This dynamic relationship between an increased abundance of pathogens in the respiratory tract and the progression of airway damage during COPD has also been described by a phenomenon widely known as the “vicious circle hypothesis” [76]. While this hypothesis primarily refers to pathogens, it is important to consider that changes in the environmental conditions within the lungs and respiratory tract will have a wider effect on the microbiota, and to consider how this might modify the vicious circle hypothesis. Factors that contribute to this sustained cycle of damage include the release of bacterial metabolites and virulence factors as well as increased expression of PAMPs, thus leading to a “vicious cycle” of pro-inflammatory response mechanisms by AMs and a decline in lung function [78, 80]. As discussed previously, the expression of PAMPs is not exclusive to pathogens or pathobionts and these are commonly possessed by non-pathogenic, commensal members of the microbiota. It is difficult to distinguish whether the increased inflammation and host defence mechanisms or altered microbiome are causes or consequences of each other, because both factors can be described as a driving force for one another.

Commensal bacteria are essential for homeostasis throughout the human body with regards to maintaining metabolic conditions. Macrophages can discriminate between “self” and “non-self” signalling molecules; however, this idea becomes more complex as we attempt to understand the lack of immune response to commensal bacteria, which identify as non-self. Because both pathogens and commensals can share the same signalling molecules and antigen, it raises the question as to whether the microbiome plays a role in this differentiation. It is important to note that pathogenicity is not always a trait possessed by a microbial organism, rather changes in the environmental conditions as well as host–microbe and microbe–microbe interactions can lead to pathogenicity. This has been studied extensively in the gut, where commensals such as Helicobacter pylori, which are part of the normal flora of an individual, can also cause gastritis [11]. The ability of bacterial organisms to undergo phase variation in response to the slightest changes in host physiological conditions makes it difficult to distinguish between what may be described as a pathogen or a member of the microbiome (figure 3a) [81].

The presence of S. aureus, commonly found to reside in the URT, has been found to have a protective effect against a lethal inflammatory response in the lungs following challenge with influenza virus, compared to specific pathogen-free mice [82]. According to this study, S. aureus mediates the recruitment of CCR2+CD11b+ blood monocytes into the alveoli, which then differentiate into macrophages that exhibit an anti-inflammatory phenotype. The release of anti-inflammatory cytokines and inhibitory ligands can prevent lethal inflammation caused by influenza infection. This priming effect demonstrated by S. aureus shows one way in which the respiratory microbiome can aid the host's immune response in preventing infection of the airways and the subsequent progression of disease.

Subtle variations in the genotype and phenotype of pathogenic bacterial strains between individuals may also be a contributory factor in defective phagocytosis by lung macrophages. In S. pneumoniae, some multi-locus sequence types (STs) have been associated with disease more than others, although this is not specific to COPD [83]. It has been found that strains of the same ST and capsule serotype exhibit important genetic and phenotypic differences [84]. Ackland et al. [85] found that MDM response was altered with different clinical strains of NTHi in healthy individuals, in whom the ST14 strain induced an increase in the expression of IL-10 and NF-κB compared to ST201. Similarly, it has been found that clinical isolates of NTHi from COPD patients can adapt their genome to enhance their persistence in the respiratory tract during chronic inflammation [86]. Some of the genetic adaptations observed had direct links to immune escape and antigenic variation, such as an increase in single sequence repeats of sialyltransferase, which aid molecular mimicry to evade the host immune response. It is possible that these differences in clinical isolates of some pathogenic strains may be a driver behind defective phagocytosis by COPD macrophages. However, there is a lack of research into the interface between these individual-level strain variations and, specifically, how these contribute to defective phagocytosis by macrophages during COPD.

Do macrophages control clearance, or does pathogen evasion drive this interaction? Are pathobionts and the microbiota involved and how do they influence this process? Can these interactions also be targeted therapeutically? Macrophages may be a useful therapeutic target in COPD. Manipulation of phagocytosis, phagocytic receptors and the release of signalling molecules or changing the phenotype of macrophages may improve their function.

A common treatment for COPD is inhaled corticosteroids (ICS) in combination with bronchodilators [87]. ICS reduce exacerbations and improve lung function by suppressing airway inflammation through the activation of anti-inflammatory genes as well as the inhibition of inflammatory cells, such as macrophages [88]. The use of ICS also influences changes in the microbiome through both the promotion and the inhibition of intracellular persistence of P. aeruginosa and H. influenzae, respectively [89, 90]. Leitao Filho et al. [91] have found that the use of combined salmeterol and fluticasone in patients with stable COPD decreased abundance of Haemophilus. Other studies have reported a decrease in the ratio of Proteobacteria:Firmicutes following the use of ICS [87], although Belchamber et al. [92] reported no changes in macrophage phagocytosis after budesonide and fluticasone treatment. Overall, the effect of ICS on both macrophage immunology as well as microbiome composition appears to vary depending on subject cohorts, sampling methods and study design (figure 3b) [93].

Macrophages have been targeted using the antibiotic azithromycin, which inhibits bacterial protein synthesis. While an in vitro study found that azithromycin did not alter phagocytosis of H. influenzae in MDMs [29], some in vivo studies have shown that administration of low-dose azithromycin significantly improves bacterial phagocytosis by both AMs and MDMs in COPD patients [94, 95]. Although these changes were not directly attributed to changes in receptor expression, previous studies have shown that azithromycin increases levels of the mannose receptor, which is involved in bacterial phagocytosis [94]. This suggests that the pro-phagocytic effects of azithromycin could be a potential therapy for COPD patients to improve clearance by macrophages. Further research is needed to investigate the biological basis of these effects, because the work made use of heat­-killed Escherichia coli and polystyrene beads rather than pathogens, pathobionts or other members of the LRT microbiota (figure 3c).

Furthermore, Vecchiarelli et al. [96] showed that the antioxidant N-acetylcysteine improves phagocytosis by monocytes of Candida albicans in COPD; however, its oral administration did not improve AM antifungal activity. Sulforaphane, an activator of nuclear erythroid-related factor 2, has also been shown to restore H. influenzae recognition and uptake by COPD macrophages [97], by inducing greater expression of macrophage receptor with a collagenous structure (MARCO) receptors [98]. Despite these promising targets, another study showed no improvement in AM or MDM phagocytosis after exposure to p38, mitogen-activated protein kinase 1, Pi3kinase or rhodopsin kinase inhibitors, suggesting that these pathways are not key in mediating this defect [99]. Targeting other aspects of macrophage function, including mitochondrial dysfunction, has the potential to restore AM phagocytic function and requires further study [32].

Antibiotics are often used to aid the clearance of airway infection during exacerbation episodes. The effects of antibiotic use on the composition of the microbiome should also be acknowledged. While azithromycin has been proven to be effective in the clearance of exacerbation-associated pathogens such as S. pneumoniae, H. influenzae and M. catarrhalis, it has broad-spectrum activity against many gram-positive and gram-negative species [100]. Therefore, its administration is likely to cause inevitable depletion of the respiratory microbiome, as observed in patients with asthma [101], where although there is a reduction in the abundance of pathogens associated with asthma, its use is also associated with an overall decrease in bacterial richness. The specific effects of macrolide therapy on microbial colonisation of the airways during COPD are yet to be explored (figure 3d); however, given that the pathogenic genera for these two diseases overlap, it is likely that a similar effect will be observed.

Vaccinations are another mode of preventing infections during COPD, whereby the pneumococcal vaccine has been widely used to stimulate a humoral response against the S. pneumoniae capsular polysaccharides [102]. Efforts are also being put towards the development of vaccination therapies against other respiratory pathogens such as NTHi, and preliminary trials have found an overall decrease in rates of exacerbation [103]. Other studies have investigated the NTHi outer protein D as a potential candidate for vaccination against NTHi strains [104]. In the context of host–microbiome interactions, the effects of both bacterial and viral vaccinations on the function and composition of the respiratory microbiome are important to consider and require further study.

Furthermore, there is a need for more longitudinal analyses of macrophage phagocytosis, given that Singh et al. [31] found that there were no changes in phagocytic ability of COPD macrophages over the duration of a year. Longitudinal studies would also help improve the understanding of patterns of phagocytosis during health and disease and account for variability of sampling across studies and experimental models.

Targeting the microbiome as a therapeutic approach to improve the survival and quality of life of COPD patients has also been investigated. A commensal species, Rothia mucilaginosa, that predominantly resides in the oral cavity has been detected in the LRT of patients with chronic respiratory diseases and is associated with inhibition of pathogen-induced inflammation [105]. Both in vivo and in vitro studies have shown that the presence of R. mucilaginosa in sputum samples from patients with bronchiectasis and COPD is linked to reduced levels of MMPs as well as inflammatory cytokines IL-8 and IL-1B. Similarly, some commensal microbes can inhibit pathogenic colonisation, such as the ability of Staphylococcus epidermidis to prevent biofilm formation of S. aureus through the secretion of a serine protease [106]. Budden et al. [107] have more recently discovered the benefits of faecal microbiome transplantation in alleviating hallmark symptoms of COPD, including a reduction in macrophages in bronchoalveolar lavage fluid of mice following cigarette smoke-induced inflammation.

Additionally, Yan et al. [108] reported that intranasal treatment of mice with Lactobacillus salivaris and L. oris increased indole-3-acetic acid levels in the airways, which in turn increased IL-22 production by alveolar and interstitial macrophages in mice. IL-22 is known to have protective effects in the lungs, including defence against bacterial and viral infections [109]. This indicates the potential of manipulating the microbial and metabolite composition of the airways to reduce infection-induced inflammation during COPD (figure 3a). It is important that these studies are validated in alternative models, because the majority of these studies have been performed in murine models, which are known to be considerably different to human lungs [110]. Overall, further understanding of macrophage–bacteria interactions in health and COPD may lead to the identification of novel therapeutic agents that could improve macrophage clearance of bacteria, and thus reduce exacerbations of this disease (figure 3b).