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Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitudinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial isolates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable population sizes within and across humans and that commonly used ‘omics’ survey methods are more reliable when using averages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels, and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be used to infer eco-evolutionary dynamics and in vivo selection pressures for strains within individuals. The BIO-ML is a unique resource designed to enable hypothesis-driven microbiome research.
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ResouRce
https://doi.org/10.1038/s41591-019-0559-3
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. 2Center for Microbiome Informatics and
Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA. 3The Broad Institute of MIT and Harvard, Cambridge, MA, USA. 4Institute for
Systems Biology, Seattle, WA, USA. 5Finch Therapeutics, Somerville, MA, USA. 6OpenBiome, Somerville, MA, USA. 7Gastrointestinal Unit and Center for
Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA. 8These authors contributed equally: M. Poyet, M. Groussin,
S. M. Gibbons. *e-mail: xavier@molbio.mgh.harvard.edu; ejalm@mit.edu
Engineering the gut microbiome to treat disease is an exciting
new direction in medical science13. Fecal microbiota trans-
plant (FMT) from a healthy donor into patients with recurrent
Clostridium difficile infections is the first widely adopted microbi-
ome-related therapy and has a ~90% success rate4,5. Investigational
trials are underway in new disease areas, such as inflammatory
bowel disease, liver disease, Parkinson’s disease, severe acute malnu-
trition and infection by antibiotic-resistant pathogens69 (see ongo-
ing clinical trials at https://clinicaltrials.gov/). OpenBiome is a stool
bank that has provided material for over 48,000 fecal transplants.
Stool banks like OpenBiome represent an attractive opportunity
for building a well-characterized culture collection because living
biomass is preserved, allowing cultivation of isolated strains, and
because dense longitudinal sampling (that is, several samples being
collected per week) enables analysis of within-host dynamics. In
addition, a resource of isolate genomes together with longitudinal
dynamics can be useful in designing and analyzing future clinical
trials. Finally, a comprehensive culture collection from successful
donors could ultimately be used to replace FMT, which is a blunt
tool for engineering the gut microbiome and may have long-term
consequences due to the introduction of a wide variety of exoge-
nous strains with unknown function1012.
While comprehensive strain collections are essential for mecha-
nistic studies, culturing a diverse representation of gut bacteria has
been challenging. Seminal work by several groups1317 has addressed
many of the technological challenges of growing wide arrays of
gut bacterial lineages, and two recent studies reported isolate and
genome collections with broad phylogenetic representation18,19.
However, existing isolate and genome collections are still limited,
especially in strain-level diversity, for most of the bacterial species in
the human gut. In addition, current collections are limited in exam-
ples of coexisting strain-level diversity from the same human host
because the majority of strains were cultured from a large number of
individuals or were targeted for maximizing phylogenetic diversity.
Recent work has shown that this within-host strain diver-
sity is extensive in the human population20 and within individual
people2123. New studies increasingly point to functional differ-
ences between strains of the same species that can impact human
health21,24,25. For instance, strain-level differences can influence the
metabolism of dietary compounds, such as galacto-oligosaccha-
rides26 or nondigestible fibers27,28. Bacteria-mediated metabolism of
drugs can also differ across strains, influencing drug efficacy and
toxicity29,30. In addition, genomic variation in virulence genes can
alter pathogenicity among strains3133. Finally, distinct strains can
elicit different immune responses, such as cytokine production25.
For these reasons, a large collection of isolates of multiple strains
from many gut bacterial species, sampled both within and across
people, is needed to better understand host–microbe interactions
and to efficiently screen for candidate features that could ultimately
be leveraged in rationally designed microbiome-based therapeutics.
Here, we introduce a comprehensive biobank of human gut bac-
teria: a library of 7,758 bacterial isolates obtained from healthy FMT
donors recruited in the Boston area. This library covers most of the
phylogenetic diversity found in the human gut, contains extensive
A library of human gut bacterial isolates paired
with longitudinal multiomics data enables
mechanistic microbiome research
M. Poyet1,2,3,8, M. Groussin1,2,3,8, S. M. Gibbons 1,2,3,4,8, J. Avila-Pacheco3, X. Jiang1,2,3, S. M. Kearney1,2,3,
A. R. Perrotta1,2, B. Berdy 1,2,3, S. Zhao1,2, T. D. Lieberman1,2,3, P. K. Swanson1,5, M. Smith5,6,
S. Roesemann 3, J. E. Alexander3, S. A. Rich3, J. Livny3, H. Vlamakis3, C. Clish 3, K. Bullock3, A. Deik3,
J. Scott3, K. A. Pierce3, R. J. Xavier2,3,7* and E. J. Alm 1,2,3,5,6*
Our understanding of how the gut microbiome interacts with its human host has been restrained by limited access to longitu-
dinal datasets to examine stability and dynamics, and by having only a few isolates to test mechanistic hypotheses. Here, we
present the Broad Institute-OpenBiome Microbiome Library (BIO-ML), a comprehensive collection of 7,758 gut bacterial iso-
lates paired with 3,632 genome sequences and longitudinal multi-omics data. We show that microbial species maintain stable
population sizes within and across humans and that commonly used ‘omics’ survey methods are more reliable when using aver-
ages over multiple days of sampling. Variation of gut metabolites within people over time is associated with amino acid levels,
and differences across people are associated with differences in bile acids. Finally, we show that genomic diversification can be
used to infer eco-evolutionary dynamics and invivo selection pressures for strains within individuals. The BIO-ML is a unique
resource designed to enable hypothesis-driven microbiome research.
NATURE MEDICINE | VOL 25 | SEPTEMBER 2019 | 1442–1452 | www.nature.com/naturemedicine
1442
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... higher-quality representative genomes, having more samples from different individuals elevates the chances of assembling rare microbial species' genomes, that in most people exist in lower abundance than is required for the genome assembling process. Our metagenomic samples are mostly of Israeli adults (range 4-93 years old, median 55) but we also complimented the 142,912 newly assembled genomes produced from our samples with assemblies we gathered and curated from previously published studies (up to 2019) originating in different countries (short-read metagenome sequencing-based assemblies: 86,191 from ref. 7 and 7211 from ref. 15 , isolate-based assemblies: 94 from ref. 16 , 1327 from ref. 17 , and 528 from ref. 18 and ref. 19 , and nanopore metagenome sequencing-based assemblies: 2855) ( Table 1 and "Methods") 7, [15][16][17][18][19] . Metadata of all 241,118 assemblies used is available in Supplementary Data 1. ...
... higher-quality representative genomes, having more samples from different individuals elevates the chances of assembling rare microbial species' genomes, that in most people exist in lower abundance than is required for the genome assembling process. Our metagenomic samples are mostly of Israeli adults (range 4-93 years old, median 55) but we also complimented the 142,912 newly assembled genomes produced from our samples with assemblies we gathered and curated from previously published studies (up to 2019) originating in different countries (short-read metagenome sequencing-based assemblies: 86,191 from ref. 7 and 7211 from ref. 15 , isolate-based assemblies: 94 from ref. 16 , 1327 from ref. 17 , and 528 from ref. 18 and ref. 19 , and nanopore metagenome sequencing-based assemblies: 2855) ( Table 1 and "Methods") 7, [15][16][17][18][19] . Metadata of all 241,118 assemblies used is available in Supplementary Data 1. ...
... Different methods of producing genomes. In order to produce this improved quality and more divergent reference set, we complemented the short-read devised metagenome-assembled genomes (MAG) with data from nanopore sequencing and sequencing of isolates, both methods produce higher-quality assemblies [16][17][18][19] . These alternative method assemblies represent 2% of our assembled genomes and 21% of our chosen species representative genomes. ...
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The gut is the richest ecosystem of microbes in the human body and has great influence on our health. Despite many efforts, the set of microbes inhabiting this environment is not fully known, limiting our ability to identify microbial content and to research it. In this work, we combine new microbial metagenomic assembled genomes from 51,052 samples, with previously published genomes to produce a curated set of 241,118 genomes. Based on this set, we procure a new and improved human gut microbiome reference set of 3594 high quality species genomes, which successfully matches 83.65% validation samples’ reads. This improved reference set contains 310 novel species, including one that exists in 19% of validation samples. Overall, this study provides a gut microbial genome reference set that can serve as a valuable resource for further research. Here, Leviatan et al. produce 241,118 genome assemblies to produce a new human gut microbiome reference set of 3,594 species genomes, of which 310 represent previously undescribed species, making the catalog a valuable resource for further research.
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... However, the choice of study design (e.g., parallel, crossover, factorial, cluster), the duration of intervention, and the sampling timescales are critical to addressing the relevant biological mechanisms and timescales on which interventions-induced changes might occur (75). Prior work in a healthy human cohort found that 5-9 longitudinal samples, taken 2-3 days apart from one another, were optimal for estimating the average population sizes of commensal gut bacteria within an individual's gut (65,76). Additionally, inter-individual heterogeneity in microbiome composition makes traditional randomized trials difficult to interpret, which suggests that N-of-1 trial designs and crossover trials, where individuals serve as their own controls, are best when considering personalized microbiota-intervention interactions (77-79). ...
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