Loss of Microbial Topography Precedes Infection in Infants.

Studies demonstrating that breastfeeding protected infants from respiratory infections began in the early 20th century. At the time, it was presumed that this was a result of nutritional deficiencies in formula (1). In the mid-20th century, it became apparent that breast milk was more than a source of calories, but also a vehicle for the transmission of antibodies, immune cells, and oligosaccharides meant for microbial, rather than infant, nutrition (2). As a consequence, infant formulas now include substances meant to promote a healthy microbiome, yet formula-fed infants are still more susceptible to respiratory infections (3). Despite more than a century of data on the role of breast milk in protection from respiratory infections, we still do not know whether or how maternal antibodies help shape the composition of the upper respiratory tract microbiome, whether breast milk directly promotes the growth of some respiratory microbes over others, or whether protection from respiratory infections is primarily a consequence of immune maturation.

Mode of delivery also alters the oral and nasopharyngeal microbiota, and ultimately affects susceptibility to infection. Infants born by vaginal birth are quicker to acquire species such as Corynebacterium spp., Moraxella spp., and Dolosigranulum spp., which are associated with reduced colonization of respiratory pathogens, than their Caesarian-born counterparts (4). How colonization of the nasopharynx by microbes that are not major components of the vaginal microbiota occurs is not clear, but may be a result of immune development as opposed to direct seeding of microbes (5). Although the mechanisms of microbiome development are not fully elucidated, in this issue of the Journal, Man and colleagues (pp. 760–770) provide provocative evidence that both the composition of the infant microbiome and the ability to maintain the topography of the nasopharyngeal community are important for protection from respiratory infections early in life (6).

Expanding a previous study of the nasopharyngeal microbiome from birth to 6 months (7), Man and colleagues examined the oral microbiome in the same cohort and investigated whether changes in oral and nasopharyngeal communities were associated with respiratory tract infections in early life. They previously had confirmed findings that breastfeeding and mode of birth influences these microbial communities (5, 8), and identified that the presence of certain microbes such as Neisseria spp. and Prevotella spp. in the first month of life are predictive of future respiratory infection. These data might lead one to conclude that the presence of some microbes enriched by birth mode or breastfeeding protect against infections. Indeed, this is consistent with decades of carriage studies that demonstrate that carriage of some pathobionts will protect against colonization by others (9). The surprising element of this study is that changes in the nasopharyngeal microbiome occurred up to a month before the occurrence of a respiratory infection and were characterized by an increase in primarily oral taxa (e.g., Neisseria lactamica, Prevotella nanceiensis, Fusobacterium spp.) in the nasopharyngeal microbiota. It is well documented, and Man and colleagues confirm, that the nasopharyngeal microbiome changes during a respiratory infection. These changes may be a result of direct microbial competition, leukocyte recruitment and concomitant changes in the oxidative environment (10), and/or changes in mucus production (11). It is possible, but not proven, that the infant nasopharyngeal microbiome becomes supportive of oral species, which include many anaerobic species, before infection as a result of changes in oxidative tension resulting from subclinical inflammation or immune involvement.

Limitations of the study include the fact that respiratory tract infections were confirmed by symptoms rather than definitive virologic testing. Timing of childhood vaccinations was also not recorded. The majority of the children in the study would have been vaccinated with the pneumococcal conjugate vaccine at 6–9 weeks, and again at 4 months (12). Pneumococcal vaccination alters the composition of the respiratory tract microbiota, and could conceivably contribute to observed changes in the microbiota that precede infection (13). In general, 16s rRNA sequencing does not provide sufficient resolution of Streptococcus spp. to determine whether acquisition of S. pneumoniae was one of the events that triggered a loss of topography.

Another counterintuitive finding was the role of daycare in microbial dysbiosis. As many parents will attest, having a child enter daycare can be the start of several months of fevers and runny noses. Five of the children in the study developed respiratory tract infections in their first month of daycare, but the loss of nasopharyngeal topography was apparent a month earlier. This implies that the loss of topography may predispose children to infections once there is a second insult, such as exposure to new microbes or the stress of beginning daycare.

Collectively, these data imply that the upper respiratory tract microbiome is modified by factors we do not yet understand. Despite the physiologic differences between the nasopharynx and oral cavity, the distinction between these topographies is blurred at times of immunological or possibly physiological stress. Older adults are also highly susceptible to respiratory infections and also lose topographical distinctions between the naso- and oropharynx (14). Although the processes of immune development and immunosenescence are quite different, perhaps the end result, loss of topography preceding respiratory infections, is the same.