Is It Time for a Metagenomic Basis of Therapeutics?

Henry J. Haiser and Peter J. Turnbaugh

Science 336, 1253 (2012);
DOI: 10.1126/science.1224396

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birth to an infant or to a mother just before or
immediately after parturition. The goal may be
to achieve benefits in the context of a diet or diets
consumed by a given human population or by a
broad range of populations. How will expanding
knowledge of diet-microbiota interactions affect
claims for the health benefits of foods in con-
sumer populations with different gut microbial
community configurations and on strategies for
differentiation of food products? The result could
herald a new epoch of precision nutrition but
will also put increasing focus on foods as drugs
for disease prevention as well as treatment. The
effects of this focus on the strategic plans and
investments of food, dairy, and pharmaceutical
companies will be important to follow. Thus,
with so much opportunity and hope associated
with the gut microbiome, it would be wise to ad-
dress these issues now rather than later, through a
process that takes lessons from the group of
individuals who, illustrating the precautionary
principle, gathered together in 1975 to discuss
recombinant DNA research and its implications
(31, 32).
PERSPECTIVE
Is It Time for a Metagenomic Basis
of Therapeutics?
Henry J. Haiser and Peter J. Turnbaugh*
The trillions of microbes associated with the human body are a key part of a comprehensive
view of pharmacology. A mechanistic understanding of how the gut microbiota directly and
indirectly affects drug metabolism is beginning to emerge.
he human microbiota, the vast number
T of microbes that live within and upon us,
is an important but largely underexplored
component of therapeutics, prompting efforts to
complement pharmacological studies with de-
tailed analyses of our microbial communities.
Recent studies suggest that opportunities to de-
velop new diagnostics and treatments may arise
through a mechanistic understanding of our res-
ident microbial communities abilities to extend
human metabolism and an exploration of their
impacts on human health and predisposition to
disease. Indeed, our emerging view of the hu-
man microbiomethe aggregate genomes of our
microbiota and the diverse metabolic activities
that they encodehas the potential to revolution-
ize the way we view modern therapeutics.
Faculty of Arts and Sciences Center for Systems Biology,
Harvard University, Cambridge, MA, USA.
*To whom correspondence should be addressed. E-mail:
pturnbaugh@fas.harvard.edu
www.sciencemag.org
References and Notes
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The past century has provided a wealth of
information in the field of pharmacology, elu-
cidating the rates of absorption, distribution,
metabolism, and excretion for hundreds of xeno-
biotics (compounds foreign to a living organism,
including therapeutic drugs, antibiotics, and diet-
derived bioactive compounds) (1). Combining
knowledge of environmental risk factors and hu-
man genetics has further advanced our under-
standing of the basis for interindividual variations
in drug bioavailability, toxicity, and efficacy (2).
However, the existing clinical and genetic bio-
markers often fail to explain a large part of the
variation in patient response; for example, even
in the case of the well-studied anticoagulant war-
farin, up to 50% of the variation is still un-
explained (2).
A neglected but critical component of xeno-
biotic metabolism is the influence of the trillions
of microorganisms inhabiting our gastrointestinal
tract. In addition to merely expanding the set of
human-associated enzymes that can directly mod-
ify xenobiotics (there are more than 30 known
SCIENCE VOL 336 8 JUNE 2012
SPECIALSECTION
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Acknowledgments: Work cited from the authors lab was
supported by grants from the NIH, the Bill and Melinda
Gates Foundation, and the Crohns and Colitis Foundation of
America. The author declares no competing interests.
10.1126/science.1224686
drugs for which this contribution likely plays an
important role) (3), members of the gut micro-
biota can also influence xenobiotic metabolism by
altering host gene expression (4) and producing
compounds that interfere with metabolism out-
side of the gut (Fig. 1) (5). Importantly, these
interactions are reciprocal, as exposure to xe-
nobiotics, especially antibiotics, can affect the
structure of our indigenous microbial commu-
nities (6, 7).
The discovery of antibiotics changed the way
we have viewed infectious disease over the past
century, yet we are just beginning to assess the
unintended collateral damage that antibiotics
often impart on the symbiotic microorganisms
living in our gastrointestinal tract (8). Repeated
exposure to broad-spectrum antibiotics can dra-
matically alter the composition of human gut mi-
crobial communities, which can persist for long
periods of time (6, 7). Antibiotic exposure has
also been linked to marked changes in the meta-
bolic output of the intestinal tract; for example,
almost 88% of the ~2000 detectable metabolites
derived from fecal samples were present in al-
tered amounts after antibiotic treatment in mice
(9). The functional consequences of such shifts
are not always obvious; however, it is clear that
antibiotic treatment can render individuals more
susceptible to infection (10). This is exempli-
fied by Clostridium difficile, a microbe that can
cause severe diarrheal illness with potentially
life-threatening complications following a reduc-
tion in diversity of the gut microbiota after anti-
biotic treatment (11).
Although we are still in the early stages of in-
vestigating the impact of xenobiotics on the compo-
sition and function of gut microbial communities,
1253
 The Gut Microbiota
we know even less about how the microbes living
in the gut influence the metabolism of therapeutic
drugs. A review of the pharmacological literature
from the past few decades reveals several cases in
which a particular biotransformation (the chemi-
cal alteration of a compound by an organism) is
suspected to result directly from a reaction carried
out by gut microbes (3). Typically, these studies
involve either monitoring drug metabolism during
the ex vivo incubation of fecal samples with a giv-
en drug or observing that antibiotic pretreatment
abolishes the biotransformation, presumably due
to the widespread depletion of the gut microbiota.
The classical examples of direct microbial
biotransformations often consist of either the ac-
tivation or inactivation of a parent compound.
An example of the former comes from the anti-
creasing toxicity. This was recently demonstrated
by monitoring pre- and postdose metabolite pro-
files in human participants who were given the
drug acetaminophen. A microbial compound,
p-cresol, was abundant in the predose metab-
olite profiles of individuals who did not fully
metabolize acetaminophen (5). Because the ex-
cretion of both p-cresol and acetaminophen de-
pends on the same O-sulfonation conjugation
reaction in the liver, the results suggest that p-
cresolproducing members of the gut microbiota
can indirectly inhibit the metabolism of this
widely used xenobiotic.
The gut microbiome also affects the metabo-
lism of diet-derived bioactive compounds. A
metabolomics screen of human plasma revealed
that the phosphatidylcholine metabolites choline,
Can the efficacy of a therapeutic agent be im-
proved through a mechanistic understanding of
how the indigenous microbiota interact with the
compound? Administered as a prodrug, the che-
motherapeutic agent irinotecan becomes activated
by enzymes in serum and tissue, where it inhibits
topoisomerase I (an enzyme that regulates the
structure and replication of DNA) in rapidly
growing tumor cells. Before excretion, the drug
is converted in the liver to a nontoxic metabolite;
however, bacterial enzymes (b-glucuronidases)
can reactivate this metabolite after it is released
back into the intestine, resulting in severe diarrhea
that often prevents further increases in dosage.
Although the administration of broad-spectrum
antimicrobials prevents this undesirable bio-
transformation of irinotecan, this approach also

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inflammatory drug sulfasalazine, which is used
to treat rheumatoid arthritis and inflammatory
bowel disease. Sulfasalazine is subject to metab-
olism by microbial azoreductases that split the
drug into two halves: 5-aminosalicylic acid, which
is pharmacologically active, and sulfapyridine,
which is thought to cause the undesirable side
effects associated with this drug (3). The role of
the individual bacterial species involved and the
molecular mechanisms underlying the biotrans-
formation are largely uncharacterized. Converse-
ly, the cardioactive drug digoxin is susceptible to
almost complete inactivation through the reduc-
tion of a single double bond in the lactone ring of
this compound. A common member of the gut
microbiota, Eggerthella lenta, can carry out this
reduction reaction in isolation (12). Activation of
a drug by the gut microbiota can be undesirable if
the reaction occurs in an unintended body site.
This is the case for levodopa, an orally admin-
istered drug used to treat Parkinsons disease by
ameliorating a dopamine imbalance. Levodopa
can cross the blood-brain barrier, after which it
depends on a host-catalyzed decarboxylation
reaction to convert it to dopamine in the central
nervous system (CNS). However, the gut micro-
biota can also perform this biotransformation (3);
having this modification take place in the gut
prevents dopamine from reaching the CNS, po-
tentially contributing to the variability in patient
responses to levodopa treatment. An integral part
of translating these observations into practical
recommendations that improve drug efficacy
will be identifying which particular microbes, or
microbial consortia, carry out the relevant bio-
transformations and unraveling the underlying
molecular mechanisms.
Our capacity to metabolize therapeutic drugs
is also affected indirectly by the gut microbiota.
Microbes can secrete metabolites that act as
substrates for host enzymes essential to process a
given drug, thus titrating away their activity. By
diminishing the hosts capacity to metabolize
drugs, the gut microbiota may indirectly affect
the desired pharmacological action, potentially
prolonging the time spent in circulation or in-
trimethylamine N-oxide, and betaine serve as leaves individuals susceptible to other serious
predictive biomarkers for the development of complications. A recent study addressed this
cardiovascular disease (13). In this same study, issue by harnessing a chemical screen to iden-
germ-free mice revealed that the gut microbiota tify compounds that specifically inhibit bacterial
is directly involved in producing these metabo- b-glucuronidase (14). Remarkably, the admin-
lites and that suppression of the gut microbiota istration of irinotecan with a b-glucuronidase in-
(via antibiotic treatment) can prevent choline- hibitor alleviated the negative side effects in mice.
induced atherosclerosis. These findings highlight Advances in DNA sequencing, cell sorting,
the critical role of the gut microbiota in extending mass spectrometry, microfluidics, and computa-
our own metabolism through modifying the mi- tional biology are contributing an array of new
cronutrient component of our diet and also serve tools to the study of human-associated microbial
as a notable example of how the composition of communities. These approaches could lead to the
commensal microbial communities can directly first metagenomic basis of therapeutics that
affect disease. merges the vast knowledge of pharmacology
Drug administration
Active Prodrugs and
compounds inactive compounds
Direct interactions Gut microbiota Indirect interactions
Activation
Inactivation
Host gene
expression Microbial
changes metabolites
Byproduct
toxic to host
Altered host drug metabolism
Antimicrobial
Fig. 1. A microbial view of xenobiotic metabolism. The gut microbiota interacts with xenobiotics directly
by catalyzing various biotransformations. In turn, many xenobiotics inhibit microbial growth or cause cell
damage. Indirect interactions have also been described, including microbial effects on the expression and
activity of components of host xenobiotic metabolism.

1254 8 JUNE 2012 VOL 336 SCIENCE www.sciencemag.org


with a quantitative understanding of key envi-
ronmental risk factors and their interactions with
our human and microbial genomes. To complete
this picture, it is important to move beyond large-
ly DNA sequencingbased association studies
toward a mechanistic understanding of how
members of the gut microbiota, either in isola-
tion or through mutualistic interactions with each
other, can transform each compound. This will
require multiple complementary top-down and
bottom-up approaches, including detailed in vitro
analyses of culturable microbes; studies in germ-
free and intentionally colonized animal models;
metagenomic surveys of patients before, during,
and after treatment; and large-scale clinical trials.
These types of studies will likely lead to new
microbial therapeutic targets, noninvasive bio-
understanding of the short- and long-term impact
of xenobiotics on host and microbial physiology.
Furthermore, the detailed study of pharmaceuti-
cally active compounds may be a tractable first
step toward understanding the fundamental rules
that govern the immense phylogenetic and meta-
bolic diversity of our microbial partners and how
they influence our predisposition to and recovery
from disease.
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Acknowledgments: H.J.H. is supported by a postdoctoral
fellowship from the Canadian Institutes of Health
Research (MFE-112991). P.J.T. is supported by a grant
from the NIH (P50 GM068763).

Downloaded from www.sciencemag.org on June 9, 2012

markers for drug toxicity or efficacy, and a broader (2009). 10.1126/science.1224396

spatial patterns of diversity. Here, we explore

REVIEW
how community assembly theory can be used to
understand the human-associated microbiota and
The Application of Ecological Theory its role in health and disease.

Toward an Understanding of the Ecological Processes Within Humans

The essential building blocks of community as-
sembly theory encompass the processes that
Human Microbiome create and shape diversity in local assemblages:
dispersal, diversification, environmental selection,
Elizabeth K. Costello,1 Keaton Stagaman,2 Les Dethlefsen,1,3 and ecological drift (6). In addition, coevolution
Brendan J. M. Bohannan,2 David A. Relman1,3,4* provides another lens through which to view the
human-microbial ecosystem (7), although in this
The human-microbial ecosystem plays a variety of important roles in human health and disease. review we focus on shorter-term dynamics at the
Each person can be viewed as an island-like patch of habitat occupied by microbial assemblages level of individual hosts.
formed by the fundamental processes of community ecology: dispersal, local diversification, Dispersal, or the movement of organisms
environmental selection, and ecological drift. Community assembly theory, and metacommunity across space, is a fundamental process by which
theory in particular, provides a framework for understanding the ecological dynamics of the human diversity accumulates in local microbial com-
microbiome, such as compositional variability within and between hosts. We explore three core munities. The concept put forth in the late 19th
scenarios of human microbiome assembly: development in infants, representing assembly in and early 20th centuries that everything is ev-
previously unoccupied habitats; recovery from antibiotics, representing assembly after disturbance; erywhere, but the environment selects had a
and invasion by pathogens, representing assembly in the context of invasive species. Judicious powerful impact on thinking about community
application of ecological theory may lead to improved strategies for restoring and maintaining the assembly (8), but a more recent appreciation of
microbiota and the crucial health-associated ecosystem services that it provides. microbial dispersal limitation suggests that this
conceptualization was overly simplistic. Think-
ach person is an assemblage of not only ciated with alterations in host-associated microbial ing in terms of dispersal leads to a view of the

E human cells but also many symbiotic spe-

cies. The abundant and diverse microbial
members of the assemblage play critical roles in
the maintenance of human health by liberating
nutrients and/or energy from otherwise inacces-
sible dietary substrates, promoting differentiation
of host tissues, stimulating the immune system,
and protecting the host from invasion by path-
ogens. A number of clinical disorders are asso-
1
Department of Microbiology and Immunology, Stanford Uni-
versity School of Medicine, Stanford, CA 94305, USA. 2Institute
of Ecology and Evolution, University of Oregon, Eugene, OR
97403, USA. 3Department of Medicine, Stanford University
School of Medicine, Stanford, CA 94305, USA. 4Veterans Affairs
Palo Alto Health Care System, Palo Alto, CA 94304, USA.
*To whom correspondence should be addressed. E-mail:
relman@stanford.edu
communities (the microbiota), including obe-
sity, malnutrition, and a variety of inflammatory
diseases of the skin, mouth, and intestinal tract.
Thus, the human body can be viewed as an eco-
system, and human health can be construed as a
product of ecosystem services delivered in part
by the microbiota.
There is growing interest in the use of theo-
retical methods to study microbial community
ecology in general and host-associated micro-
biota in particular (1, 2). Recent discoveries of
unexpected variation in the composition of the
microbiome of healthy individuals (35) high-
light the importance of identifying the processes
that could possibly give rise to such variation.
Ecological theory seeks to explain and predict
observable phenomena, such as temporal and
human body as an island, a patch of habitat
that is continually sampling the pool of available
colonists. The list of available colonists may
be influenced by microbial traitsthose affect-
ing dispersal efficiency, transmission routes, and
ex-host survivabilityand by patterns of host
contact and carriage, among other factors. Con-
trol of infectious disease transmission depends
on accurate models of host-to-host microbial dis-
persal (9), and these could guide investigations
into the dissemination of the human microbiome.
Selection favors efficient dispersal in pathogens,
but perhaps less so among beneficial bacteria,
because the host is harmed by the first and not by
the second; for beneficial microbes, transmission
routes such as direct or close contact may be more
important. The density and spatial arrangement

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