The Human Respiratory Microbiome: Current Understandings and Future Directions

Abstract

Microorganisms colonize the human body. The lungs and respiratory tract, previously believed to be sterile, harbor diverse microbial communities and the genomes of bacteria (bacteriome), viruses (virome), and fungi (mycobiome). Recent advances in amplicon and shotgun metagenomic sequencing technologies and data-analyzing methods have greatly aided the identification and characterization of microbial populations from airways. The respiratory microbiome has been shown to play roles in human health and disease and is an area of rapidly emerging interest in pulmonary medicine. In this review, we provide updated information in the field by focusing on four lung conditions, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis. We evaluate gut, oral, and upper airway microbiomes and how they contribute to lower airway flora. The discussion is followed by a systematic review of the lower airway microbiome in health and disease. We conclude with promising research avenues and implications for evolving therapeutics.

Keywords: microbial metabolites; microbiome; mucus; respiratory diseases; therapeutics.

Figure 1.

Human microbiomes in health and four chronic respiratory diseases. (A) T-helper cell type 2 (Th2)-low and Th2-high inflammation characterizes two subtypes of asthma, the Th2-high subtype being more sensitive to viral infections than Th2-low. Excessive mucus and increased inflammation are the two prominent features of asthma. (B) Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that is characterized by irreversible airflow obstruction and damaged alveoli. The Global Initiative for Chronic Obstructive Lung Disease spirometric staging system classifies COPD into early and advanced stages. Early COPD exhibits damaged alveolar membranes, and advanced COPD demonstrates significantly enlarged alveoli. (C) Cystic fibrosis (CF) is a genetic disease caused by four different CFTR (CF transmembrane conductance regulator) gene mutation types. Transmissible infectious microbes can be detected in patients with CF. CF bronchioles are dilated and coated with occlusive mucus. (D) IPF is of unknown etiology and pathogenesis and features damaged bronchioles and a reduction in terminal bronchioles. Microbial infection may drive the alveolar inflammation and fibrosis. (E) The anatomy of healthy human respiratory and digestive systems. Airway microbiomes, especially the lower airway microbiome, are like a desert, with fewer microbes than the gastrointestinal (GI) microbiome (lower GI; like a rainforest with diverse and abundant microbes). The gut–lung axis connects these two microbiomes. The oralome and upper airway microbiome interact with the lower airway, which form the oral–lung axis. Healthy lungs have normal bronchioles and alveoli. IPF = idiopathic pulmonary fibrosis.

Figure 2.

Four research directions, perspectives, and open questions in the respiratory microbiome. (A) Tai Chi diagram’s transparent background comes in yin (black) and yang (white), which indicates things are connected and affect one another. Four boxes on a second transparent background have different contents to better match the future needs of the four research areas. More specifically, (A) molecular chemical structures, (B) the anatomy of a human body, (C) mucosa-associated lymphoid tissue network, and (D) lung-associated pathogens. Open questions for each of the future directions are marked in red. (A) Tryptophan catabolites and short-chain fatty acids (SCFAs) are the two major microbiota-derived small molecule metabolites. Tryptophan catabolites, such as indole and tryptamine, are functioning as signals and antimicrobial agents; kynurenine, on the other hand, is associated with the increased risk of pulmonary hypertension and lung cancer. Acetate, propionate, and butyrate are among the three members of SCFAs, and multiple beneficial effects are associated with these metabolites. Other constituents of microbiota-derived small molecule metabolites and related mechanisms are expected. (B) The gut–lung and oral–lung axis are bidirectional at each level, connecting the lungs with the gut and the oral cavity, respectively. Gut plays a more important role in the gut–lung axis (with more weights). GI contains the largest microbiome in the human body; dysbiosis is associated with many GI-related disorders; and associated gastroesophageal reflux (GER) is a common digestive disorder. Several interventions, such as maintaining a healthy diet, fecal microbiota transplants, and probiotics and/or antibiotics can help to treat both gut and lung diseases. The oral and upper airway microbiomes are considered as a whole, which contains the second largest microbial community after the gut. The oral microbes tend to form structured multispecies communities, known as biofilms, and the focal infection theory implies that a primary localized infection in the oral cavity can cause secondary chronic diseases elsewhere in the body. Thus, practicing good oral hygiene and treating existing dental infections are critical for a healthy lung. GER substances from gut, upper airway microbes based on the adapted island models, and oral microbes based on the neutral model can better explain the sources of the lung microbiome. Lung microbes can migrate to the upper airway and gut by mucosal dispersion; cough, breath, and other mechanisms are also involved in the microbial communications between the lung and the oral and upper airway. The field of the gut–oral–lung axis appears significant but is relatively unexplored. (C) The MALT network consists of both innate and adaptive immunities, which are connected by two puzzles to indicate the interactions between them. Macrophages, lymphoid, NK, and dendritic cells form the mucosal innate immunity. Th1/Th2/Th17, Treg, CD4⁺, and CD8⁺ T cells are among the components of adaptive immunity. Both innate and adaptive immune cells form novel response networks. The four most promising microbial signatures for each respiratory disease are listed in a table on the right. (D) The respiratory bacteriome impacts the pathogenesis of chronic respiratory diseases (CRDs), and the microbial metabolites influence the host. The mycobiome has been implicated in impacting the clinical outcome of CRDs. The virome plays a role in asthma exacerbations, and the coronavirus disease (COVID-19) pandemic emphasizes the need to accelerate research on viral infections and lung disease. The respiratory bacteriome, mycobiome, and virome form the respiratory microbiome. Future studies in three different directions are listed in the right. B. cenocepacia = Burkholderia cenocepacia; B. multivorans = Burkholderia multivorans; EBV = Epstein-Barr virus; HCV = Hepatitis C virus; H. influenzae = Haemophilus influenzae; MALT = mucosa-associated lymphoid tissue; M. catarrhalis = Moraxella catarrhalis; NK = natural killer; P. aeruginosa = Pseudomonas aeruginosa; S. aureus = Staphylococcus aureus; S. pneumoniae = Streptococcus pneumoniae; Treg = T-regulatory.