The microbiota of the respiratory tract: gatekeeper to respiratory health

The anatomical development and maturation of the human respiratory tract is a complex multistage process that occurs not only in prenatal life but also postnatally. This maturation process

depends, in part, on exposure to microbial and environmental triggers, and results in a highly specialized organ system that contains several distinct niches, each of which is subjected to

specific microbial, cellular and physiological gradients.

The respiratory microbiome during early life is dynamic and its development is affected by a range of host and environmental factors, including mode of birth, feeding type, antibiotic

treatment and crowding conditions, such as the presence of siblings and day-care attendance.

The upper respiratory tract is colonized by specialized resident bacterial, viral and fungal assemblages, which presumably prevent potential pathogens from overgrowing and disseminating

towards the lungs, thereby functioning as gatekeepers to respiratory health.

The upper respiratory tract is the primary source of the lung microbiome. In healthy individuals, the lung microbiome seems to largely consist of transient microorganisms and its composition

is determined by the balance between microbial immigration and elimination.

Next-generation sequencing has identified intricate interbacterial association networks that comprise true mutualistic, commensal or antagonistic direct or indirect relationships.

Alternatively, bacterial co-occurrence seems to be driven by host and environmental factors, as well as by interactions with viruses and fungi.

The respiratory microbiome provides cues to the host immune system that seem to be vital for immune training, organogenesis and the maintenance of immune tolerance. Increasing evidence

supports the existence of a window of opportunity early in life, during which adequate microbiota sensing is essential for immune maturation and consecutive respiratory health.

Future studies should focus on large-scale, multidisciplinary holistic approaches and adequately account for host and environmental factors. Associations that are identified by these studies

can then be corroborated in reductionist surveys; for example, by using in vitro or animal studies.

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.

The authors apologize to all colleagues whose work could not be cited owing to space limitations. This work was supported by the Netherlands Organization for Scientific Research through

NWO-Vidi (grant 91715359 to D.B.), a Scottish Senior Clinical Fellowship award (to D.B.), the Spaarne Gasthuis Academy Hoofddorp (to W.H.M.) and Wilhelmina Children's Hospital intramural

funds (to W.A.A.d.S.P.). The authors thank colleagues in Utrecht, Hoofddorp and Edinburgh for in-depth discussions in regard to topics covered in this manuscript: these discussions have

substantially contributed to the content of this work.

Wing Ho Man and Wouter A.A. de Steenhuijsen Piters: These authors contributed equally to this work.

Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, Utrecht, 3584 EA, The Netherlands

Wing Ho Man, Wouter A.A. de Steenhuijsen Piters & Debby Bogaert

Spaarne Gasthuis Academy, Spaarnepoort 1, Hoofddorp, 2134 TM, The Netherlands

The University of Edinburgh/MRC Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK

The microorganisms (including bacteria, archaea and single-celled eukaryotes) and viruses that inhabit a particular niche.

Openings in the nose that connect the external environment and the nasal cavity.

The act of settlement and reproduction of organisms that are subject to selective pressure.

A close biological interaction between two different species.

A thickening of the embryonic head ectoderm that occurs in the fifth embryonic week and marks the start of the formation of the nose and nasal cavity.

A transient bilaminar (ectoderm and endoderm) membrane that appears in the fourth embryonic week during the development of the primitive mouth and pharynx.

A pair of endodermal outgrowths of the foregut that develop into the larynx, trachea and lungs.

(NALT). One of the anatomical locations of mucosa-associated lymphoid tissue (MALT), which, in humans, consists of the lymphoid tissue of Waldeyer's pharyngeal ring, including the adenoids

(the unpaired nasopharyngeal tonsil) and the paired palatine tonsils.

The composite of species richness (the number of species present in an ecosystem) and evenness (the equitability of the abundance of these species).

(AOM). An acute-onset viral and/or bacterial infection of the middle ear.

A common condition that is typified by prolonged inflammation of the paranasal sinuses.

A sole species that is typically not highly abundant but is disproportionally important in maintaining the organization and structure of an entire community.

Microorganisms embedded in a self-produced matrix of extracellular polymeric substances that are adherent to each other and/or a surface.

(BALs). A technique in which fluid that contains bronchoalveolar cells is obtained by infusing and extracting saline during bronchoscopy.

An interaction between two species in which each species benefits (win-win).

An interaction between two species in which one species benefits and the other is unaffected (win-neutral).

An interaction between two species in which one species is inhibited or adversely affected by another species, comprising: amensalism (lose-neutral), predatism and parasitism (win-lose) or

competition (lose-lose).

A communication system between bacterial cells that is capable of triggering microbial group behaviour (for example, the formations of biofilms) once a certain threshold of signalling

molecules is reached.

(Treg cells). A subpopulation of T cells that modulate the host immune system and are pivotal in the maintenance of tolerance.

(ARDS). A clinical phenotype that occurs in patients who are critically ill and is characterized by overt lung inflammation in response to various pathologies, including trauma, sepsis and

pneumonia.

An evolutionary conserved transmembrane protein that has a crucial role in innate immune responses against invading pathogens.

T helper cells that are characterized as preferential producers of interleukin-17 (IL-17), mediate host defence mechanisms to various infections, and are involved in the pathogenesis of

several autoimmune disorders.

(LPS). The main constituent of the cell wall of Gram-negative bacteria and a potent Toll-like receptor 4 (TLR4) ligand.

A viscous secretion that is produced by goblet cells and is composed of a diverse range of mucin proteins.

A class of gel-forming glycoproteins that give mucus its viscosity.

A mixture of proteins and lipids that reduce surface tension and prevent alveolar collapse, and, additionally, have antimicrobial and anti-inflammatory properties.

A layer of loose connective tissue that is located directly underneath the epithelium.

An antimicrobial peptide that is produced by epithelial cells in the respiratory tract following microbial stimulation.

(NOD-like receptors). Intracellular, innate pattern recognition receptors that recognize molecular fragments in peptidoglycan (a constituent of the bacterial cell wall).

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