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      Healthy human gut phageome

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          Abstract

          <p id="d10525042e224">Humans need a stable, balanced gut microbiome (GM) to be healthy. The GM is influenced by bacteriophages that infect bacterial hosts. In this work, bacteriophages associated with the GM of healthy individuals were analyzed, and a healthy gut phageome (HGP) was discovered. The HGP is composed of core and common bacteriophages common to healthy adult individuals and is likely globally distributed. We posit that the HGP plays a critical role in maintaining the proper function of a healthy GM. As expected, we found that the HGP is significantly decreased in individuals with gastrointestinal disease (ulcerative colitis and Crohn’s disease). Together, these results reveal a large community of human gut bacteriophages that likely contribute to maintaining human health. </p><p class="first" id="d10525042e227">The role of bacteriophages in influencing the structure and function of the healthy human gut microbiome is unknown. With few exceptions, previous studies have found a high level of heterogeneity in bacteriophages from healthy individuals. To better estimate and identify the shared phageome of humans, we analyzed a deep DNA sequence dataset of active bacteriophages and available metagenomic datasets of the gut bacteriophage community from healthy individuals. We found 23 shared bacteriophages in more than one-half of 64 healthy individuals from around the world. These shared bacteriophages were found in a significantly smaller percentage of individuals with gastrointestinal/irritable bowel disease. A network analysis identified 44 bacteriophage groups of which 9 (20%) were shared in more than one-half of all 64 individuals. These results provide strong evidence of a healthy gut phageome (HGP) in humans. The bacteriophage community in the human gut is a mixture of three classes: a set of core bacteriophages shared among more than one-half of all people, a common set of bacteriophages found in 20–50% of individuals, and a set of bacteriophages that are either rarely shared or unique to a person. We propose that the core and common bacteriophage communities are globally distributed and comprise the HGP, which plays an important role in maintaining gut microbiome structure/function and thereby contributes significantly to human health. </p>

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          Most cited references11

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          Towards the human intestinal microbiota phylogenetic core.

          The paradox of a host specificity of the human faecal microbiota otherwise acknowledged as characterized by global functionalities conserved between humans led us to explore the existence of a phylogenetic core. We investigated the presence of a set of bacterial molecular species that would be altogether dominant and prevalent within the faecal microbiota of healthy humans. A total of 10 456 non-chimeric bacterial 16S rRNA sequences were obtained after cloning of PCR-amplified rDNA from 17 human faecal DNA samples. Using alignment or tetranucleotide frequency-based methods, 3180 operational taxonomic units (OTUs) were detected. The 16S rRNA sequences mainly belonged to the phyla Firmicutes (79.4%), Bacteroidetes (16.9%), Actinobacteria (2.5%), Proteobacteria (1%) and Verrumicrobia (0.1%). Interestingly, while most of OTUs appeared individual-specific, 2.1% were present in more than 50% of the samples and accounted for 35.8% of the total sequences. These 66 dominant and prevalent OTUs included members of the genera Faecalibacterium, Ruminococcus, Eubacterium, Dorea, Bacteroides, Alistipes and Bifidobacterium. Furthermore, 24 OTUs had cultured type strains representatives which should be subjected to genome sequence with a high degree of priority. Strikingly, 52 of these 66 OTUs were detected in at least three out of four recently published human faecal microbiota data sets, obtained with very different experimental procedures. A statistical model confirmed these OTUs prevalence. Despite the species richness and a high individual specificity, a limited number of OTUs is shared among individuals and might represent the phylogenetic core of the human intestinal microbiota. Its role in human health deserves further study.
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            Explaining microbial population genomics through phage predation.

            The remarkable differences that have been detected by metagenomics in the genomes of strains of the same bacterial species are difficult to reconcile with the widely accepted paradigm that periodic selection within bacterial populations will regularly purge genomic diversity by clonal replacement. We have found that many of the genes that differ between strains affect regions that are potential phage recognition targets. We therefore propose the constant-diversity dynamics model, in which the diversity of prokaryotic populations is preserved by phage predation. We provide supporting evidence for this model from metagenomics, mathematical analysis and computer simulations. Periodic selection and phage predation dynamics are not mutually exclusive; we compare their predictions to shed light on the ecological circumstances under which each type of dynamics could predominate.
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              Antibiotic Treatment Expands the Resistance Reservoir and Ecological Network of the Phage Metagenome

              The mammalian gut ecosystem has significant influence on host physiology 1–4 , but the mechanisms that sustain this complex environment in the face of different stresses remain obscure. Perturbations to this ecosystem, such as through antibiotic treatment or diet, are currently interpreted at the level of bacterial phylogeny 5–7 . Less is known about the contributions of the abundant population of phage to this ecological network. Here, we explore the phageome as a potential genetic reservoir for bacterial adaptation by sequencing murine fecal phage populations following antibiotic perturbation. We show that antibiotic treatment leads to the enrichment of phage-encoded genes that confer resistance via disparate mechanisms to the administered drug as well as genes that confer resistance to antibiotics unrelated to the administered drug, and we demonstrate experimentally that phage from treated mice afford aerobically cultured naïve microbiota increased resistance. Systems-wide analyses uncover post-treatment phage-encoded processes related to host colonization and growth adaptation, indicating that the phageome broadly enriches for functionally beneficial genes under stress-related conditions. We also show that antibiotic treatment expands the interactions between phage and bacterial species, leading to a more highly connected phage-bacterial network for gene exchange. Our work implicates the phageome in the emergence of multidrug resistance and indicates that the adaptive capacity of the phageome may represent a community-based mechanism for protecting the gut microflora, preserving its functional robustness during antibiotic stress.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proc Natl Acad Sci USA
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                September 13 2016
                September 13 2016
                : 113
                : 37
                : 10400-10405
                Article
                10.1073/pnas.1601060113
                5027468
                27573828
                2b20341b-e4af-4504-b2ba-464762a6b98f
                © 2016

                http://www.pnas.org/site/misc/userlicense.xhtml

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