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CHaPter 14 The Microbiota in Immunity and Inflammation 217

innate immune response that subsequently induces development lungs extremely low relative to that of the gut. In a healthy
of Th1 and Th17 cells in the draining lymph nodes. The culpability individual, community composition at any given time is largely
of IL-17 expression in psoriasis has been confirmed by early determined by the relative amount of microbial immigration
clinical trials in which antibody-based targeting of IL-17 or the and elimination. The major routes of immigration are micro-
IL-17 receptor resulted in improvements in Psoriasis Area Severity aspiration, air inhalation, and direct dispersion along the mucosal
Index (PASI) in at least 80% of patients after 12 weeks. 47 surface. Elimination is a continuous process mediated by the
Atopic dermatitis (AD; Chapter 44) is characterized by dry ciliated epithelial cells, by coughing, and by the actions of the
skin (xerosis), which, along with the associated change in skin pulmonary immune system. Colonization and growth contribute
pH, favors the colonization and expansion of some microbes minimally to microbiota composition during homeostasis but
more than others. Colonization with Staphylococcus aureus has are favored by changes in regional conditions that promote and/
been linked to development of AD, and S. aureus is detectable or sustain chronic inflammatory diseases of the lung.
48
in the skin lesions of over 90% of patients with AD. S. aureus Similar to the intestinal microbiota, the microbiota of the
infection induces both innate and adaptive immune activation. upper respiratory tract stabilizes in early childhood and can be
The expression of IL-37 transcript is markedly reduced in AD influenced by external factors, including breastfeeding and use
50
lesions, whereas other AMPs, including psoriasin, human β of antibiotics. In a healthy lung, there is little spatial variation
defensin-2, and RNase 7, are overexpressed. within the same individual. This lack of variation supports the
theory that the composition of the lung microbiota is more
THE RESPIRATORY TRACT MICROBIOTA IN heavily influenced by immigration and elimination than by local
HEALTH AND DISEASE growth. The most abundant bacterial phyla in the lung are
Bacteroidetes and Firmicutes. At the genus level, Prevotella,
Inhaled air contains bacteria, viruses, and fungi. Thus the respira- Veillonella, and Streptococcus predominate. There are also
tory tract serves as the main entry portal for these airborne prominent fungal communities, with dramatic differences in
microbes. Yet, for over a century, the healthy lung was considered composition observed in different healthy cohorts. The oral cavity
a sterile environment, free of culturable and/or resident reproduc- is home to several genera of fungi, including Candida, Clado-
ing microbes. The detection of microbes in samples collected sporium, and Aspergillus, but the fungal colonization of a
using instruments that had to traverse the mouth or nasal cavities healthy lung is unclear. Considering the constant exposure of
was often assumed to have resulted from contamination with the lung to oral and inhaled fungi, it is likely that the immune
microbes from these sites. The emergence of culture-independent apparatus of the lung does, indeed, encounter fungal antigens
techniques for detection of microbial communities has precipi- in the steady state.
tated a revision of this concept and an appreciation of the presence The involvement of the bacterial communities of other body
and diversity of microbial communities along the respiratory sites, particularly the intestines, in lung immune homeostasis is
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tract even in the absence of overt disease. Thus although the still being actively explored. This phenomenon is commonly
airway and lung microbiota does resemble the bacterial popula- referred to as the “gut–lung axis” and involves the action of
tions of the upper respiratory tract, there are differences that soluble mediators produced and/or induced by the gut microbiota
ultimately point to the existence of a specific lung microbiota that can enter the systemic circulation. By this rationale, this
in healthy individuals. phenomenon is more a reflection of the intestinal microbiota
Although the concept of a lung microbiota during health is on the organism as a whole, and not representative of a unique
relatively new, the role of microbial agents in the pathogenesis relationship between these two organs. Nevertheless, there is
of chronic lung diseases has been widely examined. In the healthy compelling evidence that modulation of the gut microbiota,
lung, the immune system eradicates potential pathogens and particularly during infancy, can have lifelong effects on lung
overcomes environmental disturbances that threaten to impair immunity and susceptibility to chronic diseases.
lung function. Direct impairment or intrinsic failure of the
pulmonary defense mechanisms can lead to infection and/or MICROBES AS THERAPY
chronic lung diseases, including asthma, chronic obstructive
pulmonary disorder (COPD), cystic fibrosis, and bronchiectasis. Certain infections or chronic inflammatory disorders are associ-
Although microbial expansion in the lung is a characteristic of ated with a severely damaged microbiota. Transplantation of
many lung diseases, it is not always clear whether the dysbiotic healthy donor microbiota has emerged as a successful therapeutic
microbiota is the cause, the consequence, or both. approach to repair and/or restore microbial communities. Fecal
microbiota therapy (FMT), or fecal transplantation, has been
The Shaping of the Healthy Respiratory Microbiota safely and effectively utilized as a last resort to treat chronic
6
4
The bacterial density of inhaled air is approximately 10 –10 Clostridium difficile infection. FMT presents the risk of adverse
3
cells/m . Thus with each breath, mammals are constantly exposing effects because the transplanted microbes, which are dormant
their lungs to airborne bacteria. There are system-intrinsic in the donor, experience propathogenic conditions in the recipient.
mechanisms that serve to regulate entry and colonization of the Because of the successes to date, empirical information regarding
lungs by microbes. The lung, like skin, and in stark contrast to the long-term stability and resilience of one individual’s micro-
the GI tract, is a very low nutrient resource. The thin mucus biota transplanted into another should emerge over time. Other,
layer, which might seem to represent reduced barrier protection more focused approaches that employ distinct microbes, groups
relative to the intestine, also means the absence of a valuable of microbes, or microbial products known to have immune
source of nutrients for certain mucophilic microbes. Furthermore, cell-specific effects to treat inflammatory diseases, such as IBD,
the combination of oxygen tension, temperature, regional pH, are also being considered.
the diverse architecture of the respiratory tract, and the proximity In Western, industrialized societies, there has been a consistent
of inflammatory cells all help keep the bacterial biomass of the upward trend in the incidence of autoimmune diseases, and this