The role of the bacterial microbiome in lung disease.
TL;DR: In this paper, the authors review and synthesize published reports of the lung microbiota of healthy and diseased subjects, discuss trends of microbial diversity and constitution across disease states, and look to the extrapulmonary microbiome for hypotheses and future directions for study.
Abstract: Novel culture-independent techniques have recently demonstrated that the lower respiratory tract, historically considered sterile in health, contains diverse communities of microbes: the lung microbiome. Increasing evidence supports the concept that a distinct microbiota of the lower respiratory tract is present both in health and in various respiratory diseases, although the biological and clinical significance of these findings remains undetermined. In this article, the authors review and synthesize published reports of the lung microbiota of healthy and diseased subjects, discuss trends of microbial diversity and constitution across disease states, and look to the extrapulmonary microbiome for hypotheses and future directions for study.
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TL;DR: Molecular immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotella bacteria derived from the upper airways.
Abstract: No studies have examined the relationships between bacterial communities along sites of the upper aerodigestive tract of an individual subject. Our objective was to perform an intrasubject and intersite analysis to determine the contributions of two upper mucosal sites (mouth and nose) as source communities for the bacterial microbiome of lower sites (lungs and stom- ach). Oral wash, bronchoalveolar lavage (BAL)fluid, nasal swab, and gastric aspirate samples were collected from 28 healthy subjects. Extensive analysis of controls and serial intrasubject BALfluid samples demonstrated that sampling of the lungs by bronchoscopy was not confounded by oral microbiome contamination. By quantitative PCR, the oral cavity and stomach con- tained the highest bacterial signal levels and the nasal cavity and lungs contained much lower levels. Pyrosequencing of 16S rRNA gene amplicon libraries generated from these samples showed that the oral and gastric compartments had the greatest species richness, which was significantly greater in both than the richness measured in the lungs and nasal cavity. The bacterial communities of the lungs were significantly different from those of the mouth, nose, and stomach, while the greatest similarity was between the oral and gastric communities. However, the bacterial communities of healthy lungs shared significant member- ship with the mouth, but not the nose, and marked subject-subject variation was noted. In summary, microbial immigration from the oral cavity appears to be the significant source of the lung microbiome during health, but unlike the stomach, the lungs exhibit evidence of selective elimination of Prevotellabacteria derived from the upper airways. IMPORTANCE We have demonstrated that the bacterial communities of the healthy lung overlapped those found in the mouth but were found at lower concentrations, with lower membership and a different community composition. The nasal microbiome, which was distinct from the oral microbiome, appeared to contribute little to the composition of the lung microbiome in healthy subjects. Our studies of the nasal, oral, lung, and stomach microbiomes within an individual illustrate the microbiological conti- nuity of the aerodigestive tract in healthy adults and provide culture-independent microbiological support for the concept that microaspiration is common in healthy individuals.
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TL;DR: The topography and population dynamics of the respiratory tract is described, both in health and as altered by acute and chronic lung disease.
Abstract: Although the notion that “the normal lung is free from bacteria” remains common in textbooks, it is virtually always stated without citation or argument. The lungs are constantly exposed to diverse communities of microbes from the oropharynx and other sources, and over the past decade, novel culture-independent techniques of microbial identification have revealed that the lungs, previously considered sterile in health, harbor diverse communities of microbes. In this review, we describe the topography and population dynamics of the respiratory tract, both in health and as altered by acute and chronic lung disease. We provide a survey of current techniques of sampling, sequencing, and analysis of respiratory microbiota and review technical challenges and controversies in the field. We review and synthesize what is known about lung microbiota in various diseases and identify key lessons learned across disease states.
569 citations
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TL;DR: The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and 'instruct' the professional immune system to protect the lungs from infection and injury.
Abstract: The epithelial surfaces of the lungs are in direct contact with the environment and are subjected to dynamic physical forces as airway tubes and alveoli are stretched and compressed during ventilation. Mucociliary clearance in conducting airways, reduction of surface tension in the alveoli, and maintenance of near sterility have been accommodated by the evolution of a multi-tiered innate host-defense system. The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and 'instruct' the professional immune system to protect the lungs from infection and injury.
569 citations
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TL;DR: The study of the fungal microbiota is a new and rapidly emerging field that lags behind the authors' understanding of the bacterial microbiome, especially as a reservoir for blooms of pathogenic microbes when the host is compromised and as a potential cofactor in inflammatory diseases and metabolic disorders.
435 citations
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TL;DR: The lung microbiome in health is more influenced by microbial immigration and elimination (the adapted island model) than by the effects of local growth conditions on bacterial reproduction rates, which are more determinant in advanced lung diseases.
Abstract: Rationale: The lung microbiome is spatially heterogeneous in advanced airway diseases, but whether it varies spatially in health is unknown We postulated that the primary determinant of lung microbiome constitution in health is the balance of immigration and elimination of communities from the upper respiratory tract (URT; “adapted island model of lung biogeography”), rather than differences in regional bacterial growth conditionsObjectives: To determine if the lung microbiome is spatially varied in healthy adultsMethods: Bronchoscopy was performed on 15 healthy subjects Specimens were sequentially collected in the lingula and right middle lobe (by bronchoalveolar lavage [BAL]), then in the right upper lobe, left upper lobe, and supraglottic space (by protected-specimen brush) Bacterial 16S ribosmal RNA–encoding genes were sequenced using MiSeq (Illumina, San Diego, CA)Measurements and Main Results: There were no significant differences between specimens collected by BAL and protected-specimen brush
361 citations
References
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University of Massachusetts Amherst1, University of Michigan2, University of New Mexico3, University of British Columbia4, Texas A&M University5, University of Minnesota6, University of Warwick7, Dalhousie University8, Colorado School of Mines9, University of Ljubljana10, Graz University of Technology11, Louisiana State University12
TL;DR: M mothur is used as a case study to trim, screen, and align sequences; calculate distances; assign sequences to operational taxonomic units; and describe the α and β diversity of eight marine samples previously characterized by pyrosequencing of 16S rRNA gene fragments.
Abstract: mothur aims to be a comprehensive software package that allows users to use a single piece of software to analyze community sequence data. It builds upon previous tools to provide a flexible and powerful software package for analyzing sequencing data. As a case study, we used mothur to trim, screen, and align sequences; calculate distances; assign sequences to operational taxonomic units; and describe the alpha and beta diversity of eight marine samples previously characterized by pyrosequencing of 16S rRNA gene fragments. This analysis of more than 222,000 sequences was completed in less than 2 h with a laptop computer.
17,350 citations
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TL;DR: A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms, and significant intersubject variability and differences between stool and mucosa community composition were discovered.
Abstract: The human endogenous intestinal microflora is an essential “organ” in providing nourishment, regulating epithelial development, and instructing innate immunity; yet, surprisingly, basic features remain poorly described. We examined 13,355 prokaryotic ribosomal RNA gene sequences from multiple colonic mucosal sites and feces of healthy subjects to improve our understanding of gut microbial diversity. A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms. We discovered significant intersubject variability and differences between stool and mucosa community composition. Characterization of this immensely diverse ecosystem is the first step in elucidating its role in health and disease.
7,049 citations
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TL;DR: The need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization is underscored, as distinctive features of the functional maturation of the gut microbiome are evident in early infancy as well as adulthood.
Abstract: Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.
6,047 citations
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University of Évry Val d'Essonne1, Institut national de la recherche agronomique2, Technical University of Denmark3, Barcelona Supercomputing Center4, University of Copenhagen5, University of Tokyo6, University of Miyazaki7, Wageningen University and Research Centre8, Tokyo Institute of Technology9, French Alternative Energies and Atomic Energy Commission10
TL;DR: Three robust clusters (referred to as enterotypes hereafter) are identified that are not nation or continent specific and confirmed in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous.
Abstract: Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.
5,566 citations
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TL;DR: Alternative enterotype states are associated with long-term diet, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella) and other enterotypes distinguished primarily by levels of Bacteroide and Prevotella.
Abstract: Diet strongly affects human health, partly by modulating gut microbiome composition. We used diet inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals. Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. Enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella). A controlled-feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study. Thus, alternative enterotype states are associated with long-term diet.
5,174 citations