The microbiota of the respiratory tract: gatekeeper to respiratory health

Abstract

The respiratory tract is a complex organ system that is responsible for the exchange of oxygen and carbon dioxide. The human respiratory tract spans from the nostrils to the lung alveoli and is inhabited by niche-specific communities of bacteria. The microbiota of the respiratory tract probably acts as a gatekeeper that provides resistance to colonization by respiratory pathogens. The respiratory microbiota might also be involved in the maturation and maintenance of homeostasis of respiratory physiology and immunity. The ecological and environmental factors that direct the development of microbial communities in the respiratory tract and how these communities affect respiratory health are the focus of current research. Concurrently, the functions of the microbiome of the upper and lower respiratory tract in the physiology of the human host are being studied in detail. In this Review, we will discuss the epidemiological, biological and functional evidence that support the physiological role of the respiratory microbiota in the maintenance of human health.

Figure 1. Physiological and microbial gradients along the respiratory tract.

Physiological and microbial gradients exist along the nasal cavity, nasopharynx, oropharynx, trachea and the lungs. The pH gradually increases along the respiratory tract^,,,, whereas most of the increases in relative humidity (RH) and temperature occur in the nasal cavity^,,. Furthermore, the partial pressures of oxygen (pO₂) and carbon dioxide (pCO₂) have opposing gradients that are determined by environmental air conditions and gas exchange at the surface of the lungs^,,. Inhalation results in the deposition of particles from the environment into the respiratory tract; inhaled particles that are more than 10 μm in diameter are deposited in the upper respiratory tract (URT), whereas particles less than 1 μm in diameter can reach the lungs. These particles include bacteria-containing and virus-containing particles, which are typically larger than 0.4 μm in diameter. These physiological parameters determine the niche-specific selective growth conditions that ultimately shape the microbial communities along the respiratory tract. The unit by which bacterial density is measured varies per niche; the density in the environment is depicted as bacteria per cm³ (indoor) air, density measures in the nasal cavity and nasopharynx are shown as an estimated number of bacteria per nasal swab, and the densities in the oropharynx and the lungs represent the estimated number of bacteria per ml of oral wash^, or bronchoalveolar lavage (BAL)^,,, respectively. PowerPoint slide

Figure 2. Host and environmental factors that influence the respiratory microbiota.

During early life, microbial communities in the respiratory tract are highly dynamic and are driven by multiple factors, including mode of birth, feeding type, crowding conditions and antibiotic treatment. Together, these host and environmental factors can change the composition of the microbiota towards a stable community at equilibrium that is resistant to pathogen overgrowth, or, conversely, an unstable community develops that is predisposed to infection and inflammation. PowerPoint slide

Figure 3. Host–microbiota interactions in the respiratory tract.

Host–microbiota interactions in the respiratory tract occur mostly at the mucosal surface. Resident microorganisms prime immune cells either locally or systemically; these include epithelial cells, neutrophils and dendritic cells, which all contribute to the clearance of pathogens. Moreover, microbial signalling is necessary for the recruitment and activation of regulatory cells, such as anti-inflammatory alveolar macrophages (AMs) and regulatory T cells (T_reg cells). Locally, the host will respond to microbial colonization through the release of antimicrobial peptides (AMPs) and secretory immunoglobulin A (sIgA). Sensing of the microbiota involves microfold (M) cells that activate tolerogenic dendritic cells. In addition, alveolar dendritic cells can directly sample luminal microorganisms. Together, these pathways lead to the regulation of inflammation and the induction of tolerance, which, in turn, shape resident bacterial communities. It is also plausible that early bacterial colonization is key to long-term immune regulation, which is illustrated by the microbiota-induced decrease in hypermethylation of the CXC-motif chemokine ligand 16 (Cxcl16) gene, which prevents the accumulation of inducible natural killer T cells (iNKT cells), and by the programmed death ligand 1 (PDL1)-mediated induction of tolerogenic dendritic cells (Box 3). This tolerant milieu, in turn, contributes to the normal development and maintenance of resident bacterial communities, which are also influenced by host and environmental factors (Fig. 1). AEC, alveolar epithelial cell; LPS: lipopolysaccharide; PRR: pattern recognition receptor; URT, upper respiratory tract. PowerPoint slide