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      Gut microbiota signatures in cystic fibrosis: Loss of host CFTR function drives the microbiota enterophenotype

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          Abstract

          Background

          Cystic fibrosis (CF) is a disorder affecting the respiratory, digestive, reproductive systems and sweat glands. This lethal hereditary disease has known or suspected links to the dysbiosis gut microbiota. High-throughput meta-omics-based approaches may assist in unveiling this complex network of symbiosis modifications.

          Objectives

          The aim of this study was to provide a predictive and functional model of the gut microbiota enterophenotype of pediatric patients affected by CF under clinical stability.

          Methods

          Thirty-one fecal samples were collected from CF patients and healthy children (HC) (age range, 1–6 years) and analysed using targeted-metagenomics and metabolomics to characterize the ecology and metabolism of CF-linked gut microbiota. The multidimensional data were low fused and processed by chemometric classification analysis.

          Results

          The fused metagenomics and metabolomics based gut microbiota profile was characterized by a high abundance of Propionibacterium, Staphylococcus and Clostridiaceae, including Clostridium difficile, and a low abundance of Eggerthella, Eubacterium, Ruminococcus, Dorea, Faecalibacterium prausnitzii, and Lachnospiraceae, associated with overexpression of 4-aminobutyrate (GABA), choline, ethanol, propylbutyrate, and pyridine and low levels of sarcosine, 4-methylphenol, uracil, glucose, acetate, phenol, benzaldehyde, and methylacetate. The CF gut microbiota pattern revealed an enterophenotype intrinsically linked to disease, regardless of age, and with dysbiosis uninduced by reduced pancreatic function and only partially related to oral antibiotic administration or lung colonization/infection.

          Conclusions

          All together, the results obtained suggest that the gut microbiota enterophenotypes of CF, together with endogenous and bacterial CF biomarkers, are direct expression of functional alterations at the intestinal level. Hence, it’s possible to infer that CFTR impairment causes the gut ecosystem imbalance.This new understanding of CF host-gut microbiota interactions may be helpful to rationalize novel clinical interventions to improve the affected children’s nutritional status and intestinal function.

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          Most cited references32

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Cystic fibrosis genetics: from molecular understanding to clinical application.

            The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to apply genetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate how genetics can provide insights into disease. Cystic fibrosis, one of the more common lethal autosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.
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              Rapid denoising of pyrosequencing amplicon data: exploiting the rank-abundance distribution

              We developed a fast method for denoising pyrosequencing for community 16S rRNA analysis. We observe a 2–4 fold reduction in the number of observed OTUs (operational taxonomic units) comparing denoised with non-denoised data. ~50,000 sequences can be denoised on a laptop within an hour, two orders of magnitude faster than published techniques. We demonstrate the effects of denoising on alpha and beta diversity of large 16S rRNA datasets.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: Methodology
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Methodology
                Role: Investigation
                Role: Formal analysisRole: Methodology
                Role: Formal analysisRole: Methodology
                Role: Investigation
                Role: Investigation
                Role: Data curation
                Role: Investigation
                Role: Data curationRole: Validation
                Role: Investigation
                Role: Writing – review & editing
                Role: Investigation
                Role: Data curationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 December 2018
                2018
                : 13
                : 12
                : e0208171
                Affiliations
                [1 ] Unit of Human Microbiome, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
                [2 ] Cystic Fibrosis Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
                [3 ] Diagnostics of Cystic Fibrosis, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
                [4 ] Department of Chemistry, Sapienza University of Rome, Rome, Italy
                [5 ] Department of Agricultural Sciences, Division of Microbiology, University of Naples Federico II, Portici, Napoli, Italy
                [6 ] Division of Metabolism, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
                [7 ] Department of Environmental Biology; Sapienza University of Rome, Rome, Italy
                [8 ] CNR-Institute for Systems Analysis and Computer Science (IASI), Rome, Italy
                [9 ] Scientific Directorate, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
                [10 ] Unit of Parasitology Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
                Institut Pasteur, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ These authors are joint senior authors on this work.

                Author information
                http://orcid.org/0000-0003-0134-2830
                Article
                PONE-D-17-43072
                10.1371/journal.pone.0208171
                6283533
                30521551
                7e3f76bd-e73c-402a-904a-e6e1bbf125f6
                © 2018 Vernocchi et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 December 2017
                : 13 November 2018
                Page count
                Figures: 4, Tables: 1, Pages: 23
                Funding
                Funded by: Ministry of Health, Ricerca Corrente
                Award ID: 201502P003534/201602P003702
                Award Recipient :
                This work was supported by the Ministry of Health, Ricerca Corrente 201502P003534 and 201602P003702 assigned to LP.
                Categories
                Research Article
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Antibiotics
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antibiotics
                Biology and Life Sciences
                Organisms
                Bacteria
                Gut Bacteria
                Medicine and Health Sciences
                Clinical Genetics
                Genetic Diseases
                Autosomal Recessive Diseases
                Cystic Fibrosis
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Cystic Fibrosis
                Medicine and Health Sciences
                Pulmonology
                Cystic Fibrosis
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbiome
                Biology and Life Sciences
                Genetics
                Genomics
                Microbial Genomics
                Microbiome
                Biology and Life Sciences
                Microbiology
                Microbial Genomics
                Microbiome
                Biology and Life Sciences
                Organisms
                Bacteria
                Gut Bacteria
                Clostridium Difficile
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Clostridium
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Bacterial Pathogens
                Clostridium
                Biology and Life Sciences
                Organisms
                Bacteria
                Gut Bacteria
                Clostridium
                Biology and Life Sciences
                Organisms
                Bacteria
                Gut Bacteria
                Ruminococcus
                Biology and Life Sciences
                Organisms
                Bacteria
                Gut Bacteria
                Eubacterium
                Custom metadata
                All relevant data are within the paper and its Supporting Information files. The 16S rRNA sequences were deposited in the sequence-read archive (SRA) of NCBI ( https://www.ncbi.nlm.nih.gov/).

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                Uncategorized

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