skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics

Abstract

Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection and shows promise for treating other medical conditions associated with intestinal dysbioses. However, we lack a sufficient understanding of which microbial populations successfully colonize the recipient gut, and the widely used approaches to study the microbial ecology of FMT experiments fail to provide enough resolution to identify populations that are likely responsible for FMT-derived benefits. Here, we used shotgun metagenomics together with assembly and binning strategies to reconstruct metagenome-assembled genomes (MAGs) from fecal samples of a single FMT donor. We then used metagenomic mapping to track the occurrence and distribution patterns of donor MAGs in two FMT recipients. Our analyses revealed that 22% of the 92 highly complete bacterial MAGs that we identified from the donor successfully colonized and remained abundant in two recipients for at least 8 weeks. Most MAGs with a high colonization rate belonged to the order Bacteroidales. The vast majority of those that lacked evidence of colonization belonged to the order Clostridiales, and colonization success was negatively correlated with the number of genes related to sporulation. Our analysis of 151 publicly available gut metagenomes showed that the donor MAGs that colonized both recipientsmore » were prevalent, and the ones that colonized neither were rare across the participants of the Human Microbiome Project. Although our dataset showed a link between taxonomy and the colonization ability of a given MAG, we also identified MAGs that belong to the same taxon with different colonization properties, highlighting the importance of an appropriate level of resolution to explore the functional basis of colonization and to identify targets for cultivation, hypothesis generation, and testing in model systems. Lastly, the analytical strategy adopted in our study can provide genomic insights into bacterial populations that may be critical to the efficacy of FMT due to their success in gut colonization and metabolic properties, and guide cultivation efforts to investigate mechanistic underpinnings of this procedure beyond associations.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [3];  [1];  [1];  [4]
  1. Univ. of Chicago Medicine, Chicago, IL (United States)
  2. Univ. of Chicago Medicine, Chicago, IL (United States); Boston Children's Hospital, Boston, MA (United States)
  3. Marine Biological Lab., Woods Hole, MA (United States)
  4. Univ. of Chicago Medicine, Chicago, IL (United States); Marine Biological Lab., Woods Hole, MA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
Gastro-Intestinal Research Foundation (GIRF); University of Chicago; USDOE
OSTI Identifier:
1415981
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Microbiome
Additional Journal Information:
Journal Volume: 5; Journal Issue: 1; Journal ID: ISSN 2049-2618
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; colonization; fecal microbiota transplantation; metagenome-assembled genomes; metagenomics

Citation Formats

Lee, Sonny T. M., Kahn, Stacy A., Delmont, Tom O., Shaiber, Alon, Esen, Ozcan C., Hubert, Nathaniel A., Morrison, Hilary G., Antonopoulos, Dionysios A., Rubin, David T., and Eren, A. Murat. Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics. United States: N. p., 2017. Web. doi:10.1186/s40168-017-0270-x.
Lee, Sonny T. M., Kahn, Stacy A., Delmont, Tom O., Shaiber, Alon, Esen, Ozcan C., Hubert, Nathaniel A., Morrison, Hilary G., Antonopoulos, Dionysios A., Rubin, David T., & Eren, A. Murat. Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics. United States. doi:10.1186/s40168-017-0270-x.
Lee, Sonny T. M., Kahn, Stacy A., Delmont, Tom O., Shaiber, Alon, Esen, Ozcan C., Hubert, Nathaniel A., Morrison, Hilary G., Antonopoulos, Dionysios A., Rubin, David T., and Eren, A. Murat. Thu . "Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics". United States. doi:10.1186/s40168-017-0270-x. https://www.osti.gov/servlets/purl/1415981.
@article{osti_1415981,
title = {Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics},
author = {Lee, Sonny T. M. and Kahn, Stacy A. and Delmont, Tom O. and Shaiber, Alon and Esen, Ozcan C. and Hubert, Nathaniel A. and Morrison, Hilary G. and Antonopoulos, Dionysios A. and Rubin, David T. and Eren, A. Murat},
abstractNote = {Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection and shows promise for treating other medical conditions associated with intestinal dysbioses. However, we lack a sufficient understanding of which microbial populations successfully colonize the recipient gut, and the widely used approaches to study the microbial ecology of FMT experiments fail to provide enough resolution to identify populations that are likely responsible for FMT-derived benefits. Here, we used shotgun metagenomics together with assembly and binning strategies to reconstruct metagenome-assembled genomes (MAGs) from fecal samples of a single FMT donor. We then used metagenomic mapping to track the occurrence and distribution patterns of donor MAGs in two FMT recipients. Our analyses revealed that 22% of the 92 highly complete bacterial MAGs that we identified from the donor successfully colonized and remained abundant in two recipients for at least 8 weeks. Most MAGs with a high colonization rate belonged to the order Bacteroidales. The vast majority of those that lacked evidence of colonization belonged to the order Clostridiales, and colonization success was negatively correlated with the number of genes related to sporulation. Our analysis of 151 publicly available gut metagenomes showed that the donor MAGs that colonized both recipients were prevalent, and the ones that colonized neither were rare across the participants of the Human Microbiome Project. Although our dataset showed a link between taxonomy and the colonization ability of a given MAG, we also identified MAGs that belong to the same taxon with different colonization properties, highlighting the importance of an appropriate level of resolution to explore the functional basis of colonization and to identify targets for cultivation, hypothesis generation, and testing in model systems. Lastly, the analytical strategy adopted in our study can provide genomic insights into bacterial populations that may be critical to the efficacy of FMT due to their success in gut colonization and metabolic properties, and guide cultivation efforts to investigate mechanistic underpinnings of this procedure beyond associations.},
doi = {10.1186/s40168-017-0270-x},
journal = {Microbiome},
number = 1,
volume = 5,
place = {United States},
year = {2017},
month = {5}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 10 works
Citation information provided by
Web of Science

Figures / Tables:

Figure 1 Figure 1: Distribution of MAGs across samples and HMP metagenomes. a The 92 MAGs and their level of detection in four donor samples (four inner circles) as well as two recipients (R01 and R02) before FMT (pre-FMT), 4 weeks after FMT (W4), and 8 weeks after FMT (W8). Rectangles withmore » red and blue colors in donor and recipient layers indicate the level of detection of a given MAG in a given sample. The outermost two layers display the genus- and order-level taxonomy for each MAG. Selections in a represent four groups of MAGs based on their distribution patterns: group I with 20 MAGs that colonized both recipients, group II with 11 MAGs that colonized only R01, group III with 8 MAGs that colonized only R02, and finally, group IV with 13 MAGs that colonized neither recipient. b The detection for each contig in two example MAGs summarized to a single detection value in a. c The coverage of each nucleotide position in two example contigs from the MAGs displayed in b. d The prevalence of MAGs in groups I and IV across 151 HMP gut metagenomes and detection of MAG 54 (group I) and MAG 26 (group IV) in HMP gut metagenomes as two examples« less

Save / Share:

Works referenced in this record:

Anvi’o: an advanced analysis and visualization platform for ‘omics data
journal, January 2015

  • Eren, A. Murat; Esen, Özcan C.; Quince, Christopher
  • PeerJ, Vol. 3
  • DOI: 10.7717/peerj.1319

Temporal and technical variability of human gut metagenomes
journal, April 2015


Long-Term Follow-Up of Colonoscopic Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection
journal, January 2012

  • Brandt, Lawrence J.; Aroniadis, Olga C.; Mellow, Mark
  • American Journal of Gastroenterology, Vol. 107, Issue 7
  • DOI: 10.1038/ajg.2012.60

Evaluation of genomic high-throughput sequencing data generated on Illumina HiSeq and Genome Analyzer systems
journal, January 2011


Systematic Review of Intestinal Microbiota Transplantation (Fecal Bacteriotherapy) for Recurrent Clostridium difficile Infection
journal, November 2011

  • Gough, Ethan; Shaikh, Henna; Manges, Amee R.
  • Clinical Infectious Diseases, Vol. 53, Issue 10
  • DOI: 10.1093/cid/cir632

Fecal Transplants: What Is Being Transferred?
journal, July 2016


Review article: faecal transplantation therapy for gastrointestinal disease: Review: faecal transplantation
journal, June 2011


High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria
journal, January 2013

  • Hamilton, Matthew J.; Weingarden, Alexa R.; Unno, Tatsuya
  • Gut Microbes, Vol. 4, Issue 2
  • DOI: 10.4161/gmic.23571

Safety, Tolerability, and Clinical Response After Fecal Transplantation in Children and Young Adults With Ulcerative Colitis
journal, January 2013

  • Kunde, Sachin; Pham, Angela; Bonczyk, Sarah
  • Journal of Pediatric Gastroenterology and Nutrition, Vol. 56, Issue 6
  • DOI: 10.1097/MPG.0b013e318292fa0d

Genome-wide analysis of the interaction between the endosymbiotic bacterium Wolbachia and its Drosophila host
journal, January 2008


Toward an Understanding of Changes in Diversity Associated with Fecal Microbiome Transplantation Based on 16S rRNA Gene Deep Sequencing
journal, October 2012


Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial
journal, July 2015


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


Centrifuge: rapid and sensitive classification of metagenomic sequences
journal, October 2016

  • Kim, Daehwan; Song, Li; Breitwieser, Florian P.
  • Genome Research, Vol. 26, Issue 12
  • DOI: 10.1101/gr.210641.116

Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile
journal, January 2013

  • van Nood, Els; Vrieze, Anne; Nieuwdorp, Max
  • New England Journal of Medicine, Vol. 368, Issue 5
  • DOI: 10.1056/NEJMoa1205037

Clostridium difficile infection: new developments in epidemiology and pathogenesis
journal, July 2009

  • Rupnik, Maja; Wilcox, Mark H.; Gerding, Dale N.
  • Nature Reviews Microbiology, Vol. 7, Issue 7
  • DOI: 10.1038/nrmicro2164

Fecal Microbiota Transplantation Inducing Remission in Crohn’s Colitis and the Associated Changes in Fecal Microbial Profile
journal, January 2014


Durable coexistence of donor and recipient strains after fecal microbiota transplantation
journal, April 2016


Prodigal: prokaryotic gene recognition and translation initiation site identification
journal, March 2010


Temporal Bacterial Community Dynamics Vary Among Ulcerative Colitis Patients After Fecal Microbiota Transplantation
journal, January 2013

  • Angelberger, Sieglinde; Reinisch, Walter; Makristathis, Athanasios
  • American Journal of Gastroenterology, Vol. 108, Issue 10
  • DOI: 10.1038/ajg.2013.257

An Overview of Ensembl
journal, May 2004


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

Gastrointestinal Microflora Studies in Late‐Onset Autism
journal, September 2002

  • Finegold, Sydney M.; Molitoris, Denise; Song, Yuli
  • Clinical Infectious Diseases, Vol. 35, Issue s1
  • DOI: 10.1086/341914

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

Relationship Between Thyroid Autoimmunity and Yersinia Enterocolitica Antibodies
journal, July 2002


Transfusion-transmitted infections
journal, June 2007

  • Bihl, Florian; Castelli, Damiano; Marincola, Francesco
  • Journal of Translational Medicine, Vol. 5, Issue 1
  • DOI: 10.1186/1479-5876-5-25

UGA is an additional glycine codon in uncultured SR1 bacteria from the human microbiota
journal, March 2013

  • Campbell, J. H.; O'Donoghue, P.; Campbell, A. G.
  • Proceedings of the National Academy of Sciences, Vol. 110, Issue 14, p. 5540-5545
  • DOI: 10.1073/pnas.1303090110

A core gut microbiome in obese and lean twins
journal, November 2008

  • Turnbaugh, Peter J.; Hamady, Micah; Yatsunenko, Tanya
  • Nature, Vol. 457, Issue 7228
  • DOI: 10.1038/nature07540

Colonization potential to reconstitute a microbe community in patients detected early after fecal microbe transplant for recurrent C. difficile
journal, January 2016


Fecal Microbiota Transplantation — An Old Therapy Comes of Age
journal, January 2013


Seres's pioneering microbiome drug fails mid-stage trial
journal, October 2016


A patient with severe Crohn's colitis responds to Faecal Microbiota Transplantation
journal, March 2014


Recovery of the Gut Microbiome following Fecal Microbiota Transplantation
journal, June 2014


Fecal Microbiota Transplantation for Clostridium difficile Infection: Systematic Review and Meta-Analysis
journal, January 2013

  • Kassam, Zain; Lee, Christine H.; Yuan, Yuhong
  • American Journal of Gastroenterology, Vol. 108, Issue 4
  • DOI: 10.1038/ajg.2013.59

Transfer of Viral Communities between Human Individuals during Fecal Microbiota Transplantation
journal, March 2016


Reset of a critically disturbed microbial ecosystem: faecal transplant in recurrent Clostridium difficile infection
journal, February 2014

  • Fuentes, Susana; van Nood, Els; Tims, Sebastian
  • The ISME Journal, Vol. 8, Issue 8
  • DOI: 10.1038/ismej.2014.13

Systematic review: faecal microbiota transplantation in the management of inflammatory bowel disease
journal, July 2012


Transfusion Reactions Due to Bacterial Contamination of Blood and Blood Products
journal, March 1991

  • Morduchowicz, Gabriel; Pitlik, Silvio D.; Huminer, David
  • Clinical Infectious Diseases, Vol. 13, Issue 2
  • DOI: 10.1093/clinids/13.2.307

Dynamic changes in short- and long-term bacterial composition following fecal microbiota transplantation for recurrent Clostridium difficile infection
journal, March 2015


Systematic Review: Adverse Events of Fecal Microbiota Transplantation
journal, August 2016


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

Environmental Genome Shotgun Sequencing of the Sargasso Sea
journal, April 2004


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

Patient-Specific Bacteroides Genome Variants in Pouchitis
journal, November 2016

  • Vineis, Joseph H.; Ringus, Daina L.; Morrison, Hilary G.
  • mBio, Vol. 7, Issue 6
  • DOI: 10.1128/mBio.01713-16

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

Machine Learning Meta-analysis of Large Metagenomic Datasets: Tools and Biological Insights
journal, July 2016


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

Fecal microbiota transplantation in relapsing Clostridium difficile infection
journal, July 2012


A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection
journal, February 2016

  • Khanna, Sahil; Pardi, Darrell S.; Kelly, Colleen R.
  • Journal of Infectious Diseases, Vol. 214, Issue 2
  • DOI: 10.1093/infdis/jiv766

Should We Standardize the 1,700-Year-Old Fecal Microbiota Transplantation?
journal, January 2012

  • Zhang, Faming; Luo, Wensheng; Shi, Yan
  • American Journal of Gastroenterology, Vol. 107, Issue 11
  • DOI: 10.1038/ajg.2012.251

PhyloSift: phylogenetic analysis of genomes and metagenomes
journal, January 2014

  • Darling, Aaron E.; Jospin, Guillaume; Lowe, Eric
  • PeerJ, Vol. 2
  • DOI: 10.7717/peerj.243

HMMER web server: interactive sequence similarity searching
journal, May 2011

  • Finn, R. D.; Clements, J.; Eddy, S. R.
  • Nucleic Acids Research, Vol. 39, Issue suppl
  • DOI: 10.1093/nar/gkr367

16S rRNA Gene Sequencing for Bacterial Identification in the Diagnostic Laboratory: Pluses, Perils, and Pitfalls
journal, July 2007

  • Janda, J. M.; Abbott, S. L.
  • Journal of Clinical Microbiology, Vol. 45, Issue 9
  • DOI: 10.1128/JCM.01228-07

Insights into the phylogeny and coding potential of microbial dark matter
journal, July 2013

  • Rinke, Christian; Schwientek, Patrick; Sczyrba, Alexander
  • Nature, Vol. 499, Issue 7459
  • DOI: 10.1038/nature12352

FastTree: Computing Large Minimum Evolution Trees with Profiles instead of a Distance Matrix
journal, April 2009

  • Price, M. N.; Dehal, P. S.; Arkin, A. P.
  • Molecular Biology and Evolution, Vol. 26, Issue 7
  • DOI: 10.1093/molbev/msp077

Fecal Flora Reconstitution for Recurrent Clostridium difficile Infection: Results and Methodology
journal, January 2010

  • Rohlke, Faith; Surawicz, Christina M.; Stollman, Neil
  • Journal of Clinical Gastroenterology, Vol. 44, Issue 8
  • DOI: 10.1097/MCG.0b013e3181dadb10

The Sequence Alignment/Map format and SAMtools
journal, June 2009


A Filtering Method to Generate High Quality Short Reads Using Illumina Paired-End Technology
journal, June 2013


Identifying biologically relevant differences between metagenomic communities
journal, February 2010


    Works referencing / citing this record:

    Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    dataset, May 2017

    • Lee, Sonny; Kahn, Stacy; Delmont, Tom
    • Figshare-Supplementary information for journal article at DOI: 10.1186/s40168-017-0270-x, 7 items
    • DOI: 10.6084/m9.figshare.c.3772019

    Additional file 1: Table S3. of Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    dataset, May 2017

    • Lee, Sonny; Kahn, Stacy; Delmont, Tom
    • figshare-Supplementary information for journal article at DOI: 10.1186/s40168-017-0270-x, 1 XLSX file (775.18 kB)
    • DOI: 10.6084/m9.figshare.c.3772019_d1

    Additional file 2: Table S1. of Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    dataset, May 2017

    • Lee, Sonny; Kahn, Stacy; Delmont, Tom
    • figshare-Supplementary information for journal article at DOI: 10.1186/s40168-017-0270-x, 1 XLSX file (181 kB)
    • DOI: 10.6084/m9.figshare.c.3772019_d2

    Additional file 3: Figure S1. of Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    dataset, May 2017

    • Lee, Sonny; Kahn, Stacy; Delmont, Tom
    • figshare-Supplementary information for journal article at DOI: 10.1186/s40168-017-0270-x, 1 PNG file (6.97 MB)
    • DOI: 10.6084/m9.figshare.c.3772019_d3

    Additional file 4: Figure S2. of Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    dataset, May 2017

    • Lee, Sonny; Kahn, Stacy; Delmont, Tom
    • Figshare-Supplementary information for journal article at DOI: 10.1186/s40168-017-0270-x, 1 png file (1.69 MB)
    • DOI: 10.6084/m9.figshare.c.3772019_d4

    Additional file 5: Figure S3. of Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    figure, May 2017

    • Lee, Sonny; Kahn, Stacy; Delmont, Tom
    • Figshare-Supplementary information for journal article at DOI: 10.1186/s40168-017-0270-x, 1 png file (983.05 kB)
    • DOI: 10.6084/m9.figshare.c.3772019_d5

    Additional file 6: Table S2. of Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    dataset, May 2017

    • Lee, Sonny; Kahn, Stacy; Delmont, Tom
    • Figshare-Supplementary information for journal article at DOI: 10.1186/s40168-017-0270-x, 1 xlsx file (240.41 kB)
    • DOI: 10.6084/m9.figshare.c.3772019_d6

    Additional file 7: Figure S4. of Tracking microbial colonization in fecal microbiota transplantation experiments via genome-resolved metagenomics
    figure, May 2017

    • Lee, Sonny; Kahn, Stacy; Delmont, Tom
    • figshare-Supplementary information for journal article at DOI: 10.1186/s40168-017-0270-x, 1 PNG file (2.18 MB)
    • DOI: 10.6084/m9.figshare.c.3772019_d7

    Sunbeam: an extensible pipeline for analyzing metagenomic sequencing experiments
    journal, March 2019


      Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.