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The human respiratory microbiota in health shows interpersonal differences related, among other factors, to unique anatomic and physiological characteristics, individual immune response, and environmental conditions. The stable but probably transient lung microbiota is originated by the continuous microaspirations of the oropharyngeal secretions that are later subjected to the clearance processes that take place in the lower respiratory tract. In exacerbations of chronic pulmonary diseases, a positive feedback cycle of inflammation and dysbiosis is produced that commonly ends in a reduction of the lung microbial diversity. In acute respiratory infections, the entrance of a respiratory pathogen in the lower respiratory tract triggers an inflammatory process that causes the imbalance in the stable microbiota. Results of the research on the human respiratory microbiome are occasionally controversial, and more longitudinal studies are needed to analyze the trends in the composition of the bacterial respiratory community. The establishment of common methodological protocols, from sample collection to primers’ selection, or sequence analysis processing, will aid in comparing data from different studies. Yet, there are many unsolved questions as to whether an altered microbial community is the cause or the consequence of a respiratory disease, how adaptive immunity influences the microbiota composition and vice versa, or what environmental factors might impact the respiratory microbiome. Another pending issue is the role of other nonbacterial microorganisms such as fungi or viruses in the microbiome composition in health and disease. The characterization of the whole genomic content and the functional analysis of all the genes found in a respiratory specimen will improve our comprehension of the relationships between microbiome and disease.