The Infant Nose. Introducing the Respiratory Tract to the World

The nasopharynx is extraordinarily hospitable to bacteria. These upper airway microbes form an interface between the outside world and our lower respiratory tract, and as such, they have many implications for pulmonary biology and respiratory disease. Thanks to recent improvements in sequencing technologies, our appreciation of the upper airway bacteria is progressing rapidly. While in the womb, the airways are sterile and free of microbial exposures. With birth, however, these tissues are abruptly and ever-after exposed to a vast panoply of microbes, many of which thrive in the nasopharyngeal niche. The dynamics of nasopharyngeal colonization during these young ages was almost completely mysterious before a contribution in this issue of the Journal by Biesbroek and colleagues (pp. 1283–1292) (1). These investigators profiled nasopharyngeal samples serially collected from healthy children beginning at 1.5 months of age and continuing until 2 years of age. They used deep sequencing of 16S rRNA genes to characterize the microbial communities in these samples and machine learning algorithms to search for patterns within these communities and their changes over time. In some children, the microbiome observed at 1.5 months of age remained largely consistent throughout the examination period, suggesting early establishment of a stable microbiome structure that persisted during infancy and the toddler years. In contrast, other children had upper airway microbiomes that were less stable, changing markedly over time. Several factors were associated with the greater stability of the infant upper airway microbiome, including the types of bacteria predominating (in particular, an early colonization with Moraxella), breastfeeding, and fewer upper respiratory tract infections (URTIs). A major strength of these studies is the serial sampling of a cohort during this pivotal and interesting age range. These are first insights into the dynamics of nasopharyngeal microbiomes during infancy. Another strength of this work is the sophisticated approaches to resolving patterns among these large and complex data sets involving time series. Important limitations include the rather small size and narrow composition of the population studied and the reliance on parental reporting for outcomes of interest beyond microbiome data (e.g., URTIs were based on parental reports). Associations based on small numbers of participants with crude clinical information deserve caution. Another limitation is that the microbiome characterization was restricted entirely to bacterial inferences from 16S rRNA sequencing, so components of these microbial communities other than the relative composition of bacterial members were unexamined. This combination of strengths and limitations in the study design enabled the investigators to conclude that stable bacterial microbiomes are established quite early in the nasopharynges of some, but not all, infants and suggest that unstable nasopharyngeal microbiomes may associate positively with URTIs and negatively with Moraxella and breastfeeding. The association of nasopharyngeal microbiome instability with increased URTIs is intriguing. Does a stable microbiome help prevent infection? Do underlying host factors such as immunity parameters independently drive both outcomes, making microbiomes less stable and infections more likely? Do infections (e.g., by respiratory viruses) disrupt the nasopharyngeal microbiome and make it less stable? All seem reasonable possibilities, and they may be interacting (2). An experimental rhinovirus infection in adults is sufficient to alter the lower airway microbiome in patients with chronic obstructive pulmonary disease, but not healthy participants (3), suggesting that the relationships among URTIs, host factors, and airway microbiota are not linear, one-way relationships. The present publication does not shed light on mechanistic or causal relationships between microbiome stability and URTIs in young children, but by forwarding these relationships, it inspires future lines of investigation. In addition to the URTIs investigated here, the infant microbiome may also influence lower airway infections of infants and toddlers. Pneumonia is the leading cause of childhood death globally and the leading cause of hospitalization for U.S. children (4). Prior colonization of the upper airway with respiratory pathogens typically precedes lower respiratory infections (5), and colonization of infant upper airways of neonates with respiratory pathogens including Streptococcus pneumoniae and Haemophilus influenzae associates with increased lower airway infection in the first 3 years of life (6). Bogaert and colleagues found that S. pneumoniae and H. influenzae associate with less-stable microbiomes in infant noses (1), which raises the question of whether microbiome instability of the upper airways may increase the susceptibility of young children to pneumonia. If so, microbiome manipulations (e.g., based on the present data, perhaps colonization by some Moraxella species) that enhance stability of the upper airway microbiome in infants could conceivably diminish pathogen colonization and childhood pneumonia. The overall effect of microbes in the infant nasopharynx is still only beginning to be gleaned. Certainly, the microbiome is an important contributor to respiratory health and pulmonary disease in adults (7, 8). The lower airways are connected directly to the upper airways at all ages, and microbiota from adults’ upper airways are found in the lower respiratory tract as well (9). Thus, the infant microbiome may be important as a predecessor to the adult nasopharyngeal microbiome and as a precursor to the lung microbiome in both infants and adults. In addition, some of these microbes in the nasopharynges of infants and toddlers likely establish immunological memories and influence immune activities that may persist for months, years, or even lifetimes. Adaptive immune responses against microbes in the respiratory tract are important to respiratory infections, as well as to, perhaps, all chronic pulmonary diseases (4). The dynamics of nasopharyngeal microbiomes and respiratory infections in infants and toddlers may have profound effects on the developing adaptive immune system and its contributions to pulmonary disease. Supporting this, infant airway microbiomes and infections associate with pulmonary disease later in life (10–13). The present studies lay important groundwork for future investigations of early microbiome dynamics and later respiratory health. The dynamics of microbes in the nasopharynx during the first months and years of life have major implications for the health of the lungs. The infant nasopharynx is where much of the field of pulmonary medicine begins.