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Title: New insights from uncultivated genomes of the global human gut microbiome

Abstract

The genome sequences of many species of the human gut microbiome remain unknown, largely owing to challenges in cultivating microorganisms under laboratory conditions. Here we address this problem by reconstructing 60,664 draft prokaryotic genomes from 3,810 faecal metagenomes, from geographically and phenotypically diverse humans. These genomes provide reference points for 2,058 newly identified species-level operational taxonomic units (OTUs), which represents a 50% increase over the previously known phylogenetic diversity of sequenced gut bacteria. On average, the newly identified OTUs comprise 33% of richness and 28% of species abundance per individual, and are enriched in humans from rural populations. A meta-analysis of clinical gut-microbiome studies pinpointed numerous disease associations for the newly identified OTUs, which have the potential to improve predictive models. Finally, our analysis revealed that uncultured gut species have undergone genome reduction that has resulted in the loss of certain biosynthetic pathways, which may offer clues for improving cultivation strategies in the future.

Authors:
 [1];  [2];  [1];  [3];  [1]
  1. USDOE Joint Genome Inst. (JGI), Walnut Creek, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Environmental Genomics and System Biology Divison
  2. Gladstone Inst., San Francisco, CA (United States); Chan-Zuckerberg Biohub, San Francisco, CA (United States)
  3. Gladstone Inst., San Francisco, CA (United States); Chan-Zuckerberg Biohub, San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States). Inst. for Human Genetics, Inst. for Computational Health Sciences, Quantitative Biology Inst., and Dept of Epidemiology and Biostatistics
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1572809
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 568; Journal Issue: 7753; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Nayfach, Stephen, Shi, Zhou Jason, Seshadri, Rekha, Pollard, Katherine S., and Kyrpides, Nikos C. New insights from uncultivated genomes of the global human gut microbiome. United States: N. p., 2019. Web. doi:10.1038/s41586-019-1058-x.
Nayfach, Stephen, Shi, Zhou Jason, Seshadri, Rekha, Pollard, Katherine S., & Kyrpides, Nikos C. New insights from uncultivated genomes of the global human gut microbiome. United States. doi:10.1038/s41586-019-1058-x.
Nayfach, Stephen, Shi, Zhou Jason, Seshadri, Rekha, Pollard, Katherine S., and Kyrpides, Nikos C. Wed . "New insights from uncultivated genomes of the global human gut microbiome". United States. doi:10.1038/s41586-019-1058-x. https://www.osti.gov/servlets/purl/1572809.
@article{osti_1572809,
title = {New insights from uncultivated genomes of the global human gut microbiome},
author = {Nayfach, Stephen and Shi, Zhou Jason and Seshadri, Rekha and Pollard, Katherine S. and Kyrpides, Nikos C.},
abstractNote = {The genome sequences of many species of the human gut microbiome remain unknown, largely owing to challenges in cultivating microorganisms under laboratory conditions. Here we address this problem by reconstructing 60,664 draft prokaryotic genomes from 3,810 faecal metagenomes, from geographically and phenotypically diverse humans. These genomes provide reference points for 2,058 newly identified species-level operational taxonomic units (OTUs), which represents a 50% increase over the previously known phylogenetic diversity of sequenced gut bacteria. On average, the newly identified OTUs comprise 33% of richness and 28% of species abundance per individual, and are enriched in humans from rural populations. A meta-analysis of clinical gut-microbiome studies pinpointed numerous disease associations for the newly identified OTUs, which have the potential to improve predictive models. Finally, our analysis revealed that uncultured gut species have undergone genome reduction that has resulted in the loss of certain biosynthetic pathways, which may offer clues for improving cultivation strategies in the future.},
doi = {10.1038/s41586-019-1058-x},
journal = {Nature (London)},
number = 7753,
volume = 568,
place = {United States},
year = {2019},
month = {3}
}

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Works referenced in this record:

Quinones are growth factors for the human gut microbiota
journal, December 2017


Shifting the genomic gold standard for the prokaryotic species definition
journal, October 2009

  • Richter, Michael; Rosselló-Móra, Ramon
  • Proceedings of the National Academy of Sciences, Vol. 106, Issue 45
  • DOI: 10.1073/pnas.0906412106

1,520 reference genomes from cultivated human gut bacteria enable functional microbiome analyses
journal, February 2019


High speed BLASTN: an accelerated MegaBLAST search tool
journal, January 2015

  • Chen, Ying; Ye, Weicai; Zhang, Yongdong
  • Nucleic Acids Research, Vol. 43, Issue 16
  • DOI: 10.1093/nar/gkv784

Alterations of the human gut microbiome in liver cirrhosis
journal, July 2014


Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea
journal, August 2017

  • Bowers, Robert M.; Kyrpides, Nikos C.; Stepanauskas, Ramunas
  • Nature Biotechnology, Vol. 35, Issue 8
  • DOI: 10.1038/nbt.3893

A Catalog of Reference Genomes from the Human Microbiome
journal, May 2010


The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment
journal, July 2015

  • Zhang, Xuan; Zhang, Dongya; Jia, Huijue
  • Nature Medicine, Vol. 21, Issue 8
  • DOI: 10.1038/nm.3914

Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania
journal, August 2017


Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation
journal, May 2016

  • Browne, Hilary P.; Forster, Samuel C.; Anonye, Blessing O.
  • Nature, Vol. 533, Issue 7604
  • DOI: 10.1038/nature17645

Targeted Access to the Genomes of Low-Abundance Organisms in Complex Microbial Communities
journal, March 2007

  • Podar, M.; Abulencia, C. B.; Walcher, M.
  • Applied and Environmental Microbiology, Vol. 73, Issue 10
  • DOI: 10.1128/AEM.02985-06

Critical Assessment of Metagenome Interpretation—a benchmark of metagenomics software
journal, October 2017

  • Sczyrba, Alexander; Hofmann, Peter; Belmann, Peter
  • Nature Methods, Vol. 14, Issue 11
  • DOI: 10.1038/nmeth.4458

Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life
journal, May 2015


The “Most Wanted” Taxa from the Human Microbiome for Whole Genome Sequencing
journal, July 2012


KEGG: Kyoto Encyclopedia of Genes and Genomes
journal, January 2000

  • Kanehisa, Minoru; Goto, Susumu
  • Nucleic Acids Research, Vol. 28, Issue 1, p. 27-30
  • DOI: 10.1093/nar/28.1.27

The species concept for prokaryotes
journal, January 2001


The Black Queen Hypothesis: Evolution of Dependencies through Adaptive Gene Loss
journal, March 2012

  • Morris, J. Jeffrey; Lenski, Richard E.; Zinser, Erik R.
  • mBio, Vol. 3, Issue 2
  • DOI: 10.1128/mBio.00036-12

TIGRFAMs and Genome Properties in 2013
journal, November 2012

  • Haft, Daniel H.; Selengut, Jeremy D.; Richter, Roland A.
  • Nucleic Acids Research, Vol. 41, Issue D1
  • DOI: 10.1093/nar/gks1234

Reconstructing 16S rRNA genes in metagenomic data
journal, June 2015


MEGAHIT: an ultra-fast single-node solution for large and complex metagenomics assembly via succinct de Bruijn graph
journal, January 2015


The Sequence Read Archive
journal, November 2010

  • Leinonen, R.; Sugawara, H.; Shumway, M.
  • Nucleic Acids Research, Vol. 39, Issue Database
  • DOI: 10.1093/nar/gkq1019

tRNAscan-SE: A Program for Improved Detection of Transfer RNA Genes in Genomic Sequence
journal, March 1997


BioProject and BioSample databases at NCBI: facilitating capture and organization of metadata
journal, December 2011

  • Barrett, T.; Clark, K.; Gevorgyan, R.
  • Nucleic Acids Research, Vol. 40, Issue D1
  • DOI: 10.1093/nar/gkr1163

FastTree 2 – Approximately Maximum-Likelihood Trees for Large Alignments
journal, March 2010


MetaBAT, an efficient tool for accurately reconstructing single genomes from complex microbial communities
journal, January 2015


Genomic Encyclopedia of Bacteria and Archaea: Sequencing a Myriad of Type Strains
journal, August 2014


Phylogeny-corrected identification of microbial gene families relevant to human gut colonization
journal, August 2018

  • Bradley, Patrick H.; Nayfach, Stephen; Pollard, Katherine S.
  • PLOS Computational Biology, Vol. 14, Issue 8
  • DOI: 10.1371/journal.pcbi.1006242

MaxBin 2.0: an automated binning algorithm to recover genomes from multiple metagenomic datasets
journal, October 2015


A standardized bacterial taxonomy based on genome phylogeny substantially revises the tree of life
journal, August 2018

  • Parks, Donovan H.; Chuvochina, Maria; Waite, David W.
  • Nature Biotechnology, Vol. 36, Issue 10
  • DOI: 10.1038/nbt.4229

Microbial species delineation using whole genome sequences
journal, July 2015

  • Varghese, Neha J.; Mukherjee, Supratim; Ivanova, Natalia
  • Nucleic Acids Research, Vol. 43, Issue 14
  • DOI: 10.1093/nar/gkv657

CheckM: assessing the quality of microbial genomes recovered from isolates, single cells, and metagenomes
journal, May 2015

  • Parks, Donovan H.; Imelfort, Michael; Skennerton, Connor T.
  • Genome Research, Vol. 25, Issue 7
  • DOI: 10.1101/gr.186072.114

A new genomic blueprint of the human gut microbiota
journal, February 2019


An integrated metagenomics pipeline for strain profiling reveals novel patterns of bacterial transmission and biogeography
journal, October 2016

  • Nayfach, Stephen; Rodriguez-Mueller, Beltran; Garud, Nandita
  • Genome Research, Vol. 26, Issue 11
  • DOI: 10.1101/gr.201863.115

FAMSA: Fast and accurate multiple sequence alignment of huge protein families
journal, September 2016

  • Deorowicz, Sebastian; Debudaj-Grabysz, Agnieszka; Gudyś, Adam
  • Scientific Reports, Vol. 6, Issue 1
  • DOI: 10.1038/srep33964

Mash: fast genome and metagenome distance estimation using MinHash
journal, June 2016


Recovery of genomes from metagenomes via a dereplication, aggregation and scoring strategy
journal, May 2018

  • Sieber, Christian M. K.; Probst, Alexander J.; Sharrar, Allison
  • Nature Microbiology, Vol. 3, Issue 7
  • DOI: 10.1038/s41564-018-0171-1

Interactive tree of life (iTOL) v3: an online tool for the display and annotation of phylogenetic and other trees
journal, April 2016

  • Letunic, Ivica; Bork, Peer
  • Nucleic Acids Research, Vol. 44, Issue W1
  • DOI: 10.1093/nar/gkw290

Adaptive seeds tame genomic sequence comparison
journal, January 2011


Extensive Unexplored Human Microbiome Diversity Revealed by Over 150,000 Genomes from Metagenomes Spanning Age, Geography, and Lifestyle
journal, January 2019


The Human Intestinal Microbiome in Health and Disease
journal, December 2016

  • Lynch, Susan V.; Pedersen, Oluf
  • New England Journal of Medicine, Vol. 375, Issue 24
  • DOI: 10.1056/NEJMra1600266

A human gut bacterial genome and culture collection for improved metagenomic analyses
journal, February 2019

  • Forster, Samuel C.; Kumar, Nitin; Anonye, Blessing O.
  • Nature Biotechnology, Vol. 37, Issue 2
  • DOI: 10.1038/s41587-018-0009-7

Interconnected microbiomes and resistomes in low-income human habitats
journal, May 2016

  • Pehrsson, Erica C.; Tsukayama, Pablo; Patel, Sanket
  • Nature, Vol. 533, Issue 7602
  • DOI: 10.1038/nature17672

VSEARCH: a versatile open source tool for metagenomics
journal, January 2016


Accelerated Profile HMM Searches
journal, October 2011


Unusual biology across a group comprising more than 15% of domain Bacteria
journal, June 2015

  • Brown, Christopher T.; Hug, Laura A.; Thomas, Brian C.
  • Nature, Vol. 523, Issue 7559
  • DOI: 10.1038/nature14486

Binning metagenomic contigs by coverage and composition
journal, September 2014

  • Alneberg, Johannes; Bjarnason, Brynjar Smári; de Bruijn, Ino
  • Nature Methods, Vol. 11, Issue 11
  • DOI: 10.1038/nmeth.3103

A metagenome-wide association study of gut microbiota in type 2 diabetes
journal, September 2012


MetaPhlAn2 for enhanced metagenomic taxonomic profiling
journal, September 2015

  • Truong, Duy Tin; Franzosa, Eric A.; Tickle, Timothy L.
  • Nature Methods, Vol. 12, Issue 10
  • DOI: 10.1038/nmeth.3589

Metagenomic species profiling using universal phylogenetic marker genes
journal, October 2013

  • Sunagawa, Shinichi; Mende, Daniel R.; Zeller, Georg
  • Nature Methods, Vol. 10, Issue 12
  • DOI: 10.1038/nmeth.2693

Measurement of bacterial replication rates in microbial communities
journal, November 2016

  • Brown, Christopher T.; Olm, Matthew R.; Thomas, Brian C.
  • Nature Biotechnology, Vol. 34, Issue 12
  • DOI: 10.1038/nbt.3704

PATRIC, the bacterial bioinformatics database and analysis resource
journal, November 2013

  • Wattam, Alice R.; Abraham, David; Dalay, Oral
  • Nucleic Acids Research, Vol. 42, Issue D1
  • DOI: 10.1093/nar/gkt1099

Fast gapped-read alignment with Bowtie 2
journal, March 2012

  • Langmead, Ben; Salzberg, Steven L.
  • Nature Methods, Vol. 9, Issue 4
  • DOI: 10.1038/nmeth.1923

Assembly of 913 microbial genomes from metagenomic sequencing of the cow rumen
journal, February 2018


Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes
journal, July 2014

  • Nielsen, H. Bjørn; Almeida, Mathieu; Juncker, Agnieszka Sierakowska
  • Nature Biotechnology, Vol. 32, Issue 8
  • DOI: 10.1038/nbt.2939

Culture of previously uncultured members of the human gut microbiota by culturomics
journal, November 2016

  • Lagier, Jean-Christophe; Khelaifia, Saber; Alou, Maryam Tidjani
  • Nature Microbiology, Vol. 1, Issue 12
  • DOI: 10.1038/nmicrobiol.2016.203

Community structure and metabolism through reconstruction of microbial genomes from the environment
journal, February 2004

  • Tyson, Gene W.; Chapman, Jarrod; Hugenholtz, Philip
  • Nature, Vol. 428, Issue 6978
  • DOI: 10.1038/nature02340

Basic local alignment search tool
journal, October 1990

  • Altschul, Stephen F.; Gish, Warren; Miller, Webb
  • Journal of Molecular Biology, Vol. 215, Issue 3, p. 403-410
  • DOI: 10.1016/S0022-2836(05)80360-2

dRep: a tool for fast and accurate genomic comparisons that enables improved genome recovery from metagenomes through de-replication
journal, July 2017

  • Olm, Matthew R.; Brown, Christopher T.; Brooks, Brandon
  • The ISME Journal, Vol. 11, Issue 12
  • DOI: 10.1038/ismej.2017.126

Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans
journal, May 2016


Metagenome Sequencing of the Hadza Hunter-Gatherer Gut Microbiota
journal, June 2015

  • Rampelli, Simone; Schnorr, Stephanie L.; Consolandi, Clarissa
  • Current Biology, Vol. 25, Issue 13
  • DOI: 10.1016/j.cub.2015.04.055

Richness of human gut microbiome correlates with metabolic markers
journal, August 2013

  • Le Chatelier, Emmanuelle; Nielsen, Trine; Qin, Junjie
  • Nature, Vol. 500, Issue 7464
  • DOI: 10.1038/nature12506

Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life
journal, September 2017

  • Parks, Donovan H.; Rinke, Christian; Chuvochina, Maria
  • Nature Microbiology, Vol. 2, Issue 11
  • DOI: 10.1038/s41564-017-0012-7

A Linear-Time Algorithm for Gaussian and Non-Gaussian Trait Evolution Models
journal, February 2014


IMG/M v.5.0: an integrated data management and comparative analysis system for microbial genomes and microbiomes
journal, October 2018

  • Chen, I-Min A.; Chu, Ken; Palaniappan, Krishna
  • Nucleic Acids Research, Vol. 47, Issue D1
  • DOI: 10.1093/nar/gky901

Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease
journal, May 2017


Thousands of microbial genomes shed light on interconnected biogeochemical processes in an aquifer system
journal, October 2016

  • Anantharaman, Karthik; Brown, Christopher T.; Hug, Laura A.
  • Nature Communications, Vol. 7, Issue 1
  • DOI: 10.1038/ncomms13219

The human gut and groundwater harbor non-photosynthetic bacteria belonging to a new candidate phylum sibling to Cyanobacteria
journal, October 2013


Gut metagenome in European women with normal, impaired and diabetic glucose control
journal, May 2013

  • Karlsson, Fredrik H.; Tremaroli, Valentina; Nookaew, Intawat
  • Nature, Vol. 498, Issue 7452
  • DOI: 10.1038/nature12198

The reconstruction of 2,631 draft metagenome-assembled genomes from the global oceans
journal, January 2018

  • Tully, Benjamin J.; Graham, Elaina D.; Heidelberg, John F.
  • Scientific Data, Vol. 5, Issue 1
  • DOI: 10.1038/sdata.2017.203

Individual genome assembly from complex community short-read metagenomic datasets
journal, October 2011

  • Luo, Chengwei; Tsementzi, Despina; Kyrpides, Nikos C.
  • The ISME Journal, Vol. 6, Issue 4
  • DOI: 10.1038/ismej.2011.147

An integrated catalog of reference genes in the human gut microbiome
journal, July 2014

  • Li, Junhua; Jia, Huijue; Cai, Xianghang
  • Nature Biotechnology, Vol. 32, Issue 8
  • DOI: 10.1038/nbt.2942

Mobile genes in the human microbiome are structured from global to individual scales
journal, July 2016


Efficient algorithms for accurate hierarchical clustering of huge datasets: tackling the entire protein space
journal, June 2008


Characteristics of a Lipolytic and Fatty Acid-requiring Butyrivibrio sp. Isolated from the Ovine Rumen
journal, May 1979


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