Fig 1.
Innate and adaptive immune response to NTM infection in the lung.
Alveolar macrophages are integral in the initiation of an immune response against inhaled NTM. This occurs in part through phagocytosis of NTM as well as the release of chemokines and cytokines by alveolar macrophages that recruit additional macrophages and other phagocytes to the site of infection. Macrophage activation by NTM is facilitated by pattern recognition receptors (PRRs), of which Toll-like receptor 2 (TLR2) plays a central role [28–31]. Macrophage recognition of NTM initiates phagosome maturation, lysosome acidification and antimicrobial defence mechanisms (e.g., generation of reactive oxygen species, expression of degradative enzymes), facilitating intracellular killing of mycobacteria [32]. Dendritic cells loaded with mycobacterial antigen that migrate to draining lymph nodes present mycobacterial antigens to naïve T cells, thereby facilitating T cell differentiation [33]. The associated cytokine milieu, such as via interleukin (IL)-12 release, shapes T cell differentiation into T helper 1 (Th1) cells. Infected macrophages also present mycobacterial antigens to Th1 cells. Th1 cells, alongside other innate and adaptive lymphocytes, coordinate mycobacteria-restricting immune responses, including interferon (IFN)-γ, tumour necrosing factor (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF)-mediated macrophage activation [34–37]. Fig 1 created with Biorender.com.
Fig 2.
Model of host susceptibility factors driving lung and gut dysbiosis in NTM-PD.
The model is divided into two key categories of susceptible individuals: the ‘Lady Windermere’ phenotype and chronic lung disease. These categories are not mutually exclusive, and some individuals may exhibit features of both (or in fact neither). Common to both lies airway damage, impaired mucociliary clearance, and mucus stasis, which may promote niche colonisation by NTM or other pathogens, leading to recurrent infections and often requiring antibiotic use. This, in turn, may cause further dysbiosis in the lung and perturb the gut microbiota (see Fig 3). Fig 2 created with Biorender.com.
Fig 3.
A working model of the gut-lung axis (GLA) in nontuberculous mycobacterial pulmonary disease (NTM-PD).
The gut and lung have specialised microbiotas that are interconnected via the bloodstream and lymphatic system, via the GLA [65,68]. We propose gut microbiota dysbiosis as a potential initiating factor in the cycle of NTM-PD; however, whether it represents a cause or consequence of disease remains unclear. Dysbiosis contributes to changes in migrating immune cells, microbial immunomodulatory components and immune mediators, together representing a level of systemic immune dysregulation that affects the lung microbiota via the GLA [110–112]. Microaspiration and reflux are also implicated in the GLA and respiratory disease pathophysiology with a degree of direct seeding of gut microbes into the airways [99,104]. Lung microbiota dysbiosis may then cause lung injury and inflammation, contributing to poor clearance of NTM infection, allowing establishment of disease. Antibiotic treatment for NTM-PD then causes further dysbiosis of both the gut and lung microbiotas [61,113,114], so the cycle continues. Fig 3 created with Biorender.com.
Table 1.
Summary table of culture-independent studies characterising the impact of NTM infection or NTM-PD on the lung microbiota.
Table 2.
Summary table of studies characterising the faecal microbiota in NTM-PD.