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      Changes in the Cystic Fibrosis Airway Microbiome in Response to CFTR Modulator Therapy

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          The development of CFTR modulator therapies significantly changed the treatment scheme of people with cystic fibrosis. However, CFTR modulator therapy is still a life-long treatment, which is not able to correct the genetic defect and cure the disease. Therefore, it becomes crucial to understand the effects of such modulation of CFTR function on the airway physiology, especially on airway infections and inflammation that are currently the major life-limiting factors in people with cystic fibrosis. In this context, understanding the dynamics of airway microbiome changes in response to modulator therapy plays an essential role in developing strategies for managing airway infections. Whether and how the newly available therapies affect the airway microbiome is still at the beginning of being deciphered. We present here a brief review summarizing the latest information about microbiome alterations in light of modern cystic fibrosis modulator therapy.

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          Most cited references 60

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          Species-level functional profiling of metagenomes and metatranscriptomes

          Functional profiling from metagenomic or metatranscriptomic (“meta’omic”) sequencing provides insight into the molecular activities of microbial communities. These analyses are typically carried out using comprehensive search of sequencing reads, which is time-consuming, prone to spurious mapping, and often limited to community-level quantification. We developed a tiered meta’omic search strategy (HUMAnN2) which enables fast, accurate, and species-resolved functional profiling of host-associated and environmental communities. HUMAnN2 identifies a community’s known species, aligns reads to their pangenomes, performs translated search on unclassified reads, and finally quantifies gene families and pathways. Relative to pure translated search, HUMAnN2 is 3x faster and produces more accurate gene family profiles (89% vs. 67%). We apply HUMAnN2 to clinal variation in marine metabolism, ecological contribution patterns among human microbiome pathways, variation in species’ genomic vs. transcriptional contributions, and strain profiling. Finally, we introduce “contributional diversity” to explain patterns of ecological assembly across different microbial community types.
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            Cystic fibrosis.

             J. Elborn (2016)
            Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia. The disease is caused by mutation of a gene that encodes a chloride-conducting transmembrane channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates anion transport and mucociliary clearance in the airways. Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs. CFTR dysfunction mainly affects epithelial cells, although there is evidence of a role in immune cells. Cystic fibrosis affects several body systems, and morbidity and mortality is mostly caused by bronchiectasis, small airways obstruction, and progressive respiratory impairment. Important comorbidities caused by epithelial cell dysfunction occur in the pancreas (malabsorption), liver (biliary cirrhosis), sweat glands (heat shock), and vas deferens (infertility). The development and delivery of drugs that improve the clearance of mucus from the lungs and treat the consequent infection, in combination with correction of pancreatic insufficiency and undernutrition by multidisciplinary teams, have resulted in remarkable improvements in quality of life and clinical outcomes in patients with cystic fibrosis, with median life expectancy now older than 40 years. Innovative and transformational therapies that target the basic defect in cystic fibrosis have recently been developed and are effective in improving lung function and reducing pulmonary exacerbations. Further small molecule and gene-based therapies are being developed to restore CFTR function; these therapies promise to be disease modifying and to improve the lives of people with cystic fibrosis.
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              The microbiota of the respiratory tract: gatekeeper to respiratory health

              Key Points 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. Supplementary information The online version of this article (doi:10.1038/nrmicro.2017.14) contains supplementary material, which is available to authorized users.

                Author and article information

                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                17 March 2021
                : 11
                1 Medical Faculty, Institute of Medical Microbiology and Virology , Technische Universität Dresden, Dresden, Germany
                2 Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg , Heidelberg, Germany
                3 Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University Hospital Heidelberg , Heidelberg, Germany
                Author notes

                Edited by: Carlos Miguel Farinha, University of Lisbon, Portugal

                Reviewed by: Lucas Hoffman, University of Washington, United States; Miquéias Lopes-Pacheco, University of Lisbon, Portugal

                *Correspondence: Alexander H. Dalpke, alexander.dalpke@ 123456ukdd.de

                This article was submitted to Microbiome in Health and Disease, a section of the journal Frontiers in Cellular and Infection Microbiology

                Copyright © 2021 Yi, Dalpke and Boutin

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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                Figures: 0, Tables: 1, Equations: 0, References: 60, Pages: 7, Words: 3652
                Cellular and Infection Microbiology
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