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 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.

1 . Roussos A, Koursarakos P, Patsopoulos D, Gerogianni I, Philippou N. Increased prevalence of irritable bowel syndrome in patients with bronchial asthma. Respir Med 2003;97:7579.
2 . Baral V, Connett G. Acute intestinal obstruction as a presentation of cystic fibrosis in infancy. J Cyst Fibros 2008;7:277279.
3 . Keely S, Hansbro PM. Lung–gut cross talk: a potential mechanism for intestinal dysfunction in patients with COPD. Chest 2014;145:199200.
4 . Wang J, Li F, Wei H, Lian ZX, Sun R, Tian Z. Respiratory influenza virus infection induces intestinal immune injury via microbiota-mediated Th17 cell–dependent inflammation. J Exp Med 2014;211:23972410.
5 . Dilantika C, Sedyaningsih ER, Kasper MR, Agtini M, Listiyaningsih E, Uyeki TM, Burgess TH, Blair PJ, Putnam SD. Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness. BMC Infect Dis 2010;10:3.
6 . Abrahamsson TR, Jakobsson HE, Andersson AF, Björkstén B, Engstrand L, Jenmalm MC. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy 2014;44:842850.
7 . Bisgaard H, Li N, Bonnelykke K, Chawes BL, Skov T, Paludan-Müller G, Stokholm J, Smith B, Krogfelt KA. Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. J Allergy Clin Immunol 2011;128:646652.e641–e645.
8 . Bruzzese E, Callegari ML, Raia V, Viscovo S, Scotto R, Ferrari S, Morelli L, Buccigrossi V, Lo Vecchio A, Ruberto E, et al. Disrupted intestinal microbiota and intestinal inflammation in children with cystic fibrosis and its restoration with Lactobacillus GG: a randomised clinical trial. PLoS One 2014;9:e87796.
9 . Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol 2011;9:244253.
10 . Frank DN, Feazel LM, Bessesen MT, Price CS, Janoff EN, Pace NR. The human nasal microbiota and Staphylococcus aureus carriage. PLoS One 2010;5:e10598.
11 . Lazarevic V, Whiteson K, Huse S, Hernandez D, Farinelli L, Osterås M, Schrenzel J, François P. Metagenomic study of the oral microbiota by Illumina high-throughput sequencing. J Microbiol Methods 2009;79:266271.
12 . Kim TK, Thomas SM, Ho M, Sharma S, Reich CI, Frank JA, Yeater KM, Biggs DR, Nakamura N, Stumpf R, et al. Heterogeneity of vaginal microbial communities within individuals. J Clin Microbiol 2009;47:11811189.
13 . Maldonado-Contreras A, Goldfarb KC, Godoy-Vitorino F, Karaoz U, Contreras M, Blaser MJ, Brodie EL, Dominguez-Bello MG. Structure of the human gastric bacterial community in relation to Helicobacter pylori status. ISME J 2011;5:574579.
14 . Erb-Downward JR, Thompson DL, Han MK, Freeman CM, McCloskey L, Schmidt LA, Young VB, Toews GB, Curtis JL, Sundaram B, et al. Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS One 2011;6:e16384.
15 . Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, Davies J, Ervine A, Poulter L, Pachter L, et al. Disordered microbial communities in asthmatic airways. PLoS One 2010;5:e8578.
16 . Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science 2005;308:16351638.
17 . Cho I, Blaser MJ. The human microbiome: at the interface of health and disease. Nat Rev Genet 2012;13:260270.
18 . Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol 1977;31:107133.
19 . Robles Alonso V, Guarner F. Intestinal microbiota composition in adults. World Rev Nutr Diet 2013;107:1724.
20 . Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, et al. Enterotypes of the human gut microbiome. Nature 2011;473:174180.
21 . Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427434.
22 . Tilg H, Kaser A. Gut microbiome, obesity, and metabolic dysfunction. J Clin Invest 2011;121:21262132.
23 . Larsen N, Vogensen FK, van den Berg FW, Nielsen DS, Andreasen AS, Pedersen BK, Al-Soud WA, Sørensen SJ, Hansen LH, Jakobsen M. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS One 2010;5:e9085.
24 . Sze MA, Dimitriu PA, Hayashi S, Elliott WM, McDonough JE, Gosselink JV, Cooper J, Sin DD, Mohn WW, Hogg JC. The lung tissue microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185:10731080.
25 . Charlson ES, Bittinger K, Haas AR, Fitzgerald AS, Frank I, Yadav A, Bushman FD, Collman RG. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 2011;184:957963.
26 . Charlson ES, Diamond JM, Bittinger K, Fitzgerald AS, Yadav A, Haas AR, Bushman FD, Collman RG. Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant. Am J Respir Crit Care Med 2012;186:536545.
27 . Madan JC, Koestler DC, Stanton BA, Davidson L, Moulton LA, Housman ML, Moore JH, Guill MF, Morrison HG, Sogin ML, et al. Serial analysis of the gut and respiratory microbiome in cystic fibrosis in infancy: interaction between intestinal and respiratory tracts and impact of nutritional exposures. MBio 2012;3:110.
28 . Trompette A, Gollwitzer ES, Yadava K, Sichelstiel AK, Sprenger N, Ngom-Bru C, Blanchard C, Junt T, Nicod LP, Harris NL, et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med 2014;20:159166.
29 . Klepac-Ceraj V, Lemon KP, Martin TR, Allgaier M, Kembel SW, Knapp AA, Lory S, Brodie EL, Lynch SV, Bohannan BJ, et al. Relationship between cystic fibrosis respiratory tract bacterial communities and age, genotype, antibiotics and Pseudomonas aeruginosa. Environ Microbiol 2010;12:12931303.
30 . Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R, Grimwood K, Hiatt P, McCoy K, McNamara S, Ramsey B, et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999;28:321328.
31 . Morris A, Beck JM, Schloss PD, Campbell TB, Crothers K, Curtis JL, Flores SC, Fontenot AP, Ghedin E, Huang L, et al. Comparison of the respiratory microbiome in healthy nonsmokers and smokers. Am J Respir Crit Care Med 2013;187:10671075.
32 . Segal LN, Alekseyenko AV, Clemente JC, Kulkarni R, Wu B, Gao Z, Chen H, Berger KI, Goldring RM, Rom WN, et al. Enrichment of lung microbiome with supraglottic taxa is associated with increased pulmonary inflammation. Microbiome 2013;1:19.
33 . Huang YJ, Nelson CE, Brodie EL, Desantis TZ, Baek MS, Liu J, Woyke T, Allgaier M, Bristow J, Wiener-Kronish JP, et al. Airway microbiota and bronchial hyperresponsiveness in patients with suboptimally controlled asthma. J Allergy Clin Immunol 2011;127:372381.e371–e373.
34 . Pragman AA, Kim HB, Reilly CS, Wendt C, Isaacson RE. The lung microbiome in moderate and severe chronic obstructive pulmonary disease. PLoS One 2012;7:e47305.
35 . van der Gast CJ, Walker AW, Stressmann FA, Rogers GB, Scott P, Daniels TW, Carroll MP, Parkhill J, Bruce KD. Partitioning core and satellite taxa from within cystic fibrosis lung bacterial communities. ISME J 2011;5:780791.
36 . Zhao J, Schloss PD, Kalikin LM, Carmody LA, Foster BK, Petrosino JF, Cavalcoli JD, VanDevanter DR, Murray S, Li JZ, et al. Decade-long bacterial community dynamics in cystic fibrosis airways. Proc Natl Acad Sci USA 2012;109:58095814.
37 . Blainey PC, Milla CE, Cornfield DN, Quake SR. Quantitative analysis of the human airway microbial ecology reveals a pervasive signature for cystic fibrosis. Sci Transl Med 2012;4:153ra130.
38 . Kolak M, Karpati F, Monstein HJ, Jonasson J. Molecular typing of the bacterial flora in sputum of cystic fibrosis patients. Int J Med Microbiol 2003;293:309317.
39 . Russell SL, Gold MJ, Willing BP, Thorson L, McNagny KM, Finlay BB. Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes 2013;4:158164.
40 . Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 2001;107:129134.
41 . Yi H, Yong D, Lee K, Cho YJ, Chun J. Profiling bacterial community in upper respiratory tracts. BMC Infect Dis 2014;14:583.
42 . Rogers GB, van der Gast CJ, Serisier DJ. Predominant pathogen competition and core microbiota divergence in chronic airway infection. ISME J 2015;9:217225.
43 . Molyneaux PL, Mallia P, Cox MJ, Footitt J, Willis-Owen SA, Homola D, Trujillo-Torralbo MB, Elkin S, Kon OM, Cookson WO, et al. Outgrowth of the bacterial airway microbiome after rhinovirus exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;188:12241231.
44 . Abt MC, Osborne LC, Monticelli LA, Doering TA, Alenghat T, Sonnenberg GF, Paley MA, Antenus M, Williams KL, Erikson J, et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 2012;37:158170.
45 . Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, Iwasaki A. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc Natl Acad Sci USA 2011;108:53545359.
46 . Tsay TB, Yang MC, Chen PH, Hsu CM, Chen LW. Gut flora enhance bacterial clearance in lung through Toll-like receptors 4. J Biomed Sci 2011;18:68.
47 . Chen LW, Chen PH, Hsu CM. Commensal microflora contribute to host defense against Escherichia coli pneumonia through Toll-like receptors. Shock 2011;36:6775.
48 . Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C, Jernberg C, Björkstén B, Engstrand L, Andersson AF. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by Caesarean section. Gut 2014;63:559566.
49 . Thavagnanam S, Fleming J, Bromley A, Shields MD, Cardwell CR. A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy 2008;38:629633.
50 . Kristensen K, Fisker N, Haerskjold A, Ravn H, Simões EA, Stensballe L. Caesarean section and hospitalization for respiratory syncytial virus infection: a population based study. Pediatr Infect Dis J 2015;34:145148.
51 . Melendi GA, Coviello S, Bhat N, Zea-Hernandez J, Ferolla FM, Polack FP. Breastfeeding is associated with the production of type I interferon in infants infected with influenza virus. Acta Paediatr 2010;99:15171521.
52 . Nishimura T, Suzue J, Kaji H. Breastfeeding reduces the severity of respiratory syncytial virus infection among young infants: a multi-center prospective study. Pediatr Int 2009;51:812816.
53 . Kull I, Almqvist C, Lilja G, Pershagen G, Wickman M. Breast-feeding reduces the risk of asthma during the first 4 years of life. J Allergy Clin Immunol 2004;114:755760.
54 . Guaraldi F, Salvatori G. Effect of breast and formula feeding on gut microbiota shaping in newborns. Front Cell Infect Microbiol 2012;2:94.
55 . Fanaro S, Chierici R, Guerrini P, Vigi V. Intestinal microflora in early infancy: composition and development. Acta Paediatr Suppl 2003;91:4855.
56 . Fouhy F, Guinane CM, Hussey S, Wall R, Ryan CA, Dempsey EM, Murphy B, Ross RP, Fitzgerald GF, Stanton C, et al. High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin. Antimicrob Agents Chemother 2012;56:58115820.
57 . Ege MJ, Mayer M, Normand AC, Genuneit J, Cookson WO, Braun-Fahrländer C, Heederik D, Piarroux R, von Mutius E; GABRIELA Transregio 22 Study Group. Exposure to environmental microorganisms and childhood asthma. N Engl J Med 2011;364:701709.
58 . Riedler J, Braun-Fahrländer C, Eder W, Schreuer M, Waser M, Maisch S, Carr D, Schierl R, Nowak D, von Mutius E; ALEX Study Team. Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 2001;358:11291133.
59 . Peters M, Kauth M, Schwarze J, Körner-Rettberg C, Riedler J, Nowak D, Braun-Fahrländer C, von Mutius E, Bufe A, Holst O. Inhalation of stable dust extract prevents allergen induced airway inflammation and hyperresponsiveness. Thorax 2006;61:134139.
60 . Maslowski KM, Vieira AT, Ng A, Kranich J, Sierro F, Yu D, Schilter HC, Rolph MS, Mackay F, Artis D, et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 2009;461:12821286.
61 . Saemann MD, Böhmig GA, Osterreicher CH, Burtscher H, Parolini O, Diakos C, Stöckl J, Hörl WH, Zlabinger GJ. Anti-inflammatory effects of sodium butyrate on human monocytes: potent inhibition of IL-12 and up-regulation of IL-10 production. FASEB J 2000;14:23802382.
62 . Tedelind S, Westberg F, Kjerrulf M, Vidal A. Anti-inflammatory properties of the short-chain fatty acids acetate and propionate: a study with relevance to inflammatory bowel disease. World J Gastroenterol 2007;13:28262832.
63 . Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013;341:569573.
64 . Cox MA, Jackson J, Stanton M, Rojas-Triana A, Bober L, Laverty M, Yang X, Zhu F, Liu J, Wang S, et al. Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E(2) and cytokines. World J Gastroenterol 2009;15:55495557.
65 . De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA 2010;107:1469114696.
66 . Myles IA, Fontecilla NM, Janelsins BM, Vithayathil PJ, Segre JA, Datta SK. Parental dietary fat intake alters offspring microbiome and immunity. J Immunol 2013;191:32003209.
67 . Loss G, Depner M, Ulfman LH, van Neerven RJ, Hose AJ, Genuneit J, Karvonen AM, Hyvärinen A, Kaulek V, Roduit C, et al. Consumption of unprocessed cow’s milk protects infants from common respiratory infections. J Allergy Clin Immunol 2015;135:5662.e52.
68 . Loss G, Apprich S, Waser M, Kneifel W, Genuneit J, Büchele G, Weber J, Sozanska B, Danielewicz H, Horak E, et al. The protective effect of farm milk consumption on childhood asthma and atopy: the GABRIELA study. J Allergy Clin Immunol 2011;128:766773.e764.
69 . Chen YS, Jan RL, Lin YL, Chen HH, Wang JY. Randomized placebo-controlled trial of Lactobacillus on asthmatic children with allergic rhinitis. Pediatr Pulmonol 2010;45:11111120.
70 . Feleszko W, Jaworska J, Rha RD, Steinhausen S, Avagyan A, Jaudszus A, Ahrens B, Groneberg DA, Wahn U, Hamelmann E. 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. Clin Exp Allergy 2007;37:498505.
71 . Forsythe P, Inman MD, Bienenstock J. Oral treatment with live Lactobacillus reuteri inhibits the allergic airway response in mice. Am J Respir Crit Care Med 2007;175:561569.
72 . Giovannini M, Agostoni C, Riva E, Salvini F, Ruscitto A, Zuccotti GV, Radaelli G; Felicita Study Group. A randomized prospective double blind controlled trial on effects of long-term consumption of fermented milk containing Lactobacillus casei in pre-school children with allergic asthma and/or rhinitis. Pediatr Res 2007;62:215220.
73 . Gutkowski P, et al. Effect of orally administered probiotic strains Lactobacillus and Bifidobacterium in children with atopic asthma. Centr Eur J Immunol 2010;35:233238.
74 . Rose MA, Stieglitz F, Köksal A, Schubert R, Schulze J, Zielen S. Efficacy of probiotic Lactobacillus GG on allergic sensitization and asthma in infants at risk. Clin Exp Allergy 2010;40:13981405.
75 . Sagar S, Morgan ME, Chen S, Vos AP, Garssen J, van Bergenhenegouwen J, Boon L, Georgiou NA, Kraneveld AD, Folkerts G. Bifidobacterium breve and Lactobacillus rhamnosus treatment is as effective as budesonide at reducing inflammation in a murine model for chronic asthma. Respir Res 2014;15:46.
76 . van de Pol MA, Lutter R, Smids BS, Weersink EJ, van der Zee JS. Synbiotics reduce allergen-induced T-helper 2 response and improve peak expiratory flow in allergic asthmatics. Allergy 2011;66:3947.
77 . Jang SO, Kim HJ, Kim YJ, Kang MJ, Kwon JW, Seo JH, Kim HY, Kim BJ, Yu J, Hong SJ. Asthma prevention by Lactobacillus rhamnosus in a mouse model is associated with CD4(+)CD25(+)Foxp3(+) T cells. Allergy Asthma Immunol Res 2012;4:150156.
78 . Zuany-Amorim C, Sawicka E, Manlius C, Le Moine A, Brunet LR, Kemeny DM, Bowen G, Rook G, Walker C. Suppression of airway eosinophilia by killed Mycobacterium vaccae–induced allergen-specific regulatory T-cells. Nat Med 2002;8:625629.
79 . Zhang B, An J, Shimada T, Liu S, Maeyama K. Oral administration of Enterococcus faecalis FK-23 suppresses Th17 cell development and attenuates allergic airway responses in mice. Int J Mol Med 2012;30:248254.
80 . Hori T, Kiyoshima J, Shida K, Yasui H. Effect of intranasal administration of Lactobacillus casei Shirota on influenza virus infection of upper respiratory tract in mice. Clin Diagn Lab Immunol 2001;8:593597.
81 . Yasui H, Kiyoshima J, Hori T. Reduction of influenza virus titer and protection against influenza virus infection in infant mice fed Lactobacillus casei Shirota. Clin Diagn Lab Immunol 2004;11:675679.
82 . Harata G, He F, Hiruta N, Kawase M, Kubota A, Hiramatsu M, Yausi H. Intranasal administration of Lactobacillus rhamnosus GG protects mice from H1N1 influenza virus infection by regulating respiratory immune responses. Lett Appl Microbiol 2010;50:597602.
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


No related items
Comments Post a Comment

New User Registration

Not Yet Registered?
Benefits of Registration Include:
 •  A Unique User Profile that will allow you to manage your current subscriptions (including online access)
 •  The ability to create favorites lists down to the article level
 •  The ability to customize email alerts to receive specific notifications about the topics you care most about and special offers
Annals of the American Thoracic Society
Supplement 2

Click to see any corrections or updates and to confirm this is the authentic version of record