 40%–60% of exacerbations in COPD are caused by viral infections [119, 120], and importantly, in animal models viral infection following cigarette smoke exposure leads to enhanced pulmonary inflammation, increased alveolar apoptosis, accelerated emphysema, and airway fibrosis [120]. However, the underlying cellular mechanisms responsible for these effects remain unresolved.

It is generally accepted that the early immune response following viral infection relies on the recognition of viral PAMPs through the Toll-like receptors (TLRs) mainly TLR3, TLR7, and TLR9 [121, 122]. Stimulation of these receptors found on DCs and other inflammatory cells leads to the activation of NK cells through production of type I IFNs, IL-12, IL-18, and IL-15 [123–126]. NK cell activation is critically important to the early control of viral infections and occurs several hours to a few days following infection [127]. NK cells were originally thought of solely as killer cells due to their ability to directly destroy virus-infected cells [128]. More recently, however, attention has been given to the noncytotoxic functions of NK cells [129]. Activated NK cells produce large amounts of IFN-γ [130] and NK-cell-derived IFN-γ is critical to the inflammatory processes that control viral infections [131–133] (see Figure 1). Thus, NK cells along with their release of mediators are considered as important cells regulating the inflammatory response that occurs during COPD exacerbations.

Cigarette smoking impairs human NK-cell cytotoxic activity and cytokine release [134]. NK-cell activity is lower in smokers compared to nonsmokers [11] but daily intake of LcS increases natural killer cell activity in smokers [135]. This suggests that probiotics may be useful in COPD patients, particularly those with frequent viral infections [11]. Of interest, a diet supplemented with Lactobacillus plantarum prevents cardiovascular disease in smokers [11].

4. Future Studies on the Effects of Probiotics in Lung Disease

Recent studies suggest that commensal microorganisms are not identical in their ability to affect host physiology. Ongoing studies aimed at establishing a correlation between the presence of particular microbes and specific diseases will provide much needed insights into their relationships with the immune system. The effect of microbial influences on the immune system and specific cell types has been extensively reviewed [136, 137]. While considerable progress has been made in large-scale analysis of gut commensal microbiota and its effect on the balance of pro- and anti-inflammatory forces of the immune system, many questions remain to be solved including which immune cells are the important targets for probiotic actions. In the future, it will be important to determine the mechanisms behind the probiotic action on the respiratory tract in diseased states. This will enable a rational approach for the use of probiotics in lung disease. A greater knowledge of the intestinal microbiota seen in patients with pulmonary disorders such as allergic diseases and in healthy infants will present opportunities to select more effective strains or combinations of strains to modulate the immune response and treat disease. Because probiotics modulate the composition and/or activity of the intestinal microbiota, it is important to obtain information on the intestinal microbiota culture, not only from fecal samples as is commonly performed but also from those of the associated mucosa.

Abbreviations

APC: | Antigen presenting cells
AHR: | Airway hyper responsiveness
DCs: | Dendritic cells
GALT: | Gut-associated lymphoid tissues
FoxP3: | Forkhead box protein 3
IL: | Interleukin
IF: | Influenza virus
IFN-γ: | Interferon gamma
LGG: | Lactobacillus rhamnosus GG
LcS: | Lactobacillus casei Shirota
LAB: | Lactic acid bacteria
M: | M cells of intestinal epithelium
NK: | Natural killer cells
PBMC: | Peripheral blood mononuclear cells
PAMPs: | Pathogen-associated molecular patterns
Th: | T-helper cells
TGF: | Transforming growth factor
TNF: | Tumour necrosis factor
TLR2: | Toll-like receptor 2
Treg: | T regulatory cells.

Conflict of Interests

The authors declare that they have no conflict of interests.

References

T. J. Borody, E. F. Warren, S. M. Leis, R. Surace, O. Ashman, and S. Siarakas, “Bacteriotherapy using fecal flora: toying with human motions,” Journal of Clinical Gastroenterology, vol. 38, no. 6, pp. 475–483, 2004.

A. L. D'Souza, C. Rajkumar, J. Cooke, and C. J. Bulpitt, “Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis,” British Medical Journal, vol. 324, no. 7350, pp. 1361–1364, 2002.

S. Salminen, C. Gibson, M. C. Bouley, et al., “Gastrointestinal physiology and function: the role of prebiotics and probiotics,” British Journal of Nutrition, vol. 80, supplement 1, pp. 147–171, 1998.

F. Guarner, A. Khan, J. Garisch et al., World Gastroenterology Organisation Practice Guideline: Probiotics and Prebiotics, WGO, Munich, Germany, 2008.

C. Rousseaux, X. Thuru, A. Gelot et al., “Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors,” Nature Medicine, vol. 13, no. 1, pp. 35–37, 2007.

E. F. Verdú, P. Bercik, M. Verma-Gandhu et al., “Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice,” Gut, vol. 55, no. 2, pp. 182–194, 2006.

M. B. Roberfroid, “Prebiotics and synbiotics: concepts and nutritional properties. Université Catholique de Louvain, Department of Pharmaceutical Sciences, Brussels, Belgium,” British Journal of Nutrition, vol. 80, supplement 4, pp. S197–S202, 1998.

T. Kamiya, L. Wang, P. Forsythe et al., “Inhibitory effects of Lactobocillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats,” Gut, vol. 55, no. 2, pp. 191–196, 2006.

E. F. Verdú, P. Bercík, G. E. Bergonzelli et al., “Lactobacillus paracasei normalizes muscle hypercontractility in a murine model of postinfective gut dysfunction,” Gastroenterology, vol. 127, no. 3, pp. 826–837, 2004.

T. A. Oelschlaeger, “Mechanisms of probiotic actions—a review,” International Journal of Medical Microbiology, vol. 300, no. 1, pp. 57–62, 2010.

K. Morimoto, T. Takeshita, M. Nanno, S. Tokudome, and K. Nakayama, “Modulation of natural killer cell activity by supplementation of fermented milk containing Lactobacillus casei in habitual smokers,” Preventive Medicine, vol. 40, no. 5, pp. 589–594, 2005.

A. V. Rao, A. C. Bested, T. M. Beaulne, et al., “A randomized, double blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome,” Gut Pathology, vol. 19, pp. 1–6, 2009.

S. C. Ng, A. L. Hart, M. A. Kamm, A. J. Stagg, and S. C. Knight, “Mechanisms of action of probiotics: recent advances,” Inflammatory Bowel Diseases, vol. 15, no. 2, pp. 300–310, 2009.

G. Hörmannsperger and D. Haller, “Molecular crosstalk of probiotic bacteria with the intestinal immune system: clinical relevance in the context of inflammatory bowel disease,” International Journal of Medical Microbiology, vol. 300, no. 1, pp. 63–73, 2010.

J. S. So, C. G. Lee, H. K. Kwon et al., “Lactobacillus casei potentiates induction of oral tolerance in experimental arthritis,” Molecular Immunology, vol. 46, no. 1, pp. 172–180, 2008.

D. Ghadimi, R. Fölster-Holst, M. de Vrese, P. Winkler, K. J. Heller, and J. Schrezenmeir, “Effects of probiotic bacteria and their genomic DNA on TH1/TH2-cytokine production by peripheral blood mononuclear cells (PBMCs) of healthy and allergic subjects,” Immunobiology, vol. 213, no. 8, pp. 677–692, 2008.

H. K. Kwon, C. G. Lee, J. S. So et al., “Generation of regulatory dendritic cells and CD4⁺Foxp3⁺ T cells by probiotics administration suppresses immune disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 5, pp. 2159–2164, 2010.

M. L. Cross, L. M. Stevenson, and H. S. Gill, “Anti-allergy properties of fermented foods: an important immunoregulatory mechanism of lactic acid bacteria?” International Immunopharmacology, vol. 1, no. 5, pp. 891–901, 2001.

C. B. M. Maassen, C. van Holten-Neelen, F. Balk et al., “Strain-dependent induction of cytokine profiles in the gut by orally administered Lactobacillus strains,” Vaccine, vol. 18, no. 23, pp. 2613–2623, 2000.

K. Takeda, T. Suzuki, S. I. Shimada, K. Shida, M. Nanno, and K. Okumura, “Interleukin-12 is involved in the enhancement of human natural killer cell activity by Lactobacillus casei Shirota,” Clinical and Experimental Immunology, vol. 146, no. 1, pp. 109–115, 2006.

E. Isolauri, S. Salminen, and A. C. Ouwehand, “Probiotics,” Best Practice and Research: Clinical Gastroenterology, vol. 18, no. 2, pp. 299–313, 2004.

M. C. Noverr and G. B. Huffnagle, “The “microflora hypothesis” of allergic diseases,” Clinical and Experimental Allergy, vol. 35, no. 12, pp. 1511–1520, 2005.

N. Sudo, X. N. Yu, Y. Aiba et al., “An oral introduction of intestinal bacteria prevents the development of a long-term Th2-skewed immunological memory induced by neonatal antibiotic treatment in mice,” Clinical and Experimental Allergy, vol. 32, no. 7, pp. 1112–1116, 2002.

M. I. Alvarez-Olmos and R. A. Oberhelman, “Probiotic agents and infectious diseases: a mode rn pe rspe c tive on a tr aditional the rapy,” Clinical Infectious Diseases, vol. 32, pp. 1567–1576, 2001.

J. A. Vanderhoof and R. Young, “Probiotics in the United States,” Clinical Infectious Diseases, vol. 46, supplement 2, pp. S67–S72, 2008.

I. G. Bogdanov, V. T. Velichkov, and A. I. Gurevich, “Antitumor effect of glycopeptides from the cell wall of Lactobacillus bulgaricus,” Byulleten Eksperimentalnoi Biologii i Meditsiny, vol. 84, no. 12, pp. 709–712, 1977.

G. Hepner, R. Fried, S. St Jeor, L. Fusetti, and R. Morin, “Hypocholesterolemic effect of yogurt and milk,” The American Journal of Clinical Nutrition, vol. 32, pp. 19–24, 1979.

B. Batdorj, V. Trinetta, M. Dalgalarrondo et al., “Isolation, taxonomic identification and hydrogen peroxide production by Lactobacillus delbrueckii subsp. lactis T31, isolated from Mongolian yoghurt: inhibitory activity on food-borne pathogens,” Journal of Applied Microbiology, vol. 103, no. 3, pp. 584–593, 2007.

I. A. Abd El-Gawad, E. M. El-Sayed, S. A. Hafez, H. M. El-Zeini, and F. A. Saleh, “Inhibitory effect of yoghurt and soya yoghurt containing bifidobacteria on the proliferation of Ehrlich ascites tumour cells in vitro and in vivo in a mouse tumour model,” British Journal of Nutrition, vol. 92, no. 1, pp. 81–86, 2004.

T. Takahashi, T. Oka, H. Iwana, T. Kuwata, and Y. Yamamoto, “Immune response of mice to orally administered lactic acid bacteria,” Bioscience, Biotechnology, and Biochemistry, vol. 57, pp. 1557–1560, 1993.

Joint FAO/WHO Working Group on Drafting Guidelines for the Evaluation of Probiotics in Food. Guidelines for the evaluation of probiotics in food, 2002, ftp://ftp.fao.org/es/esn/food/wgreport2.pdf

O. N. Donkor, M. Ravikumar, O. Proudfoot et al., “Cytokine profile and induction of T helper type 17 and regulatory T cells by human peripheral mononuclear cells after microbial exposure,” Clinical & Experimental Immunology, vol. 167, pp. 282–295, 2012.

M. Girardin and E. G. Seidman, “Indications for the use of probiotics in gastrointestinal diseases,” Digestive Diseases, vol. 29, pp. 574–587, 2011.

M. C. Noverr and G. B. Huffnagle, “The “microflora hypothesis” of allergic diseases,” Clinical and Experimental Allergy, vol. 35, no. 12, pp. 1511–1520, 2005.

M. L. Cross, A. Ganner, D. Teilab, and L. M. Fray, “Patterns of cytokine induction by gram-positive and gram-negative probiotic bacteria,” FEMS Immunology and Medical Microbiology, vol. 42, no. 2, pp. 173–180, 2004.

D. Ghadimi, R. Fölster-Holst, M. de Vrese, P. Winkler, K. J. Heller, and J. Schrezenmeir, “Effects of probiotic bacteria and their genomic DNA on TH1/TH2-cytokine production by peripheral blood mononuclear cells (PBMCs) of healthy and allergic subjects,” Immunobiology, vol. 213, no. 8, pp. 677–692, 2008.

U. Helwig, K. M. Lammers, F. Rizzello et al., “Lactobacilli, bifidobacteria and E. coli nissle induce pro- and anti-inflammatory cytokines in peripheral blood mononuclear cells,” World Journal of Gastroenterology, vol. 12, no. 37, pp. 5978–5986, 2006.

A. Hosono, T. Kashina, and T. Kada, “Antimutagenic properties of lactic acid-cultured milk on chemical and fecal mutagens,” Journal of Dairy Science, vol. 69, no. 9, pp. 2237–2242, 1986.

A. Pillai and R. Nelson, “Probiotics for treatment of Clostridium difficile-associated colitis in adults,” Cochrane Database of Systematic Reviews, no. 1, Article ID CD004611, 2008.

S. J. Allen, B. Okoko, E. Martinez, G. Gregorio, and L. F. Dans, “Probiotics for treating infectious diarrhoea,” Cochrane Database of Systematic Reviews, no. 2, Article ID CD003048, 2004.

M. Hickson, “Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial,” British Medical Journal, vol. 335, article 80, 2007.

G. Harata, F. He, M. Kawase, A. Hosono, K. Takahashi, and S. Kaminogawa, “Differentiated implication of Lactobacillus GG and L. gasseri TMC0356 to immune responses of murine Peyer's patch,” Microbiology and Immunology, vol. 53, no. 8, pp. 475–480, 2009.

T. Izumo, T. Maekawa, M. Ida et al., “Effect of intranasal administration of Lactobacillus pentosus S-PT84 on influenza virus infection in mice,” International Immunopharmacology, vol. 10, no. 9, pp. 1101–1106, 2010.

G. Harata, F. He, N. Hiruta et al., “Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1 influenza virus infection by regulating respiratory immune responses,” Letters in Applied Microbiology, vol. 50, no. 6, pp. 597–602, 2010.

S. Koizumi, D. Wakita, T. Sato, et al., “Essential role of Toll-like receptors for dendritic cell and NK1. 1(+) cell-dependent activation of type 1 immunity by Lactobacillus pentosus strain S-PT84,” Immunology Letters, vol. 120, pp. 14–19, 2008.

T. S. Plantinga, W. W. van Maren, J. van Bergenhenegouwen et al., “Differential Toll-like receptor recognition and induction of cytokine profile by Bifidobacterium breve and Lactobacillus strains of probiotics,” Clinical and Vaccine Immunology, vol. 18, pp. 621–628, 2011.

L. E. Harrington, R. D. Hatton, P. R. Mangan et al., “Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages,” Nature Immunology, vol. 6, no. 11, pp. 1123–1132, 2005.

T. Korn, E. Bettelli, M. Oukka, and V. K. Kuchroo, “IL-17 and Th17 cells,” Annual Review of Immunology, vol. 27, pp. 485–517, 2009.

W. Lin, N. Truong, W. J. Grossman et al., “Allergic dysregulation and hyperimmunoglobulinemia e in Foxp3 mutant mice,” Journal of Allergy and Clinical Immunology, vol. 116, no. 5, pp. 1106–1115, 2005.

C. L. Bennett, J. Christie, F. Ramsdell et al., “The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3,” Nature Genetics, vol. 27, no. 1, pp. 20–21, 2001.

K. Karimi, M. D. Inman, J. Bienenstock, and P. Forsythe, “Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice,” American Journal of Respiratory and Critical Care Medicine, vol. 179, no. 3, pp. 186–193, 2009.

W. Feleszko, J. Jaworska, R. D. Rha et al., “Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma,” Clinical and Experimental Allergy, vol. 37, no. 4, pp. 498–505, 2007.

M. Kalliomäki, S. Salminen, T. Poussa, and E. Isolauri, “Probiotics during the first 7 years of life: cumulative risk reduction of eczema in a randomized, placebo-controlled trial,” Journal of Allergy and Clinical Immunology, vol. 119, no. 4, pp. 1019–1021, 2007.

E. Baharav, F. Mor, M. Halpern, and A. Weinberger, “Lactobacillus GG bacteria ameliorate arthritis in Lewis rats,” Journal of Nutrition, vol. 134, no. 8, pp. 1964–1969, 2004.

S. Salva, J. Villena, and S. Alvarez, “Immunomodulatory activity of Lactobacillus rhamnosus strains isolated from goat milk: impact on intestinal and respiratory infections,” International Journal of Food Microbiology, vol. 141, no. 1-2, pp. 82–89, 2010.

S. Alvarez, C. Herrero, E. Bru, and G. Perdigon, “Effect of Lactobacillus casei and yogurt administration on prevention of Pseudomonas aeruginosa infection in young mice,” Journal of Food Protection, vol. 64, no. 11, pp. 1768–1774, 2001.

T. Hori, J. Kivoshima, K. Shida, and H. Yasui, “Augmentation of cellular immunity and reduction of influenza virus titer in aged mice fed Lactobacillus casei strain Shirota,” Clinical and Diagnostic Laboratory Immunology, vol. 9, no. 1, pp. 105–108, 2002.

S. Hougee, A. J. M. Vriesema, S. C. Wijering et al., “Oral treatment with probiotics reduces allergic symptoms in ovalbumin-sensitized mice: a bacterial strain comparative study,” International Archives of Allergy and Immunology, vol. 151, no. 2, pp. 107–117, 2010.

J. K. Peat, R. H. van den Berg, W. F. Green, C. M. Mellis, S. R. Leeder, and A. J. Woolcock, “Changing prevalence of asthma in Australian children,” British Medical Journal, vol. 308, no. 6944, pp. 1591–1596, 1994.

M. I. Asher, S. Montefort, B. Björkstén et al., “Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: iSAAC phases one and three repeat multicountry cross-sectional surveys,” The Lancet, vol. 368, no. 9537, pp. 733–743, 2006.

R. C. Leung, J. B. Carlin, J. G. W. Burdon, and D. Czarny, “Asthma, allergy and atopy in Asian immigrants in Melbourne,” Medical Journal of Australia, vol. 161, no. 7, pp. 418–425, 1994.

S. H. Sicherer, R. A. Wood, D. Stablein et al., “Maternal consumption of peanut during pregnancy is associated with peanut sensitization in atopic infants,” Journal of Allergy and Clinical Immunology, vol. 126, no. 6, pp. 1191–1197, 2010.

M. Kalliomäki, S. Salminen, H. Arvilommi, P. Kero, P. Koskinen, and E. Isolauri, “Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial,” The Lancet, vol. 357, no. 9262, pp. 1076–1079, 2001.

S. Rautava, M. Kalliomäki, and E. Isolauri, “Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant,” Journal of Allergy and Clinical Immunology, vol. 109, no. 1, pp. 119–121, 2002.

M. Kalliomäki, S. Salminen, T. Poussa, H. Arvilommi, and E. Isolauri, “Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial,” The Lancet, vol. 361, no. 9372, pp. 1869–1871, 2003.

E. Isolauri, T. Arvola, Y. Sutas, E. Moilanen, and S. Salminen, “Probiotics in the management of atopic eczema,” Clinical and Experimental Allergy, vol. 30, no. 11, pp. 1604–1610, 2000.

H. Majamaa and E. Isolauri, “Probiotics: a novel approach in the management of food allergy,” Journal of Allergy and Clinical Immunology, vol. 99, no. 2, pp. 179–185, 1997.

M. Kalliomäki, S. Salminen, H. Arvilommi, P. Kero, P. Koskinen, and E. Isolauri, “Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial,” The Lancet, vol. 357, no. 9262, pp. 1076–1079, 2001.

S. Weston, A. Halbert, P. Richmond, and S. L. Prescott, “Effects of probiotics on atopic dermatitis: a randomised controlled trial,” Archives of Disease in Childhood, vol. 90, no. 9, pp. 892–897, 2005.

M. L. Brouwer, S. A. A. Wolt-Plompen, A. E. J. Dubios et al., “No effects of probiotics on atopic dermatitis in infancy: a randomized placebo-controlled trial,” Clinical and Experimental Allergy, vol. 36, no. 7, pp. 899–906, 2006.

A. L. Taylor, J. A. Dunstan, and S. L. Prescott, “Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial,” Journal of Allergy and Clinical Immunology, vol. 119, no. 1, pp. 184–191, 2007.

M. V. Kopp, I. Hennemuth, A. Heinzmann, and R. Urbanek, “Randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical effects of lactobacillus gg supplementation,” Pediatrics, vol. 121, no. 4, pp. e850–e856, 2008.

C. E. West, M. L. Hammarström, and O. Hernell, “Probiotics during weaning reduce the incidence of eczema,” Pediatric Allergy and Immunology, vol. 20, no. 5, pp. 430–437, 2009.

E. Isolauri, T. Arvola, Y. Sutas, E. Moilanen, and S. Salminen, “Probiotics in the management of atopic eczema,” Clinical and Experimental Allergy, vol. 30, no. 11, pp. 1604–1610, 2000.

O. Ozdemir, “Any benefits of probiotics in allergic disorders?” Allergy and Asthma Proceedings, vol. 31, no. 2, pp. 103–111, 2010.

P. Forsythe, M. D. Inman, and J. Bienenstock, “Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice,” American Journal of Respiratory and Critical Care Medicine, vol. 175, no. 6, pp. 561–569, 2007.

M. Kalliomäki and E. Isolauri, “Role of intestinal flora in the development of allergy,” Current Opinion in Allergy and Clinical Immunology, vol. 3, no. 1, pp. 15–20, 2003.

R. Fuller, “Probiotics in man and animals,” Journal of Applied Bacteriology, vol. 66, no. 5, pp. 365–378, 1989.

W. Feleszko, J. Jaworska, R. D. Rha et al., “Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma,” Clinical and Experimental Allergy, vol. 37, no. 4, pp. 498–505, 2007.

M. A. Rose, F. Stieglitz, A. Köksal, R. Schubert, J. Schulze, and S. Zielen, “Efficacy of probiotic Lactobacillus GG on allergic sensitization and asthma in infants at risk,” Clinical and Experimental Allergy, vol. 40, no. 9, pp. 1398–1405, 2010.

J. A. Wisniewski and X. M. Li, “Alternative and complementary treatment for food allergy,” Immunology and Allergy Clinics of North America, vol. 32, pp. 135–150, 2012.

H. H. Smits, A. Engering, D. van der Kleij et al., “Selective probiotic bacteria induce IL-10-producing regulatory T cells in vitro by modulating dendritic cell function through dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin,” Journal of Allergy and Clinical Immunology, vol. 115, no. 6, pp. 1260–1267, 2005.

C. Zuany-Amorim, E. Sawicka, C. Manlius et al., “Suppression of airway eosinophilia by killed Mycobacterium vaccae-induced allergen-specific regulatory T-cells,” Nature Medicine, vol. 8, no. 6, pp. 625–629, 2002.

W. Feleszko, J. Jaworska, R. D. Rha et al., “Probiotic-induced suppression of allergic sensitization and airway inflammation is associated with an increase of T regulatory-dependent mechanisms in a murine model of asthma,” Clinical and Experimental Allergy, vol. 37, no. 4, pp. 498–505, 2007.

C. O'Mahony, P. Scully, D. O'Mahony et al., “Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-κB activation,” PLoS Pathogens, vol. 4, no. 8, Article ID e1000112, 2008.

B. Zhang, J. An, T. Shimada, S. Liu, and K. Maeyama, “Oral administration of Enterococcus faecalis FK-23 suppresses Th17 cell development and attenuates allergic airway responses in mice,” International Journal of Molecular Medicine, vol. 24, no. 2, pp. 248–254, 2012.

M. J. Holtzman, D. E. Byers, L. A. Benoit et al., “Chapter 5 immune pathways for translating viral infection into chronic airway disease1,” Advances in Immunology, vol. 102, pp. 245–276, 2009.

J. Yoo, H. Tcheurekdjian, S. V. Lynch, M. Cabana, and H. A. Boushey, “Microbial manipulation of immune function for asthma prevention inferences from clinical trials,” Proceedings of the American Thoracic Society, vol. 4, no. 3, pp. 277–282, 2007.

M. Saxelin, S. Salminen, and E. Isolauri, “Clinical efficacy of a human Lactobacillus strain as a probiotic,” in Functional Foods: The Consumer, the Products and the Evidence, M. J. Sadler and M. Saltmarsh, Eds., Royal Society of Chemistry, Cambridge, UK, 1998.

H. Yasui, J. Kiyoshima, T. Hori, and K. Shida, “Protection against influenza virus infection of mice fed Bifidobacterium breve YIT4064,” Clinical and Diagnostic Laboratory Immunology, vol. 6, no. 2, pp. 186–192, 1999.

H. Yasui, J. Kiyoshima, and T. Hori, “Reduction of influenza virus titer and protection against influenza virus infection in infant mice fed Lactobacillus casei Shirota,” Clinical and Diagnostic Laboratory Immunology, vol. 11, no. 4, pp. 675–679, 2004.

T. Hori, J. Kiyoshima, K. Shida, and H. Yasui, “Effect of intranasal administration of Lactobacillus casei shirota on influenza virus infection of upper respiratory tract in mice,” Clinical and Diagnostic Laboratory Immunology, vol. 8, no. 3, pp. 593–597, 2001.

B. R. Goldin and S. L. Gorbach, “Clinical indications for probiotics: an overview,” Clinical Infectious Diseases, vol. 46, supplement 2, pp. S96–S100, 2008.

G. Harata, F. He, N. Hiruta et al., “Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1 influenza virus infection by regulating respiratory immune responses,” Letters in Applied Microbiology, vol. 50, no. 6, pp. 597–602, 2010.

L. E. Morrow, M. H. Kollef, and T. B. Casale, “Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial,” American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 8, pp. 1058–1064, 2010.

K. Hatakka, E. Savilahti, A. Pönkä et al., “Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind, randomised trial,” British Medical Journal, vol. 322, no. 7298, pp. 1327–1329, 2001.

I. Hojsak, S. Abdović, H. Szajewska, M. Milošević, Z. Krznarić, and S. Kolaček, “Lactobacillus GG in the prevention of nosocomial gastrointestinal and respiratory tract infections,” Pediatrics, vol. 125, no. 5, pp. e1171–e1177, 2010.

M. de Vrese, P. Winkler, P. Rautenberg et al., “Probiotic bacteria reduced duration and severity but not the incidence of common cold episodes in a double blind, randomized, controlled trial,” Vaccine, vol. 24, no. 44–46, pp. 6670–6674, 2006.

K. F. Rabe, S. Hurd, A. Anzueto et al., “Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary,” American Journal of Respiratory and Critical Care Medicine, vol. 176, no. 6, pp. 532–555, 2007.

P. J. Barnes, “Neutrophils find smoke attractive,” Science, vol. 330, no. 6000, pp. 40–41, 2010.

I. M. Adcock, G. Caramori, and P. J. Barnes, “Chronic obstructive pulmonary disease and lung cancer: new molecular insights,” Respiration, vol. 81, no. 4, pp. 265–268, 2011.

N. E. Tzanakis, I. G. Tsiligianni, and N. M. Siafakas, “Pulmonary involvement and allergic disorders in inflammatory bowel disease,” World Journal of Gastroenterology, vol. 16, no. 3, pp. 299–305, 2010.

B. Basseri, P. Enayati, A. Marchevsky, and K. A. Papadakis, “Pulmonary manifestations of inflammatory bowel disease: case presentations and review,” Journal of Crohn's and Colitis, vol. 4, no. 4, pp. 390–397, 2010.

H. Black, M. Mendoza, and S. Murin, “Thoracic manifestations of inflammatory bowel disease,” Chest, vol. 131, no. 2, pp. 524–532, 2007.

T. A. Fedorova, L. I. Spirina, N. E. Chernekhovskaia et al., “The stomach and duodenum condition in patients with chronic obstructive lung diseases,” Klinicheskaia meditsina, vol. 81, no. 10, pp. 31–33, 2003.

A. Benard, P. Desreumeaux, D. Huglo, A. Hoorelbeke, A. B. Tonnel, and B. Wallaert, “Increased intestinal permeability in bronchial asthma,” Journal of Allergy and Clinical Immunology, vol. 97, no. 6, pp. 1173–1178, 1996.

J. B. Levine and D. Lukawski-Trubish, “Extraintestinal considerations in inflammatory bowel disease,” Gastroenterology Clinics of North America, vol. 24, no. 3, pp. 633–646, 1995.

S. Keely, N. J. Talley, and P. M. Hansbro, “Pulmonary-intestinal cross-talk in mucosal inflammatory disease,” Mucosal Immunology, vol. 5, pp. 7–18, 2012.

S. I. Rennard and J. Vestbo, “COPD: the dangerous underestimate of 15%,” The Lancet, vol. 367, no. 9518, pp. 1216–1219, 2006.

M. G. Cosio, M. Saetta, and A. Agusti, “Immunologic aspects of chronic obstructive pulmonary disease,” The New England Journal of Medicine, vol. 360, no. 23, pp. 2396–2454, 2009.

J. C. Hogg, F. Chu, S. Utokaparch et al., “The nature of small-airway obstruction in chronic obstructive pulmonary disease,” The New England Journal of Medicine, vol. 350, no. 26, pp. 2645–2653, 2004.

M. G. Cosio, M. Saetta, and A. Agusti, “Immunologic aspects of chronic obstructive pulmonary disease,” The New England Journal of Medicine, vol. 360, no. 23, pp. 2396–2454, 2009.

M. T. Borchers, S. C. Wesselkamper, V. Curull et al., “Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease,” The Journal of Clinical Investigation, vol. 119, no. 3, pp. 636–649, 2009.

G. T. Motz, B. L. Eppert, G. Sun et al., “Persistence of lung CD8 T cell oligoclonal expansions upon smoking cessation in a mouse model of cigarette smoke-induced emphysema,” Journal of Immunology, vol. 181, no. 11, pp. 8036–8043, 2008.

M. T. Borchers, S. C. Wesselkamper, N. L. Harris et al., “CD8+ T cells contribute to macrophage accumulation and airspace enlargement following repeated irritant exposure,” Experimental and Molecular Pathology, vol. 83, no. 3, pp. 301–310, 2007.

E. Sapey and R. A. Stockley, “COPD exacerbations · 2: aetiology,” Thorax, vol. 61, no. 3, pp. 250–258, 2006.

A. Bhowmik, T. A. R. Seemungal, R. J. Sapsford, and J. A. Wedzicha, “Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations,” Thorax, vol. 55, no. 2, pp. 114–120, 2000.

J. K. Quint, R. Baghai-Ravary, G. C. Donaldson, and J. A. Wedzicha, “Relationship between depression and exacerbations in COPD,” European Respiratory Journal, vol. 32, no. 1, pp. 53–60, 2008.

E. Sapey and R. A. Stockley, “COPD exacerbations · 2: aetiology,” Thorax, vol. 61, no. 3, pp. 250–258, 2006.

B. R. Celli and P. J. Barnes, “Exacerbations of chronic obstructive pulmonary disease,” European Respiratory Journal, vol. 29, no. 6, pp. 1224–1238, 2007.

M. J. Kang, G. L. Chun, J. Y. Lee et al., “Cigarette smoke selectively enhances viral PAMP- and virus-induced pulmonary innate immune and remodeling responses in mice,” The Journal of Clinical Investigation, vol. 118, no. 8, pp. 2771–2778, 2008.

K. C. Newman and E. M. Riley, “Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens,” Nature Reviews Immunology, vol. 7, no. 4, pp. 279–291, 2007.

T. Kawai and S. Akira, “Innate immune recognition of viral infection,” Nature Immunology, vol. 7, no. 2, pp. 131–137, 2006.

K. C. Newman and E. M. Riley, “Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens,” Nature Reviews Immunology, vol. 7, no. 4, pp. 279–291, 2007.

T. Kawai and S. Akira, “Innate immune recognition of viral infection,” Nature Immunology, vol. 7, no. 2, pp. 131–137, 2006.

M. Lucas, W. Schachterle, K. Oberle, P. Aichele, and A. Diefenbach, “Dendritic cells prime natural killer cells by trans-presenting interleukin 15,” Immunity, vol. 26, no. 4, pp. 503–517, 2007.

T. Strowig, F. Brilot, and C. Münz, “Noncytotoxic functions of NK cells: direct pathogen restriction and assistance to adaptive immunity,” Journal of Immunology, vol. 180, no. 12, pp. 7785–7791, 2008.

J. R. Ortaldo, R. T. Winkler-Pickett, H. Yagita, and H. A. Young, “Comparative studies of CD3⁻ and CD3⁺ CD56⁺ cells: examination of morphology, functions, T cell receptor rearrangement, and pore-forming protein expression,” Cellular Immunology, vol. 136, no. 2, pp. 486–495, 1991.

T. Strowig, F. Brilot, and C. Münz, “Noncytotoxic functions of NK cells: direct pathogen restriction and assistance to adaptive immunity,” Journal of Immunology, vol. 180, no. 12, pp. 7785–7791, 2008.

K. Schroder, P. J. Hertzog, T. Ravasi, and D. A. Hume, “Interferon-γ: an overview of signals, mechanisms and functions,” Journal of Leukocyte Biology, vol. 75, no. 2, pp. 163–189, 2004.

T. Strowig, F. Brilot, and C. Münz, “Noncytotoxic functions of NK cells: direct pathogen restriction and assistance to adaptive immunity,” Journal of Immunology, vol. 180, no. 12, pp. 7785–7791, 2008.

J. S. Orange, B. Wang, C. Terhorst, and C. A. Biron, “Requirement for natural killer cell-produced interferon γ in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration,” Journal of Experimental Medicine, vol. 182, no. 4, pp. 1045–1056, 1995.

T. M. Scharton and P. Scott, “Natural killer cells are a source of interferon γ that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice,” Journal of Experimental Medicine, vol. 178, no. 2, pp. 567–577, 1993.

M. F. Mian, N. M. Lauzon, M. R. Stämpfli, K. L. Mossman, and A. A. Ashkar, “Impairment of human NK cell cytotoxic activity and cytokine release by cigarette smoke,” Journal of Leukocyte Biology, vol. 83, no. 3, pp. 774–784, 2008.

M. Naruszewicz, M. L. Johansson, D. Zapolska-Downar, and H. Bukowska, “Effect of Lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers,” American Journal of Clinical Nutrition, vol. 76, no. 6, pp. 1249–1255, 2002.

T. Chinen and A. Y. Rudensky, “The effects of commensal microbiota on immune cell subsets and inflammatory responses,” Immunological Reviews, vol. 245, pp. 45–55, 2012.

A. V. Chervonsky, “Microbial influences on immune function and more,” Immunological Reviews, vol. 245, pp. 7–12, 2012.