Annals of the American Thoracic Society

Host–microorganism interactions shape local cell functionality, immune responses, and can influence disease development. Evidence indicates that the impact of host–microbe interactions reaches far beyond the local environment, thus influencing responses in peripheral tissues. There is a vital cross-talk between the mucosal tissues of our body, as exemplified by intestinal complications during respiratory disease and vice versa. Although, mechanistically, this phenomenon remains poorly defined, the existence of the gut–lung axis and its implications in both health and disease could be profoundly important for both disease etiology and treatment. In this review, we highlight how changes in the intestinal microenvironment, with a particular focus on the intestinal microbiota, impact upon respiratory disease.

Chronic lung disorders, such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis, all exhibit a component of intestinal disease manifestation (13). In addition, respiratory viral infections are often accompanied by intestinal symptoms (4, 5). It has also been shown that the intestinal microenvironment changes in the course of several different lung diseases, including shifts in the composition of the intestinal microbiota (68). This indicates that there is a vital cross-talk between these two mucosal sites of the human body. In this review, we discuss the changes in intestinal microbial composition associated with respiratory disease. We also highlight factors that shape the intestinal microbiota and their impact on pulmonary health and disease.

The human body is inhabited by trillions of symbiotic bacteria on the skin (9), nose (10), oral cavity (11), vagina (12), stomach (13), respiratory tract (14, 15), and intestine (16). The main colonizers found in these compartments belong to six different phyla—Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, Fusobacteria, and Cyanobacteria (916). However, relative abundance and load of these phyla, and especially the bacterial composition at the genera level, differs significantly between the different compartments (17).

The Intestinal and Airway Microbiota

The most extensively studied microbiota is the one colonizing the intestinal tract. With a bacterial load in the magnitude of 1014 bacteria (18), the intestine is the most densely colonized surface of the human body. Bacteroidetes represent the most abundant phylum, followed by Firmicutes (16, 19). In healthy adults, Bacteroides, Faecalibacterium, and Bifidobacterium are the most prevalent genera (19). Moreover, the intestinal microbiota can be divided into three so-called “enterotypes”—Bacteroides (enterotype 1), Prevotella (enterotype 2), and Ruminococcus (enterotype 3)—based on the predominant genera present in an individual (19, 20). Dysbiosis of the intestinal microbiota has been associated with a variety of local (21) and systemic chronic disorders (22, 23), emphasizing the importance of a balanced microbial community in the intestine for appropriate immune function and health.

With an estimated number of 10–100 bacteria per 1,000 human cells (24), the lower respiratory tract is one of the least-populated surfaces of the human body. Similar to the intestine, the two predominant phyla detected in the airways are Firmicutes and Bacteroidetes, whereas Actinobacteria, Proteobacteria, and Fusobacteria are minor constituents of the local microbiota (14, 15). The “core microbiota” of healthy individuals consists mainly of Pseudomonas, Streptococcus, Prevotella, Fusobacteria, Veillonella, Haemophilus, Neisseria, and Porphyromonas (14, 15, 25, 26). A recent study in children with cystic fibrosis provides evidence that the intestinal and respiratory microbiota develop simultaneously after birth (27), and that there is a constant cross-talk between these two compartments. A number of bacteria appear in the intestine before being detected in the respiratory tract (27), which points toward a contribution of microaspiration of intestinal microbes in the development of the airway microbiota. Furthermore, fluctuations in the abundance of a variety of bacteria happen in the same manner at both sites (27). Factors such as diet have also been shown to not only impact on the composition of the intestinal, but also the respiratory microbiota (27, 28). However, a drawback of this pediatric study is the use of oropharyngeal swabs to evaluate the respiratory microbiota. Although it has been shown before by culture-dependent and -independent methods that, in patients with cystic fibrosis, oropharyngeal swabs are a rather precise method to define the composition of the airway microbiota (29, 30), recent studies on healthy subjects demonstrated a discordance between upper and lower respiratory tract microbiota (31, 32). Thus, it still needs to be formally proven whether the bacterial communities detected in these children with cystic fibrosis simultaneously and stably colonize the lower respiratory tract. However, taken together, these data still indicate that the intestinal and respiratory compartments are closely connected, and that changes at one of the two sites could impact on the other. As supporting evidence for this concept, a variety of respiratory diseases have been associated with a dysbiosis in not only the airway microbiota, but also in the intestinal microbiota (68). In the following part of this review, we discuss this in more detail.

Chronic Lung Disorders

Recent research has made it evident that a variety of chronic lung disorders, including asthma, COPD, and cystic fibrosis, are strongly linked to a dysbiotic airway microbiota (14, 15, 24, 3336). This is usually the result of a loss in bacterial diversity (14, 24, 36) due to the outgrowth of certain pathogenic bacteria. The airway microbiota of patients with chronic lung disorders presents a disease-specific phenotype. In contrast to healthy individuals, those with asthma or COPD demonstrate an overrepresentation of Proteobacteria (in particular Haemophilus, Moraxella, and Neisseria spp.) and Firmicutes (Lactobacillus spp.), whereas the proportion of Bacteroidetes (specifically, Prevotella spp.) is significantly decreased (15, 24). The lung microbiota of patients with cystic fibrosis is characterized by a strong increase in typical cystic fibrosis pathogens of the Proteobacteria phylum, including Pseudomonas, Haemophilus, and Burkholderia, along with an additional outgrowth of the Actinobacteria phylum (37, 38). However, not only is the airway microbiota altered during these chronic lung disorders, but shifts in the composition of the intestinal microbiota have also been noted, particularly within the context of asthma and cystic fibrosis.

A strong correlation has been made between low microbial diversity in the gut during early infancy and an asthmatic phenotype in childhood (6, 7). As early as 12 months after birth, these differences in diversity have been lost (6), long before the disease symptoms present. A study in mice has also shown that reducing the microbial load and diversity by antibiotic administration during the first 3 weeks of life exacerbates experimental allergic airway inflammation after adult exposure to aeroallergens (39). This suggests a critical window early in life, during which microbial diversity in the intestine is important for appropriate systemic immune function later in life. During this early-life timeframe, a specific reduction in the prevalence of Bifidobacteria and an increase in Clostridia have been observed in the intestine of subjects with asthma (40); however, whether this phenotype is transient or persistent has not been investigated. Children with cystic fibrosis also exhibit profound differences in their intestinal microbiota compared with healthy, age-matched individuals. Bacterial loads of Eubacterium rectale, Bacteroides vulgatus, Bacteroides uniformis, Faecalibacterium prausnitzii, Bifidobacterium catenulatum, and Bifidobacterium adolescentis were significantly diminished in children with cystic fibrosis (8). The same research group also found a negative correlation between the degree of intestinal inflammation and the diversity of the intestinal microbiota in these children (8).

Respiratory Infections

A variety of studies in recent years has focused on the microbiota during chronic airway disease. However, little is known about how viral and bacterial infections, the underlying causes of exacerbations of chronic lung disorders, can shape the microbiota. In a recent publication, Yi and colleagues (41) compared the bacterial microbiota of the upper respiratory tract of healthy individuals with patients acutely infected with influenza, parainfluenza, rhinovirus, respiratory syncytial virus, coronavirus, adenovirus, or metapneumovirus. Virus-infected individuals generally demonstrated an increased prevalence of Haemophilus and Moraxella. However, no virus-specific bacterial profile could be detected. Patients with chronic bacterial infections regularly present with either Pseudomonas aeruginosa– or Haemophilus influenzae–dominated disease. It has been shown that these two pathogens not only strongly compete with each other for the same habitat, but that infections with one or the other are also accompanied by a very distinct composition of the core microbiota (42). Whereas Prevotella and Flavobacterium dominate in the P. aeruginosa–infected samples, Neisseria is significantly more abundant in the H. influenzae group (42). These results indicate that bacterial and viral respiratory infections are accompanied by changes in the microbial composition, at least of the upper respiratory tract. Importantly, Molyneaux and colleagues (43) demonstrated that rhinovirus infection of healthy subjects does not alter the composition or load of the microbiota measured in induced-sputum samples. An outgrowth of pathogenic bacteria, mainly of the Proteobacteria phylum (e.g., H. influenzae), can only be seen in patients with COPD infected with rhinovirus, which could explain their predisposition to secondary bacterial infections. However, whether similar associations can be made between the intestinal microbiota and the incidence of respiratory infections is less clear. Murine studies using either axenic mice that do not harbor any microbes—neither in the lung nor in the gut—or antibiotic-treated mice have shown that the presence of a microbiota is critical in the defense against influenza virus (44, 45) and protection against Escherichia coli–induced pneumonia (46, 47). Whether this phenomenon is due to a lack of bacterial colonization of the gut, the airways, or a combination of both has yet to be elucidated. However, Wang and colleagues (4) demonstrated recently that respiratory influenza infection of mice can lead to alterations in their intestinal microbiota, showing an outgrowth of Enterobacteriaceae and a reduction in Lactobacilli and Lactococci. These shifts in the microbial communities were not due to active infection of the intestine with influenza virus, but ultimately led to intestinal immune injury and inflammation (4), something that is often observed in patients with severe influenza virus infection. These data certainly argue for a physiologically relevant link between respiratory viral infections and the intestinal microbiota; however, it remains to be validated in humans.

Early-Life Exposures

A variety of early-life exposures have been linked to both changes in the intestinal microbiota and the protection against or predisposition toward respiratory disease, although a clear mechanism between the two events has yet to be established. It has been shown that Caesarean birth reduces the diversity and alters the composition of the intestinal microbiota early in life (48) and is, at the same time, linked to predisposition toward asthma during childhood (49) and an increased risk of hospitalization due to respiratory syncytial virus infection in infancy (50). An inverse association has been made with breast feeding (5155). Recurrent antibiotic treatment during early infancy also impacts significantly on the diversity of the microbiota early in life (56), and has been shown to strongly correlate with the development of an asthmatic phenotype later in life (55). A direct link between changes in the gut microbiota due to early-life antibiotic exposure and the immune response toward aeroallergens has been confirmed by murine studies (39). In addition, murine studies revealed a loss of protection against respiratory viruses in the absence of a microbiota or after prolonged antibiotic regimes (44, 45). Exposures to environmental microbes (57) and a farming environment (58, 59) have also been associated with protection against asthma; however, whether this is also linked to a shift in microbial communities in the intestine has not been elucidated yet. Another question that still needs to be addressed is whether similar changes in microbial composition occur in the airways in response to such factors.

Dietary Products

Recent mouse studies have pointed out that dietary fibers and some of their fermentation products, namely, short-chain fatty acids (SCFAs), can protect against the development of allergic airway inflammation by modulating immune function (28, 60). These molecules have been shown to exert anti-inflammatory properties in a variety of contexts via their histone-deacetylase inhibitory activity (61, 62), their ability to induce regulatory T cells (63), the production of prostaglandin E2 (64), or by altering dendritic cell function (28). Dietary fiber intake led to an increase in SCFAs, which was accompanied by shifts in the composition of the intestinal, and to a lesser extent the airway, microbiota in mice (28). Similar correlations have been made in humans between changes in the intestinal microbiota after fiber intake and a low incidence of asthma (65). In contrast, it has been shown in mice that offspring from breeders fed a high-fat diet exhibited changes in the constituents of their intestinal microbiota and an elevated allergic airway inflammation, even if the offspring were fed a low-fat control diet after weaning (66). This indicates that the disease-promoting factors are maternally transferred. Whether these dietary factors also affect responses against respiratory infections is still unknown. However, a recent study by Loss and colleagues (67) demonstrated that drinking unpasteurized milk during the first year of life protects against respiratory tract infections in children. The same group previously showed similar correlations between unpasteurized milk consumption in the first year of life and the incidence of asthma and allergies during childhood (58, 68). The factors conveying this protective effect of unpasteurized milk, as well as whether this is linked to changes in the intestinal or airway microbiota, have yet to be elucidated.

Probiotics

Probiotics are live microorganisms that are suggested to provide a health benefit by integrating into the intestinal microbiota (either short or long term) and influencing the constituents of the microbial community by direct effects on immune cells or release of health-promoting metabolites. In recent years, studies have aimed to address how probiotics can influence chronic lung disorders, such as asthma. To date, however, the results are inconsistent and likely dependent on the combined efficacy of specific bacterial species and treatment regimes (6976). However, murine studies might help deciphering the mode of action of certain probiotic strains. It has been shown that oral administration of Lactobacillus rhamnosus (70, 77), Bifidobacterium lactis (70), and Bifidobacterium breve (75), or an inactivated Mycobacterium vaccae suspension (78), are able to induce antigen-specific regulatory T cells that help to dampen allergic responses. Comparatively, Enterococcus feacalis FK-23 can dampen allergic airway inflammation by decreasing T helper 17 responses (79). Preclinically, certain probiotic bacteria can have beneficial effects in models of asthma, typically via the enhancement of regulatory pathways. However, further studies are needed to address whether the beneficial effects seen in mice also apply to human disease. To date, there are no reports on the impact of probiotic use in altering pulmonary responses during COPD and cystic fibrosis. However, a common feature of all chronic lung diseases is exacerbations due to frequent respiratory viral infections. It has been demonstrated in mice that intranasal administration of Lactobacillus casei Shirota (80, 81) or L. rhamnosus (82) GG can decrease viral titers and dampen the symptoms of influenza virus infection. Hence, beyond dampening disease-causing inflammation, probiotic treatment might have beneficial effects by fortifying mucosal immunity and promoting control of respiratory viral infections. However, whether this holds true in humans is unknown.

Changes in the composition of the intestinal and airway microbiota are associated with chronic lung disorders and respiratory infections. The modifications observed in these two microbial compartments seem to overlap, at least partly, and factors including diet have recently been shown to not only shape the intestinal microbiota, but also impact upon the airway microbiota. Moreover, these diet-induced changes in the intestinal microbiota and metabolome were found to be beneficial within the context of asthma (28). Clearly, there is an important cross-talk between the two compartments. So far, mechanisms through which the lung could influence the gut environment are unclear (Figure 1). However, in recent years, it has become more evident that the intestine can play a critical role in directing immune responses outside the local environment, including the lung. This may be achieved by the systemic dissemination of metabolites, as has been shown for SCFAs. These metabolites are produced in the colon, but can reach other organs via the bloodstream, where they can exert their anti-inflammatory properties. Another possibility would be direct seeding of bacteria from the intestinal microbiota into the airways. These bacteria could then act on local immune cells to shape their responses (Figure 1). A basic understanding of the gut–lung axis during respiratory disease has been established in recent years, and further mechanistic insight into the pathways and mediators requires investigation. Importantly, however, its existence opens up new possibilities for therapeutic approaches to respiratory diseases, which extend beyond the immediate pulmonary microenvironment.

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Correspondence and requests for reprints should be addressed to Benjamin J. Marsland, Ph.D., Service de Pneumologie, CLE D02-206, Chemin des Boveresses 155–CH-1066 Epalinges, Switzerland. E-mail:

Author disclosures are available with the text of this article at www.atsjournals.org.

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Annals of the American Thoracic Society
12
Supplement 2

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