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Review
. 2023 Apr;21(4):222-235.
doi: 10.1038/s41579-022-00821-x. Epub 2022 Nov 16.

The dynamic lung microbiome in health and disease

Affiliations
Review

The dynamic lung microbiome in health and disease

Jake G Natalini et al. Nat Rev Microbiol. 2023 Apr.

Abstract

New methods and technologies within the field of lung biology are beginning to shed new light into the microbial world of the respiratory tract. Long considered to be a sterile environment, it is now clear that the human lungs are frequently exposed to live microbes and their by-products. The nature of the lung microbiome is quite distinct from other microbial communities inhabiting our bodies such as those in the gut. Notably, the microbiome of the lung exhibits a low biomass and is dominated by dynamic fluxes of microbial immigration and clearance, resulting in a bacterial burden and microbiome composition that is fluid in nature rather than fixed. As our understanding of the microbial ecology of the lung improves, it is becoming increasingly apparent that certain disease states can disrupt the microbial-host interface and ultimately affect disease pathogenesis. In this Review, we provide an overview of lower airway microbial dynamics in health and disease and discuss future work that is required to uncover novel therapeutic targets to improve lung health.

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Conflict of interest statement

All authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Normal microbiota of the respiratory and proximal gastrointestinal tracts.
The upper respiratory tract, comprised of the nasal cavity, paranasal sinuses, nasopharynx, oropharynx and the supraglottic portion of the larynx, exhibits a relatively high biomass with topographically distinct microbiota within each section. By contrast, the lower respiratory tract, comprised of the infraglottic portion of the larynx, trachea and lungs, exhibits a relatively low biomass consisting mostly of oral commensals. Several factors can contribute to dysbiotic changes along the respiratory tract, as shown in red boxes. Aspiration of oropharyngeal or gastro-oesophageal contents is the predominant means by which bacteria reach the lower airways (arrows). Three major lung clearance mechanisms are coughing, mucociliary transport and the innate immune system.
Fig. 2
Fig. 2. Lung microbial dynamics in eubiosis and dysbiosis.
a, A series of dynamic events promote eubiosis in the lower airways. Aspiration of a microorganism triggers the activation of leukocytes that orchestrate bacterial elimination by macrophage and neutrophil activity. After a transient upregulation of adaptive immunity, the immune tone returns to baseline with a low level of detectable residual microbial DNA. b, Steps commonly found in early dysbiotic events. Recurrent aspirations lead to changes in the lower airway microbial environment that can slowly become irreversible. c, Increased mucus production facilitates persistent colonization and increased bacterial burden and is associated with acute and chronic lower airway disease. Microbial immunomodulatory products, such as short-chain fatty acids (SCFAs), and host immune responses, such as a T helper 1 (TH1)/TH2 imbalance, an aggravated TH17 response and pro-inflammatory cytokines, can perpetuate neutrophilic inflammation, increased regulatory T (Treg) cell response and impaired immune surveillance. These changes can ultimately promote increased bacterial burden.
Fig. 3
Fig. 3. Disease-specific dysbiotic signals.
Different forms of dysbiosis coexist with different immune endotypes and pathological phenotypes in various disease states. a, In chronic obstructive pulmonary disease (COPD), progression to advanced stages, characterized by decrease in forced expiratory volume in one second (FEV1) and higher Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, is hallmarked by the presence of potentially pathogenic microbes, neutrophilia, and increased inflammatory cytokines and chemokines. Newer investigations are identifying early dysbiotic events involving some oral commensals and bacterial metabolites that might precede the development of advanced-stage COPD. b, Increased bacterial burden has been shown to be associated with a poorer prognosis in patients with idiopathic pulmonary fibrosis (IPF). In animal studies, germ-free mice had a survival benefit after the induction of bleomycin-induced pulmonary fibrosis as compared to conventional mice with normal bacterial burden. c, In acute respiratory distress syndrome (ARDS), there is a relationship between gut-associated bacteria and mixed oral commensals with alveolar filling, increased mucus or cellular debris, and immune activation. d, Mixed oral commensals can play a role in the progression of lung cancer by perpetuating a T helper 17 (TH17) endotype, increased PI3K signalling and immune-checkpoint inhibition. These events, in conjunction with the more direct carcinogenesis precursors (such as DNA mutations and cell apoptosis, which further contribute to a pro-inflammatory tumour microenvironment), can have serious effects on the prognosis of lung cancer. It is likely that metabolites regulated by microbial metabolism play a significant role in cancer pathogenesis, which deserves further investigation. ROS, reactive oxygen species.
Fig. 4
Fig. 4. Dysbiotic events rendering increased host susceptibility to pathogens.
a, In cases of acquisition of a dominant pathogen, dysbiotic changes occurring prior to pathogen seeding may promote host susceptibility. b, In cases of non-dominant respiratory pathogens, changes in the lower airway microbiome might continue as a dysbiotic signature once pathogens are established in the lower airways causing lung injury. c, Alternatively, non-dominant pathogens could lead to a new dysbiotic signature that favours pathogen survival and contributes to lung injury.
Fig. 5
Fig. 5. Potential modifiers of lower airway microbiome course.
The dynamic nature of the lower airway microbiome is ever evolving. The overarching factors that control the balance of the microbiota are microbial immigration via inhalation and microaspiration and microbial elimination via cough, mucociliary transport and immune responses. We postulate that factors such as vaginal delivery, exercise and a healthy diet may contribute towards eubiosis in the lower airway, whereas obesity, an unhealthy diet and frequent antibiotic use could disrupt the lower airway microbiome in an unfavourable manner. Finally, we surmise that lower airway immune resilience and the diversity of the lung microbiome (a symbol of health in its own right) follows a quasi-sinusoidal path, peaking in adulthood.

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