The Human Respiratory Microbiome: Implications and Impact

Alicia B. Mitchell, BMedSci (Hons); Allan R. Glanville, MBBS, MD, FRACP

Disclosures

Semin Respir Crit Care Med. 2018;39(2):199-212. 

In This Article

Abstract and Introduction

Abstract

Once considered a sterile site below the larynx, the tracheobronchial tree and parenchyma of the lungs are now known to harbor a rich diversity of microbial species including bacteria, viruses, fungi, and archaea. Many of these organisms, particularly the viruses which comprise the human respiratory virome, have not been identified, so their true role is unknown. It seems logical to conclude that a "healthy" respiratory microbiome exists which may be modified in disease states and perhaps by therapies such as antibiotics, antifungals, and antiviral treatments. It is likely that there is a critical relationship or equilibrium between components of the microbiome until such time as perturbations occur which lead to a state of dysbiosis or an "unhealthy" microbiome. The act of lung transplantation provides an extreme change to an individual's respiratory microbiome as, in effect, the donor respiratory microbiome is transplanted into the recipient. The mandatory ex-vivo period of the donor lungs appears to be associated with blooms of resident viral species in particular. Subsequently, allograft injury, rejection, and immune suppressive therapy all combine to create periods of dysbiosis which when combined with transient infections such as community acquired respiratory viruses may facilitate the development of chronic allograft dysfunction in predisposed individuals. As our understanding of the respiratory microbiome is rapidly expanding, based on the use of new-generation sequencing tools in particular, it is to be hoped that insights gained into the subtle relationship between the microbiome and the lung allograft will facilitate improved outcomes by directing novel therapeutic endeavors.

Introduction

The microbiome consists of all microorganisms and their products that occupy surfaces within the human body. Each major compartment of the human body appears to have a unique microbiome with species which are specific for that environment. The microbiome encompasses bacteria, fungi, viruses (including bacteriophages), and archaea. These microorganisms are an integral part of the functional human unit. The human body hosts more than a trillion microbial cells and microbiome-associated genes outnumber human-coded genes 100-fold.[1] Humans and microbes have co-evolved over millions of years, and subsequently, the human immune system and the microbiome demonstrate complex interactions. The development of the microbiome is integral in shaping the immune response, while the immune system is required to maintain this large, and highly diverse set of microbes. Thus, a symbiotic interface has been established within the human body.[2]

The advent of culture-independent new technologies such as highly parallel DNA sequencing facilitated the beginning of the human microbiome (HM) Project, which signaled a phase shift from investigating single organisms in isolation, to investigating the whole microbial community. The HM project aimed to characterize the human microbiota and to analyze the role of microorganisms in health and disease. The focus was on the bacteria found in five main body sites: oropharynx, skin, vagina, gut, and nasal cavity. During the HM project, bacterial reference genomes were determined and an open-access database was established to allow collaborative efforts from laboratories worldwide.[3,4] Collaboration between numerous laboratories has allowed the characterization of commensal bacterial species within a range of body systems. After initially concentrating on developing a reference set composed of a range of normal individuals, the role of microbial imbalance or dysbiosis in different disease states has been investigated.[5]

Many modern molecular techniques exploit the 16S ribosomal RNA (rRNA) gene, a small and highly conserved locus contained within all bacterial genomes that allows easy identification of bacterial sequences, and a target for amplification and sequencing.[6] Once sequenced, these can be referenced against the open-access databases to give genus and species level information. The next-generation sequencing (NGS) technologies such as the 454 pyrosequencing and Illumina platforms allow whole communities to be characterized simultaneously and for a greatly reduced cost compared with previous sequencing technologies.[7] The conserved 16S rRNA region is largely responsible for the large body of research now available focusing on bacteria, in comparison to the limited data regarding viruses and fungi present within human systems.

Prior to the HM project, culture-based techniques were used to investigate bacterial presence in the human body, which led to the assumption that the respiratory tract was a sterile site. Accordingly, the lungs were originally omitted from the list of priority sites for the HM project.[8] This appeared to disregard prior evidence from the 1970s and 1980s suggesting that the lungs contained bacteria aspirated from the upper respiratory tract, identified using radiotracers in a group of healthy individuals.[9,10] Subsequent to the initial efforts in mapping the HM, research studies began to emerge that demonstrated that the lower respiratory tract is home to a diverse range of bacterial species with variations between health and disease states.[11] In late 2009, the Lung human immunodeficiency virus (HIV) Microbiome Project was established with the aim "To characterize the microbiome of the lung and respiratory tract, and enhance understanding of the role of the lung microbiome in preserving health or causing disease and in the divergent effects observed in HIV-infected versus uninfected individuals."[12] Since then, numerous studies have characterized aspects of the bacterial microbiota in a range of acute and chronic respiratory conditions.

The HM is intricately involved in a range of normal and pathological processes during development and throughout life. Traditionally, it was assumed that the microbiome was established at birth, and its composition was dependent on route of delivery. The fetal gut microbiome demonstrates diverse communities within the first week of life; however, a more mature equilibrium is not reached until ~3 years of age.[13] New published evidence indicates the presence of bacterial DNA in amniotic fluid and placental specimens, raising the possibility of microbiome exposure prior to birth.[14,15] There are differences in the neonatal gut microbiome between full-term and preterm infants. The major phyla in preterm infants is Firmicutes compared with a dominance of Actinobacteria in full-term infants,[16] which further suggests that microbiome seeding may occur during pregnancy and vary with gestational age. Additionally, breastfeeding in the early neonatal period appears to have significant effects on gut microbiota development. In a group of breastfed infants, virulence genes were increased within the gut microbiome, which correlated with upregulation of immunity-related genes. Early exposure from the mother, both while in utero and in the first few weeks of life, plays an important role in the development of the microbiota in multiple organ systems.

Establishment of the microbiome is crucial in immune development. The effect of early exposure to allergens was evaluated in a murine model, where exposure to house dust mite (HDM) in the early neonatal period leads to increased airway eosinophilia and airway hyper-responsiveness. After establishment of lung microbiota and shifts from Firmicutes and Gammaproteobacteria toward a Bacteroides predominance during the first 2 weeks after birth, a decreased response to aeroallergens was observed. An emergence of a Treg subset which required interaction with programmed death ligand 1 (PD-L1) appeared to be associated with this decreased allergen response.[17] This demonstrates the importance of airway microbiota establishment in the development of atopic responses and possibly the later development of asthma. During childhood, diet, genetics, and environmental exposures affect development of the microbiome, all of which play an important role in immune system maturation. Specifically, the oral microbiota, which in turn influences the lung microbiota, has been shown to be influenced by external factors in the first 5 years of life, including breastfeeding, day care attendance, and use of antibiotics.[18,19]

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