Jeffrey I. Gordon, MD
•Director of the center for Genome Sciences and
Systems Biology at Washington University, St. Louis
Presenter: rui zhang
Resume
In 1969, he got his bachelor’s degree in Biology at Oberlin College in Ohio.
• Over the next four years, he received his medical training at the University of Chicago and
graduated with honors in 1973.
•After two years as intern and junior assistant resident in Medicine at Barnes Hospital, St Louis
•In 1975, Gordon joined the Laboratory of Biochemistry at the National Cancer Institute as a
Research Associate.
•In1978, he returned to Barnes Hospital to become Senior Assistant Resident and then Chief
Medical Resident at Washington University Medical Service.
• In 1981 he completed a fellowship in medicine (Gastroenterology) at Washington University
School of Medicine.
•Asst. Prof. (1981–1984), Assoc. Prof. (1985–1987), Prof. (1987–1991) Medicine and
Biological Chemistry at Washington University
• In 1991, he became head of the Dept. Molecular Biology & Pharmacology (1991–2004).
• 2004-present: Gordon is currently the Director of the Center for Genome Sciences at
Washington University.
Present Research
 The mutualistic interactions between humans and 10-100 trillion microbes that
colonize each person’s gastrointestinal tract.
They employ germ-free and gnotobiotic mice as model hosts, which may be colonized with
defined, simplified microbial communities. These model intestinal microbiotas are more amenable to
well-controlled experimentation.
 Jeffrey Gordon has become an international pioneer in studying gut microbial
ecology and evolution, using innovative methods to interpret metagenomic and gut
microbial genomic sequencing data.
The gut microbiota plays a role in host fat storage and obesity.
Gordon and co-workers have used DNA pyrosequencing technology to perform
metagenomics on the intestinal contents of obese mice, demonstrating that the gut microbiota of fat
mice possess an increased capacity for helping the host in harvesting energy from the diet. A study of
the microbial ecology of obese human subjects on two different weight loss diets indicate that the
same principles may be operating in humans.
His group has applied the sequencing of bacterial and archaeal genomes to describe the
microbial functional genomic and metabolomic underpinnings of microbial adaptation to the
gastrointestinal habitat. This approach has been extended to describe the role of the adaptive immune
system in maintaining the host-microbial relationship.
 Dr. Gordon is the lead author of an influential 2005 National Human
Genome Research Institute white-paper entitled “Extending Our View of Self:
the Human Gut Microbiome Initiative (HGMI)”. In 2007 the Human Microbiome
Project was listed on the NIH Roadmap for Medical Research as one of the
New Pathways to Discovery.
 His noticeable remark is: "We think that there are 10 times more microbial
cells on and in our bodies than there are human cells. That means that we're
90 percent microbial and 10 percent human. There's also an estimated 100
times more microbial genes than the genes in our human genome. So we're
really a compendium [and] an amalgamation of human and microbial
parts.", though Scientific American points out that this refers only to the number
of cells, not to the absolute weight or space occupied.
Selected Honors Received
•Alpha Omega Alpha (1973)
•John A. and George L. Hartford Foundation Fellowship (1981-1984)
•Established Investigator, American Heart Association (1985-1990)
•Young Investigator Award, American Federation for Clinical Research (1990)
•Young Scientist Award, National Institute of Diabetes and Digestive and Kidney Diseases (1990)
•Distinguished Achievement Award, American Gastroenterological Association (AGA) (1992)
•Fellow, American Association for the Advancement of Science (1992)
•MERIT Award, NIDDK (DK30292, Regulation of Gene Expression in the Intestine) (1993)
•Marion Merrell Dow Distinguished Prize in Gastrointestinal Physiology, American Physiological Society (1994)
•Fellow, American Academy of Microbiology (2001)
•Elected, National Academy of Sciences (2001)
•Janssen/AGA Sustained Achievement Award in Digestive Sciences (2003)
•Senior Scholar Award in Global Infectious Diseases, Ellison Medical Foundation (2003)
•Elected, American Academy of Arts & Sciences (2004)
•ASM Lecturer, 105th Annual Meeting, American Society of Microbiology (2005)
•MERIT Award, NIDDK (DK30292 – Genomic and Metabolic Foundations of Human-Microbial Symbiosis in the Gut,
2006; second MERIT award for grant)
•Distinguished Service Award, The University of Chicago (2008)
•Harvey Society Lecturer (2008)
•Elected, Institute of Medicine of the National Academies (2008)
•Chair, Section 42 (Medical Physiology and Metabolism), National Academy of Sciences (2010-2013)
•Distinguished Scientist Award, NIDDK, NIH (2010)
•Danone International Prize for Nutrition (2011)
•Honorary Doctorate, University of Gothenburg (2011)
•Association of American Medical Colleges (AAMC) Award for Distinguished Research in the Biomedical Sciences (2012)
•Selman A. Waksman Award in Microbiology, National Academy of Sciences (2013)
•Robert Koch Award (2013).
Awards from Washington University
and St. Louis area institutions
•Outstanding Faculty Mentor Award, Graduate Student Council, Washington University (2000,
first recipient of this annual award)
•Second Century Award, Washington University School of Medicine (2005)
•Carl and Gerty Cori Faculty Achievement Award Washington University (2009)
•Founder’s Day Distinguished Faculty Award, Washington University (2011)
•Peter H. Raven Lifetime Achievement Award, Academy of Science, St. Louis (2012)
•Danforth Science Award, Donald Danforth Plant Science Center (2012)
Publications
 Hooper, L.V., Wong, M.H., Thelin, A., Hansson, L., Falk, P.G, and Gordon, J.I. Molecular analysis of commensal hostmicrobial relationships in the intestine.Science 291: 881-884 (2001).
 Xu, J., Bjursell, M.K., Himrod, J., Deng, S. Carmichael, L.K., Chiang, H.C., Hooper, L.V., and Gordon, J.I. A genomic
view of the human-Bacteroides thetaiotaomicron symbiosis. Science, 299:2074-2076 (2003).
 Hooper, L.V., Stappenbeck, T.S., Hong, C.V., Gordon, J.I. Angiogenins: a new class of microbicidal proteins involved
in innate immunity. Nature Immunol.4: 269-273 (2003).
 Bäckhed, F., Ding, H., Wang, T., Hooper, L.V., Koh, G. Y., Nagy, A., Semenkovich, C.F. Gordon, J. I. The gut
microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 101:15718-15723 (2004).
 Sonnenburg, J.L., Xu, J., Leip, D.D., Chen, C.H., Westover, B. P., Weatherford, J., Buhler, J.D., Gordon, J.I. Glycan
foraging in vivo by an intestine-adapted bacterial symbiont. Science307:1955-1959 (2005).
 Rawls, J.F., Mahowald, M.A., Ley, R.E., Gordon, J.I. Reciprocal gut microbiota transplants from zebrafish and mice to
germ-free recipients reveal host habitat selection. Cell 127:423-33 (2006).
 Ley, R.E., Turnbaugh, P.J., Klein, S., and Gordon, J.I. Microbial ecology: human gut microbes associated with
obesity. Nature444: 1022-1023 (2006).
 Turnbaugh, P.J., Ley, R.E., Mahowald, M.A., Magrini, V., Mardis, E.R. and Gordon, J.I. An obesity-associated gut
microbiome with increased capacity for energy harvest. Nature 2006; 444:1027-1031 (2006).
 Ley, R.E., Hamady, M., Lozupone, C., Turnbaugh, P.J., Ramey, R.R., Bircher, J.S., Schlegel, M.L., Tucker, T.A., Schrenzel,
M.D., Knight, R., and Gordon, J.I. Evolution of mammals and their gut microbes. Science320:1647-1651 (2008).
Publications
 Turnbaugh, P.J., Hamady, M., Yatsunenko, T., Cantarel, B., Duncan, A., Ley, R.E., Sogin, M.L., Jones, J., Roe, B.A., Affourtit,
J.P., Egholm, M., Henrissat, B., Heath, A.C., Knight, R. and Gordon J.I. A core gut microbiome in obese and lean
twins. Nature 457:480-484 (2009).
 Reyes, A., Haynes, M., Hanson, N., Angly, F., Heath, A., Rohwer, F., and Gordon, J.I. Viruses in the fecal microbiota of
monozygotic twins and their mothers. Nature466: 334-338 (2010).
 McNulty, N, Yatsunenko, T, Hsiao, A., Faith, J., Muegge, B., Goodman, A., Henrissat, B., Oozeer, R., Cools, Portier, S.,
Gobert, G., Chervaux, C., Knights, D., Lozupone, C., Knight, R., Duncan, A.E., Bain, J.R., Muehlbauer, M.J., Newgard, C.B.,
Heath, A.C., and Gordon, J.I. The impact of a consortium of fermented milk strains on the gut microbiome of gnotobiotic mice
and monozygotic twins. Science Translational Medicine3: 106ra106, (2011).
 Muegge, B., Kuczynski, J., Knights, D., Clemente, J.C., Gonzalez, A., Fontana, L., Henrissat, L., Knight, R., and Gordon, J.I.,
Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332: 970-974
(2011).
 Faith, J.J., McNulty, N.P., Rey, F.E., and Gordon, J.I. Predicting a human gut microbiota’s response to diet in gnotobiotic
mice. Science 333: 101-104 (2011).
 Goodman, A.L., Kallstrom, G., Faith, J.J., Reyes, A., Moore, A., Dantas, G., and Gordon, J.I. Extensive personal human gut
microbiota culture collections characterized and manipulated in gnotobiotic mice Proc. Natl. Acad. Sci USA108: 6252-625
(2011).
 Yatsunenko, T., Rey, F.E., Manary, M.J., Trehan, I., Dominguez-Bello, M.G., Contreras, M., Magris, M., Hidalgo, G.,
Baldassano, R.N., Anokhin, A.P., Heath, A.C., Warner, B., Reeder, J., Kuczynski, J., Caporaso, J.G., Lozupone, C.A., Lauber, C.,
Clemente, J.C., Knights, D., Knight, R., and Gordon, J.I. Human gut microbiome viewed across age and
geography. Nature486: 222-227 (2012).
 Smith, M.I., Yatsunenko, T., Manary, M.J., Trehan, I., Mkakosya, R., Cheng, J., Kau, A., Rich, S.S., Concannon, P.,
Mychaleckyj, J.C., Liu, J., Houpt, E., Li, J.V., Holmes, E., Nicholson, J., Knights, D., Ursell, L.K., Knight, R., and Gordon, J.I. Gut
microbiomes of Malawian twin pairs discordant for kwashiorkor. Science,339: 548-554 (2013).
Annu Rev Nutr. 2002 Apr 4.
How host-microbial interactions shape the nutrient environment of the
mammalian intestine.
Humans and other mammals are colonized by a vast, complex, and dynamic consortium of
microorganisms. One evolutionary driving force for maintaining this metabolically active
microbial society is to salvage energy from nutrients, particularly carbohydrates, that are
otherwise nondigestible by the host. Much of our understanding of the molecular mechanisms
by which members of the intestinal microbiota degrade complex polysaccharides comes from
studies of Bacteroides thetaiotaomicron, a prominent and genetically manipulatable component
of the normal human and mouse gut. Colonization of germ-free mice with B.
thetaiotaomicron has shown how this anaerobe modifies many aspects of intestinal
cellular differentiation/gene expression to benefit both host and microbe. These and other
studies underscore the importance of understanding precisely how nutrient metabolism serves to
establish and sustain symbiotic relationships between mammals and their bacterial partners.
 Mammals absorb simple sugars, such as
glucose and galactose, via active transport in the
proximal regions of their small intestine. However,
they have limited intrinsic capacity to digest
dietary polysaccharides.
 Undigested polysaccharides such as cellulose,
xylan, and undigested starch, as well as hostderived glycans (mucins and glycosphingolipids)
pass into the distal regions of the small intestine
(ileum) and colon where they are degraded by
resident microbes.
 Bacteria
ferment
the
resulting
monosaccharides, and the byproducts of this
fermentation (short chain fatty acids) are
absorbed and utilized by the host.
Overview of host and bacterial contributions
to carbohydrate utilization in the intestine.
 Monosaccharides released from carbohydrate
polymers are converted in the bacterial cytoplasm
to pyruvate via glycolysis, which results in net
production of ATP.
 In the highly anaerobic environment of the
distal intestine, additional carbon and energy is
extracted
from
pyruvate
by
microbial
fermentation. The predominant end-products of
fermentation are acetate, propionate, and
butyrate.
 To recover some of the nutritional value of
polysaccharides degraded by gut microbes,
mammalian hosts absorb and utilize these short
chain fatty acid species.
Overview of bacterial
fermentation in the intestine.
Proc Natl Acad Sci U S A 2002 Nov 13.
Developmental regulation of intestinal angiogenesis by indigenous microbes via
Paneth cells.
The adult mouse intestine contains an intricate vascular network. The factors that control
development of this network are poorly understood. Quantitative three-dimensional imaging
studies revealed that a plexus of branched interconnected vessels developed in small intestinal villi
during the period of postnatal development that coincides with assembly of a complex society of
indigenous gut microorganisms (microbiota). To investigate the impact of this environmental
transition on vascular development, we compared the capillary networks of germ-free mice with
those of ex-germ-free animals colonized during or after completion of postnatal gut development.
Adult germ-free mice had arrested capillary network formation. The developmental program can
be restarted and completed within 10 days after colonization with a complete microbiota
harvested from conventionally raised mice, or with Bacteroides thetaiotaomicron, a prominent
inhabitant of the normal mouse/human gut. Paneth cells in the intestinal epithelium secrete
antibacterial peptides that affect luminal microbial ecology. Comparisons of germ-free and B.
thetaiotaomicron-colonized transgenic mice lacking Paneth cells established that microbial
regulation of angiogenesis depends on this lineage. These findings reveal a previously
unappreciated mechanism of postnatal animal development, where microbes colonizing a
mucosal surface are assigned responsibility for regulating elaboration of the underlying
microvasculature by signaling through a bacteria-sensing epithelial cell.
Rapid microbial induction of angiogenesis in
small intestinal villi of adult ex-germ-free
mice.(A) Germ-free (GF) mouse. (B) Agematched ex-germ-free conventionalized
(CONV) mouse killed 10 days after
colonization
with
an
unfractionated
microbiota harvested from a conventionally
raised “donor.” (C) Ex-germ-free mouse 10
days
after
colonization
with
B.
thetaiotaomicron (B. theta) alone.
Paneth cell and microbial regulation of
angiogenesis. (A–D) Confocal scans of 120-μmthick cryosections showing the upper thirds of
villi. (A) Germ-free, Paneth cell-deficient P28
male CR2-tox176 mouse. (B) Age- and gendermatched, germ-free, Paneth-cell-containing
normal littermate. (C) Ex-germ-free P28 CR2tox176 mouse examined 7 days after
colonization with B. thetaiotaomicron. (D) P28
nontransgenic mouse killed 7 days after monoassociation with B. thetaiotaomicron.
Science.2003 Mar 28
A genomic view of the human-Bacteroides thetaiotaomicron symbiosis.
The human gut is colonized with a vast community of indigenous microorganisms that
help shape our biology. Here, we present the complete genome sequence of the Gramnegative anaerobe Bacteroides thetaiotaomicron, a dominant member of our normal
distal intestinal microbiota. Its 4779-member proteome includes an elaborate
apparatus for acquiring and hydrolyzing otherwise indigestible dietary
polysaccharides and an associated environment-sensing system consisting of a large
repertoire of extracytoplasmic function sigma factors and one- and two-component
signal transduction systems. These and other expanded paralogous groups shed light
on the molecular mechanisms underlying symbiotic host-bacterial relationships in
our intestine.
Trends Microbiol. 2003 Apr
Commensal bacteria make a difference.
The importance of the gut microbiota has
been recognized since the days of
Pasteur. What makes today different from
yesterday, and tomorrow so exciting, is
that we now have the tools to identify the
molecular mechanisms that regulate
assembly of the microbiota and
determine how its components affect
postnatal mammalian development and
adult physiology.
Proc Natl Acad Sci U S A. 2004 Mar 30
Gnotobiotic zebrafish reveal evolutionarily conserved responses to the gut
microbiota.
Animals have developed the means for supporting complex and dynamic consortia of
microorganisms during their life cycle. A transcendent view of vertebrate biology therefore
requires an understanding of the contributions of these indigenous microbial communities to host
development and adult physiology. These contributions are most obvious in the gut, where studies
of gnotobiotic mice have disclosed that the microbiota affects a wide range of biological
processes, including nutrient processing and absorption, development of the mucosal immune
system, angiogenesis, and epithelial renewal. The zebrafish (Danio rerio) provides an opportunity
to investigate the molecular mechanisms underlying these interactions through genetic and
chemical screens that take advantage of its transparency during larval and juvenile stages.
Therefore, we developed methods for producing and rearing germ-free zebrafish through late
juvenile stages. DNA microarray comparisons of gene expression in the digestive tracts of 6 days
post fertilization germ-free, conventionalized, and conventionally raised zebrafish revealed 212
genes regulated by the microbiota, and 59 responses that are conserved in the mouse
intestine, including those involved in stimulation of epithelial proliferation, promotion of nutrient
metabolism, and innate immune responses. The microbial ecology of the digestive tracts of
conventionally raised and conventionalized zebrafish was characterized by sequencing libraries
of bacterial 16S rDNA amplicons. Colonization of germ-free zebrafish with individual members
of its microbiota revealed the bacterial species specificity of selected host responses. Together,
these studies establish gnotobiotic zebrafish as a useful model for dissecting the molecular
foundations of host-microbial interactions in the vertebrate digestive tract.
Nat Immunol. 2004 Jun
Getting a grip on things: how do communities of bacterial
symbionts become established in our intestine?
The gut contains our largest collection of resident microorganisms. One obvious
question is how microbial communities establish and maintain themselves
within a perfused intestine. The answers, which may come in part from
observations made by environmental engineers and glycobiologists, have
important implications for immunologists who wish to understand how
indigenous microbial communities are accommodated. Here we propose that
the mucus gel layer overlying the intestinal epithelium is a key contributor
to the structural and functional stability of this microbiota and its tolerance
by the host.
The fingerlike projections are villi. Most of the
mucus gel layer that normally overlies the villus
epithelium has been lost during sample processing;
arrows indicate remnants. Scale bar, 100 μm.
View of the distal small intestine of a mouse
by scanning electron microscopy.
Proposed mechanism for microbial
retention in the gut.
By analogy to anaerobic upflow bioreactors that lack static carrier
material, biofilm formation and retention of autochthonous components
of the microbiota is made possible in part by use of mucus as a key
element in the selfimmobilization process.
(i) Poorly settling materials (undigested food particles, planktonic
bacteria) are rapidly washed out.
(ii) Dense aggregates are formed by microbes themselves, undigested
food, shed elements of the mucus gel and/or exfoliated epithelial cells.
Aggregates serve as a scaffold for assembling microbial consortia, may
be further transformed through microbial or mechanical processing and
may have dynamic interactions with other granules and/or with the
mucus gel layer.
(iii) Aggregates and mucus promote nutrient harvest and metabolic
exchange. Outer membrane polysaccharide-binding proteins may
facilitate attachment of some species, such as members of Bacteroides,
to mucus glycans. These interactions can be regulated by ‘scaffolding
factors’, such as host or microbial lectins, and host IgA. Regional
variation in the glycan composition and thickness of the mucus biofilm
could serve as a ‘molecular zip code’ that helps promote niche-specific
interactions and nutrient harvest.
Proc Natl Acad Sci U S A. 2004 Nov 2
The gut microbiota as an environmental factor that regulates fat storage.
New therapeutic targets for noncognitive reductions in energy intake, absorption, or storage are
crucial given the worldwide epidemic of obesity. The gut microbial community (microbiota) is
essential for processing dietary polysaccharides. We found that conventionalization of adult
germ-free (GF) C57BL/6 mice with a normal microbiota harvested from the distal intestine
(cecum) of conventionally raised animals produces a 60% increase in body fat content and
insulin resistance within 14 days despite reduced food intake. Studies of GF and
conventionalized mice revealed that the microbiota promotes absorption of monosaccharides from
the gut lumen, with resulting induction of de novo hepatic lipogenesis. Fasting-induced adipocyte
factor (Fiaf), a member of the angiopoietin-like family of proteins, is selectively suppressed in the
intestinal epithelium of normal mice by conventionalization. Analysis of GF and conventionalized,
normal and Fiaf knockout mice established that Fiaf is a circulating lipoprotein lipase inhibitor
and that its suppression is essential for the microbiota-induced deposition of triglycerides in
adipocytes. Studies of Rag1-/- animals indicate that these host responses do not require mature
lymphocytes. Our findings suggest that the gut microbiota is an important environmental factor
that affects energy harvest from the diet and energy storage in the host.
Schematic view of how the gut microbiota effects host fat storage. The
microbiota acts through Fiaf (Fasting-induced adipocyte factor) to
coordinate increased hepatic lipogenesis with increased LPL (Lipoprotein
lipase) activity in adipocytes, thereby promoting storage of calories
harvested from the diet into fat.
Science. 2005 Mar 25
Host-bacterial mutualism in the human intestine.
The distal human intestine represents an anaerobic bioreactor programmed with an
enormous population of bacteria, dominated by relatively few divisions that are
highly diverse at the strain/subspecies level. This microbiota and its collective
genomes (microbiome) provide us with genetic and metabolic attributes we have
not been required to evolve on our own, including the ability to harvest otherwise
inaccessible nutrients. New studies are revealing how the gut microbiota has
coevolved with us and how it manipulates and complements our biology in ways
that are mutually beneficial. We are also starting to understand how certain
keystone members of the microbiota operate to maintain the stability and
functional adaptability of this microbial organ.
Representation of the diversity of bacteria in the human intestine.
Phylogenetic tree of the domain bacteria based on 8903 representative 16S rRNA gene
sequences. Wedges represent divisions: Those numerically abundant in the human gut are
red, rare divisions are green, and undetected are black. Wedge length is a measure of
evolutionary distance from the common ancestor.
Science. 2005 Mar 25
Glycan foraging in vivo by an intestine-adapted bacterial symbiont.
Germ-free mice were maintained on polysaccharide-rich or simple-sugar diets and
colonized for 10 days with an organism also found in human guts, Bacteroides
thetaiotaomicron, followed by whole-genome transcriptional profiling of bacteria and mass
spectrometry of cecal glycans. We found that these bacteria assembled on food particles
and mucus, selectively induced outer-membrane polysaccharide-binding proteins and
glycoside hydrolases, prioritized the consumption of liberated hexose sugars, and
revealed a capacity to turn to host mucus glycans when polysaccharides were absent from
the diet. This flexible foraging behavior should contribute to ecosystem stability and
functional diversity.
Proc Natl Acad Sci U S A. 2005 Aug 2
Obesity alters gut microbial ecology.
We have analyzed 5,088 bacterial 16S rRNA gene sequences from the distal intestinal
(cecal) microbiota of genetically obese ob/ob mice, lean ob/+ and wild-type siblings, and
their ob/+ mothers, all fed the same polysaccharide-rich diet. Although the majority of mouse
gut species are unique, the mouse and human microbiota(s) are similar at the division
(superkingdom) level, with Firmicutes and Bacteroidetes dominating. Microbial-community
composition is inherited from mothers. However, compared with lean mice and regardless of
kinship, ob/ob animals have a 50% reduction in the abundance of Bacteroidetes and a
proportional increase in Firmicutes. These changes, which are division-wide, indicate that, in
this model, obesity affects the diversity of the gut microbiota and suggest that intentional
manipulation of community structure may be useful for regulating energy balance in
obese individuals.
Cell. 2006 Feb 24
Ecological and evolutionary forces shaping microbial diversity in the
human intestine.
The human gut is populated with as many as 100 trillion cells, whose collective
genome, the microbiome, is a reflection of evolutionary selection pressures acting
at the level of the host and at the level of the microbial cell. The ecological rules
that govern the shape of microbial diversity in the gut apply to mutualists and
pathogens alike.
Selection pressure on
host results in group
selection of a
microbial community
Host immune
system
and intermicrobial
dynamics select
for specific
microbes
Selection of cell
phenotype results in
selection of specific
genomes
Selection of
genome results in
fixation or loss of
individual genes
Microbial
community
Emergent properties
of community
influence host fitness
Phenotypes of cells
influences emergent
properties of
community
Whole genome
interactions, such as
regulation of gene
expression, influence
phenotype of cells
Gene content
influences genomelevel functions
Schematic Diagram of the Selection Pressures
Operating at Different Levels in the Human-Microbial Hierarchy Brown
arrows indicate selection pressures and point to the unit under selection
(red). Black arrows indicate emergent properties of one level that affect
higher levels in the hierarchy.
According to hierarchy theory, higher levels place constraints on possible
organizational solutions at lower levels. Ecologic principles predict that
host-driven (‘‘topdown’’) selection for functional redundancy would result
in a community composed of widely divergent microbial lineages
(divisions) whose genomes contain functionally similar suites of genes.
Another prediction is the widespread occurrence of, and abundant
mechanisms for, lateral gene transfer. In contrast, competition between
members of the microbiota would exert ‘‘bottom-up’’ selection pressure
that results in specialized genomes with functionally distinct suites of
genes (metabolic traits). Once established, these lineage-specific traits
can be maintained by barriers to homologous recombination.
Percent representation of divisions in
each environment.
Variation in Bacterial Diversity
within the Colonic Microbiotas of
Three Healthy Humans.
These phylogenetic trees are
based on the 16S rRNA bacterial
sequence data set (n = 11,831)
and alignmen.
Science. 2006 Jun 2
Metagenomic analysis of the human distal gut microbiome.
The human intestinal microbiota is composed of 1013 to 1014 microorganisms whose collective
genome ("microbiome") contains at least 100 times as many genes as our own genome. We
analyzed approximately 78 million base pairs of unique DNA sequence and 2062
polymerase chain reaction-amplified 16S ribosomal DNA sequences obtained from the fecal
DNAs of two healthy adults. Using metabolic function analyses of identified genes, we
compared our human genome with the average content of previously sequenced microbial
genomes. Our microbiome has significantly enriched metabolism of glycans, amino acids,
and xenobiotics; methanogenesis; and 2-methyl-d-erythritol 4-phosphate pathwaymediated biosynthesis of vitamins and isoprenoids. Thus, humans are superorganisms
whose metabolism represents an amalgamation of microbial and human attributes.
Proc Natl Acad Sci U S A. 2006 Jun 27
A humanized gnotobiotic mouse model of host-archaeal-bacterial mutualism.
Our colons harbor trillions of microbes including a prominent archaeon, Methanobrevibacter
smithii. To examine the contributions of Archaea to digestive health, we colonized germ-free
mice with Bacteroides thetaiotaomicron, an adaptive bacterial forager of the polysaccharides
that we consume, with or without M. smithii or the sulfate-reducing bacterium Desulfovibrio
piger. Whole-genome transcriptional profiling of B. thetaiotaomicron, combined with mass
spectrometry, revealed that, unlike D. piger, M. smithii directs B. thetaiotaomicron to focus on
fermentation of dietary fructans to acetate, whereas B. thetaiotaomicron-derived formate is used
by M. smithii for methanogenesis. B. thetaiotaomicron-M. smithii cocolonization produces a
significant increase in host adiposity compared with monoassociated, or B. thetaiotaomicronD. piger biassociated, animals. These findings demonstrate a link between this archaeon,
prioritized bacterial utilization of polysaccharides commonly encountered in our modern diets,
and host energy balance.
Cell. 2006 Oct 20
Reciprocal gut microbiota transplants from zebrafish and mice to germfree recipients reveal host habitat selection.
The gut microbiotas of zebrafish and mice share six bacterial divisions, although
the specific bacteria within these divisions differ. To test how factors specific to host
gut habitat shape microbial community structure, we performed reciprocal
transplantations of these microbiotas into germ-free zebrafish and mouse
recipients. The results reveal that communities are assembled in predictable ways.
The transplanted community resembles its community of origin in terms of the
lineages present, but the relative abundance of the lineages changes to
resemble the normal gut microbial community composition of the recipient host.
Thus, differences in community structure between zebrafish and mice arise in part
from distinct selective pressures imposed within the gut habitat of each host.
Nonetheless, vertebrate responses to microbial colonization of the gut are ancient:
Functional genomic studies disclosed shared host responses to their
compositionally distinct microbial communities and distinct microbial species
that elicit conserved responses.
Summary of shared and distinct
bacterial divisions in the zebrafish,
mouse, and human gut microbiota.
Comparison of Input
Bacterial divisions and their lineages and Output Communities
following Reciprocal
detected in the zebrafish digestive
tract, mouse cecum, and human colon. Transplantation of Gut
Microbiotas in
Gnotobiotic Zebrafish
and Mice
Nature. 2006 Dec 21
Microbial ecology: human gut microbes associated with obesity.
Two groups of beneficial bacteria are dominant in the human gut, the
Bacteroidetes and the Firmicutes. Here we show that the relative
proportion of Bacteroidetes is decreased in obese people by comparison
with lean people, and that this proportion increases with weight loss on
two types of low-calorie diet. Our findings indicate that obesity has a
microbial component, which might have potential therapeutic implications.
Nature. 2006 Dec 21
An obesity-associated gut microbiome with increased capacity for energy
harvest.
The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors
that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice
and their lean littermates, as well as those of obese and lean human volunteers have revealed
that obesity is associated with changes in the relative abundance of the two dominant bacterial
divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through metagenomic and
biochemical analyses that these changes affect the metabolic potential of the mouse gut
microbiota. Our results indicate that the obese microbiome has an increased capacity to
harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free
mice with an 'obese microbiota' results in a significantly greater increase in total body fat
than colonization with a 'lean microbiota'. These results identify the gut microbiota as an
additional contributing factor to the pathophysiology of obesity.
Proc Natl Acad Sci U S A. 2007 May 1
In vivo imaging and genetic analysis link bacterial motility and
symbiosis in the zebrafish gut.
Complex microbial communities reside within the intestines of humans and other vertebrates.
Remarkably little is known about how these microbial consortia are established in various
locations within the gut, how members of these consortia behave within their dynamic
ecosystems, or what microbial factors mediate mutually beneficial host-microbial interactions.
Using a gnotobiotic zebrafish-Pseudomonas aeruginosa model, we show that the transparency
of this vertebrate species, coupled with methods for raising these animals under germ-free
conditions can be used to monitor microbial movement and localization within the intestine in
vivo and in real time. Germ-free zebrafish colonized with isogenic P. aeruginosa strains
containing deletions of genes related to motility and pathogenesis revealed that loss of
flagellar function results in attenuation of evolutionarily conserved host innate immune
responses but not conserved nutrient responses. These results demonstrate the utility of
gnotobiotic zebrafish in defining the behavior and localization of bacteria within the
living vertebrate gut, identifying bacterial genes that affect these processes, and
assessing the impact of these genes on host-microbial interactions.
Proc Natl Acad Sci U S A. 2007 Jun 19
Genomic and metabolic adaptations of Methanobrevibacter smithii to the human
gut.
The human gut is home to trillions of microbes, thousands of bacterial phylotypes, as well as hydrogen-consuming
methanogenic archaea. Studies in gnotobiotic mice indicate that Methanobrevibacter smithii, the dominant
archaeon in the human gut ecosystem, affects the specificity and efficiency of bacterial digestion of dietary
polysaccharides, thereby influencing host calorie harvest and adiposity. Metagenomic studies of the gut microbial
communities of genetically obese mice and their lean littermates have shown that the former contain an enhanced
representation of genes involved in polysaccharide degradation, possess more archaea, and exhibit a greater
capacity to promote adiposity when transplanted into germ-free recipients. These findings have led to the
hypothesis that M. smithii may be a therapeutic target for reducing energy harvest in obese humans. To
explore this possibility, we have sequenced its 1,853,160-bp genome and compared it to other human gutassociated M. smithii strains and other Archaea. We have also examined M. smithii's transcriptome and
metabolome in gnotobiotic mice that do or do not harbor Bacteroides thetaiotaomicron, a prominent saccharolytic
bacterial member of our gut microbiota. Our results indicate that M. smithii is well equipped to persist in the
distal intestine through (i) production of surface glycans resembling those found in the gut mucosa, (ii)
regulated expression of adhesin-like proteins, (iii) consumption of a variety of fermentation products
produced by saccharolytic bacteria, and (iv) effective competition for nitrogenous nutrient pools. These
findings provide a framework for designing strategies to change the representation and/or properties of M.
smithii in the human gut microbiota.
Nature. 2007 Oct 18
The human microbiome project.
A strategy to understand the microbial components of the human genetic and metabolic landscape
and how they contribute to normal physiology and predisposition to disease.
The core is viewed as a set of shared genes found in a
given habitat (e.g. gut, mouth, skin) in all humans. The
core is surrounded by a set of variably represented
genes: this variation could be influenced by a
combination of factors.
The hazy line surrounding the core indicates the
possibility that over the course of human ‘microevolution’ new genes may be added to the core
microbiome while others may be lost.
The concept of a core human microbiome
Cell Host Microbe. 2008 Apr 17
Diet-induced obesity is linked to marked but reversible alterations in the
mouse distal gut microbiome.
We have investigated the interrelationship between diet, gut microbial ecology, and energy balance
using a mouse model of obesity produced by consumption of a prototypic Western diet. Dietinduced obesity (DIO) produced a bloom in a single uncultured clade within the Mollicutes class
of the Firmicutes, which was diminished by subsequent dietary manipulations that limit weight
gain. Microbiota transplantation from mice with DIO to lean germ-free recipients promoted greater
fat deposition than transplants from lean donors. Metagenomic and biochemical analysis of the gut
microbiome together with sequencing and metabolic reconstructions of a related human gutassociated Mollicute (Eubacterium dolichum) revealed features that may provide a competitive
advantage to members of the bloom in the Western diet nutrient milieu, including import and
processing of simple sugars. Our study illustrates how combining comparative metagenomics with
gnotobiotic mouse models and specific dietary manipulations can disclose the niches of
previously uncharacterized members of the gut microbiota.
Science. 2008 Jun 20
Evolution of mammals and their gut microbes.
Mammals are metagenomic in that they are composed of not only their
own gene complements but also those of all of their associated microbes.
To understand the coevolution of the mammals and their indigenous
microbial communities, we conducted a network-based analysis of
bacterial 16S ribosomal RNA gene sequences from the fecal microbiota
of humans and 59 other mammalian species living in two zoos and in the
wild. The results indicate that host diet and phylogeny both influence
bacterial diversity, which increases from carnivory to omnivory to
herbivory; that bacterial communities codiversified with their hosts;
and that the gut microbiota of humans living a modern life-style is typical
of omnivorous primates.
Nat Rev Microbiol. 2008 Oct
Worlds within worlds: evolution of the vertebrate gut microbiota.
In this Analysis we use published 16S ribosomal RNA gene sequences to compare the
bacterial assemblages that are associated with humans and other mammals,
metazoa and free-living microbial communities that span a range of environments.
The composition of the vertebrate gut microbiota is influenced by diet, host
morphology and phylogeny, and in this respect the human gut bacterial community is
typical of an omnivorous primate. However, the vertebrate gut microbiota is
different from free-living communities that are not associated with animal body
habitats. We propose that the recently initiated international Human Microbiome
Project should strive to include a broad representation of humans, as well as other
mammalian and environmental samples, as comparative analyses of
microbiotas and their microbiomes are a powerful way to explore the
evolutionary history of the biosphere.
Proc Natl Acad Sci U S A. 2008 Sep 30
The convergence of carbohydrate active gene repertoires in human
gut microbes.
The extreme variation in gene content among phylogenetically related microorganisms
suggests that gene acquisition, expansion, and loss are important evolutionary forces
for adaptation to new environments. Accordingly, phylogenetically disparate organisms
that share a habitat may converge in gene content as they adapt to confront shared
challenges. This response should be especially pronounced for functional genes that are
important for survival in a particular habitat. We illustrate this principle by showing that the
repertoires of two different types of carbohydrate-active enzymes, glycoside hydrolases
and glycosyltransferases, have converged in bacteria and archaea that live in the
human gut and that this convergence is largely due to horizontal gene transfer rather
than gene family expansion. We also identify gut microbes that may have more similar
dietary niches in the human gut than would be expected based on phylogeny. The
techniques used to obtain these results should be broadly applicable to understanding the
functional genes and evolutionary processes important for adaptation in many environments
and useful for interpreting the large number of reference microbial genome sequences
being generated for the International Human Microbiome Project.
Nature. 2008 Oct 23
Innate immunity and intestinal microbiota in the development of Type 1 diabetes.
Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated
destruction of insulin-producing beta-cells. Its incidence has increased during the past several
decades in developed countries, suggesting that changes in the environment (including the human
microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in
non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal
housing facility or by exposure to microbial stimuli, such as injection with mycobacteria or various
microbial products. Here we show that specific pathogen-free NOD mice lacking MyD88 protein
(an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop
T1D. The effect is dependent on commensal microbes because germ-free MyD88-negative NOD
mice develop robust diabetes, whereas colonization of these germ-free MyD88-negative NOD
mice with a defined microbial consortium (representing bacterial phyla normally present in human
gut) attenuates T1D. We also find that MyD88 deficiency changes the composition of the distal gut
microbiota, and that exposure to the microbiota of specific pathogen-free MyD88-negative NOD
donors attenuates T1D in germ-free NOD recipients. Together, these findings indicate that
interaction of the intestinal microbes with the innate immune system is a critical epigenetic
factor modifying T1D predisposition.
Proc Natl Acad Sci U S A. 2008 Oct 28
Effects of the gut microbiota on host adiposity are modulated by the
short-chain fatty-acid binding G protein-coupled receptor, Gpr41.
The distal human intestine harbors trillions of microbes that allow us to extract calories from otherwise
indigestible dietary polysaccharides. The products of polysaccharide fermentation include short-chain fatty
acids that are ligands for Gpr41, a G protein-coupled receptor expressed by a subset of enteroendocrine
cells in the gut epithelium. To examine the contribution of Gpr41 to energy balance, we compared Gpr41-/and Gpr41+/+ mice that were either conventionally-raised with a complete gut microbiota or were reared
germ-free and then cocolonized as young adults with two prominent members of the human distal gut
microbial community: the saccharolytic bacterium, Bacteroides thetaiotaomicron and the methanogenic
archaeon, Methanobrevibacter smithii. Both conventionally-raised and gnotobiotic Gpr41-/- mice colonized
with the model fermentative community are significantly leaner and weigh less than their WT (+/+)
littermates, despite similar levels of chow consumption. These differences are not evident when germ-free WT
and germ-free Gpr41 knockout animals are compared. Functional genomic, biochemical, and physiologic
studies of germ-free and cocolonized Gpr41-/- and +/+ littermates disclosed that Gpr41-deficiency is
associated with reduced expression of PYY, an enteroendocrine cell-derived hormone that normally inhibits gut
motility, increased intestinal transit rate, and reduced harvest of energy (short-chain fatty acids) from the diet.
These results reveal that Gpr41 is a regulator of host energy balance through effects that are dependent
upon the gut microbiota.
Genome Biol. 2010
Direct sequencing of the human microbiome readily reveals community
differences.
Culture-independent studies of human microbiota by direct genomic sequencing
reveal quite distinct differences among communities, indicating that improved
sequencing capacity can be most wisely utilized to study more samples, rather
than more sequences per sample.
Nature. 2012 May 9
Human gut microbiome viewed across age and geography.
Gut microbial communities represent one source of human genetic and metabolic diversity. To
examine how gut microbiomes differ among human populations, here we characterize bacterial
species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort
encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US
metropolitan areas and included mono- and dizygotic twins. Shared features of the functional
maturation of the gut microbiome were identified during the first three years of life in all three
populations, including age-associated changes in the genes involved in vitamin biosynthesis and
metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires
were noted between US residents and those in the other two countries. These distinctive features
are evident in early infancy as well as adulthood. Our findings underscore the need to consider the
microbiome when evaluating human development, nutritional needs, physiological variations
and the impact of westernization.
Differences in the fecal microbial communities of Malawians, Amerindians and residents
of the USA at different ages(a) UniFrac distances (it is a method to calculate a distance
measure between organismal communities using phylogenetic information, and is widely used
in metagenomics.) between children and adults decrease with increasing age of children in
each population. Each point shows an average distance between a child and all adults
unrelated to that child but from the same country. Results are derived from bacterial V4-16S
rRNA datasets.
Bacterial diversity increases with age in each population
Nature. 2012 Sep 13
Diversity, stability and resilience of the human gut microbiota.
Trillions of microbes inhabit the human intestine, forming a complex ecological community that
influences normal physiology and susceptibility to disease through its collective metabolic activities
and host interactions. Understanding the factors that underlie changes in the composition and function
of the gut microbiota will aid in the design of therapies that target it. This goal is formidable. The gut
microbiota is immensely diverse, varies between individuals and can fluctuate over time - especially
during disease and early development. Viewing the microbiota from an ecological perspective
could provide insight into how to promote health by targeting this microbial community in
clinical treatments.
In some ways, maintaining a healthy microbiota is like lawn care.
Genome Res. 2013 Oct
Meta-analyses of studies of the human microbiota.
Our body habitat-associated microbial communities are of intense research interest because of their
influence on human health. Because many studies of the microbiota are based on the same bacterial
16S ribosomal RNA (rRNA) gene target, they can, in principle, be compared to determine the relative
importance of different disease/physiologic/developmental states. However, differences in
experimental protocols used may produce variation that outweighs biological differences. By comparing
16S rRNA gene sequences generated from diverse studies of the human microbiota using the QIIME
database, we found that variation in composition of the microbiota across different body sites was
consistently larger than technical variability across studies. However, samples from different studies of
the Western adult fecal microbiota generally clustered by study, and the 16S rRNA target region, DNA
extraction technique, and sequencing platform produced systematic biases in observed diversity that
could obscure biologically meaningful compositional differences. In contrast, systematic compositional
differences in the fecal microbiota that occurred with age and between Western and more agrarian
cultures were great enough to outweigh technical variation. Furthermore, individuals with ileal Crohn's
disease and in their third trimester of pregnancy often resembled infants from different studies more
than controls from the same study, indicating parallel compositional attributes of these distinct
developmental/physiological/disease states. Together, these results show that cross-study
comparisons of human microbiota are valuable when the studied parameter has a large effect size,
but studies of more subtle effects on the human microbiota require carefully selected control
populations and standardized protocols.
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