The Human Respiratory Microbiome: Implications and Impact

Alicia B. Mitchell, BMedSci (Hons); Allan R. Glanville, MBBS, MD, FRACP

Disclosures

Semin Respir Crit Care Med. 2018;39(2):199-212. 

In This Article

The Gut–Lung Axis

The gut microbiome is modified in response to respiratory illness and chronic conditions, while the lung microbiome also appears to be influenced by the gut microbiome. This complex interplay between these two body systems and the microbiomes contained within them are dubbed the "gut-lung axis" and the vital cross-talk between their mucosal surfaces may have important implications for both health and disease. A study in children with CF demonstrates that the lung and gut microbiota likely develop simultaneously after birth. Furthermore, concordant fluctuations in bacterial species at both sites have been observed.[39] Dietary intake also appears to influence changes in the lung microbiome, in addition to the gut.[39,40] As mentioned earlier, the early development of the gut microbiota is important in the development of immune responses. The absence of a normal gut microbiota increases susceptibility to lung infection,[41] providing further evidence that the intestinal microbiome may influence the development of a dysbiotic state in the lung microbiome.

Dysbiosis in both the airway and intestinal microbiota has been observed in the presence of a range of respiratory diseases.[42–44] Additionally, the course of some respiratory diseases has been shown to be modified by shifts in intestinal microbiota, such as the development of asthma and other atopic conditions.[42,44] The hygiene hypothesis stipulates that reduction in environmental exposures, use of antibiotics, and dietary changes can lead to disruptions in the gut microbiota, which in turn lead to a decrease in immune tolerance. This resultant decrease in the Th1 immune response leads to a shift toward the propensity for allergic airway changes.[45] In a murine model, early exposure to antibiotics caused a reduction in microbial load and diversity, which was strongly associated with the later development of allergic airway inflammation in adults who were exposed to aeroallergens.[46] Conversely, the oral administration of probiotics including Lactobacillus species to children with CF led to a restoration of the intestinal microbiota to similar levels as healthy controls. The resultant microbiome composition has previously been shown to be associated with a reduction in the frequency of pulmonary exacerbations.[43]

Acute bacterial and viral infections cause changes in the underlying microbiota. Chronic bacterial colonization with known pathogens such as Pseudomonas aeruginosa and Haemophilus influenzae in CF has been associated with distinct lung microbiomes, dominated by Prevotella and Flavobacterium in the case of P. aeruginosa and Neisseria when H. influenzae is present.[47] Similarly, the microbiome may play a role in determining susceptibility to viral infection. The pneumococcal vaccine and depletion of Streptococcus pneumoniae in an in vitro model have been associated with a 31% reduction in viral respiratory tract infections.[48] Molyneaux et al showed that rhinovirus infection in healthy subjects has little effect on the underlying lung microbiota when measured in induced sputum samples. They did find, however, that in patients with COPD, rhinovirus infection led to an outgrowth of certain pathogenic bacteria, mainly those in the Proteobacteria phylum including H. influenzae.[22] In a murine model, infection with influenza virus was shown to lead to changes in the gut microbiome due to intestinal injury mediated by Th-17 cell-dependent inflammation.[49]

Murine studies have shown that bacterial activation of Nod-like receptors in the gut led to increased reactive oxygen species in alveolar macrophages[50] which are associated with effective bacterial clearance mechanisms in the lung. Peptidoglycan (a bacterial cell wall component) can translocate from the gut into the blood stream and the bone marrow to cause systemic and organ-specific effects after systematic presentation to the host immune system via Nod1 receptors. This can lead to increased killing of S. pneumoniae and Staphylococcus aureus.[51] Studies have shown that lipopolysaccharides (LPS), another bacterial product, can reduce viral infection rates suggesting that development of the gut microbiota may play an important role in susceptibility to respiratory viral infections. In vitro prestimulation of human macrophages with LPS led to an 80% reduction in respiratory syncytial virus (RSV) and influenza infections,[52] demonstrating the complex interplay between bacterial and viral species.

Interorgan microbiome interactions are not only limited to the gut. Early establishment of a commensal nasopharyngeal microbiota appears to be protective of RSV-induced airway hyper-responsiveness. Mice were infected with RSV and subsequently treated with antibiotics which depleted Streptococcus viridans in the nasal passage associated with a strong immune response to the RSV infection with increased numbers of inflammatory lymphocytes, reduced Tregs, and transforming growth factor-β, and increased airway hyper-responsiveness.[53] The interactions between the resident microbiomes within different organ systems are yet to be fully characterized; however, for chronic respiratory disease sufferers, this area presents many possible future treatment avenues.

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