Obesity and the human microbiome
Ruth E. Ley
Department of Microbiology, Cornell University, Ithaca,
New York, USA
Correspondence to Ruth E. Ley, Department of
Microbiology, 260 Wing Hall, Cornell University, Ithaca,
NY 14853, USA
Tel: +1 607 255 4954; fax: +1 607 255 3904;
e-mail: rel222@cornell.edu
Current Opinion in Gastroenterology 2010,
26:5–11
Introduction
Up until the last few decades, obesity has been a
rare physiological state. Now however, the number of
obese or overweight humans has come to outnumber
those suffering from malnutrition [1]. This is an unpre-
cedented state for our species, resulting from a mis-
match between our evolutionary biology and our
modern environment. The human body is a complex
system, made all the more complex through its inter-
actions with the trillions of microorganisms that coat
the body surface and densely populate the gut. Recent
work has shown that the microbes of the gut may
play a role in human metabolism and adiposity. Because
they are environmentally acquired, microbes constitute
one part of our environment that may contribute to the
obese state. This review discusses the most recent
findings and insights into the relationship between
the human microbiota, obesity, and obesity-associated
diseases.
0267-1379 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Purpose of review
Obesity was once rare, but the last few decades have seen a rapid expansion of the
proportion of obese individuals worldwide. Recent work has shown obesity to be
associated with a shift in the representation of the dominant phyla of bacteria in the gut,
both in humans and animal models. This review summarizes the latest research into the
association between microbial ecology and host adiposity, and the mechanisms by
which microbes in the gut may mediate host metabolism in the context of obesity.
Recent findings
Studies of the effect of excess body fat on the abundances of different bacteria taxa in
the gut generally show alterations in the gastrointestinal microbiota, and changes during
weight loss. The gastrointestinal microbiota have been shown to impact insulin
resistance, inflammation, and adiposity via interactions with epithelial and endocrine
cells.
Summary
Large-scale alterations of the gut microbiota and its microbiome (gene content) are
associated with obesity and are responsive to weight loss. Gut microbes can impact
host metabolism via signaling pathways in the gut, with effects on inflammation, insulin
resistance, and deposition of energy in fat stores. Restoration of the gut microbiota to a
healthy state may ameliorate the conditions associated with obesity and help maintain a
healthy weight.
Keywords
gut microbial ecology, inflammation, insulin resistance, metagenomics, microbiota,
obesity
Curr Opin Gastroenterol 26:5–11
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
0267-1379
Patterns of microbial diversity in relation to
obesity
The initial link between gut microbial ecology and
obesity was made in leptin-deficient mice (mice homo-
zygous for an aberrant leptin gene, ob/ob) by Ley et al. [2].
Results from a 16S rRNA gene sequence survey revealed
that the bacterial communities in the ceca of ob/ob mice
had a different proportion of bacteria belonging to the
two dominant phyla when compared with those of lean
wild-type (þ/þ) or heterozygous (ob/þ) mice, with a
greater representation of Firmicutes and fewer Bacter-
oidetes characterizing the obese host microbiota. A sub-
sequent metagenomic analysis of these same microbial
communities, which was based on shotgun sequencing of
the microbial community DNA, showed an enrichment
in genes involved in energy extraction from food in the
obese host’s microbiome relative to that of the lean host’s
microbiome. A microbiota with greater energy extraction
efficiency resulted in less energy left over in feces and
DOI:10.1097/MOG.0b013e328333d751
 6 Gastrointestinal infections
greater levels of short-chain fatty acids (SCFAs) in the
cecum. Furthermore, when the luminal contents from
the ceca of obese or lean mice were provided to lean
germ-free recipients, the mice receiving the microbes
from the obese donors gained more weight over a 2-week
period than recipients of the lean microbes, despite
equivalent food intake [3]. In a study extending these
observations to humans, 12 obese participants were
randomly assigned to either carbohydrate-restricted or
fat-restricted diets, and on average, the proportion of
Bacteroidetes bacteria enumerated via 16S rRNA gene
sequencing increased over time, mirroring reductions in
host weight but not changes in diet [4]. Together these
studies showed that the gut microbiota was generally
altered in the obese host and could contribute to host
adiposity in humans and mice.
Metagenomics and obesity
A subsequent and much larger study of the microbiome
associated with obesity conducted with humans also
showed that obesity was associated with a depletion of
Bacteroidetes, together with an enrichment in carbo-
hydrate and lipid-utilizing genes in the microbiome as
a whole. Turnbaugh et al. [5] focused on twins to assess
the gut microbiota’s relationship to host weight. The
fecal microbial communities of young adult female
monozygotic (n ¼ 31) and dizygotic (n ¼ 23) twin pairs
concordant for either leanness or obesity were compared,
along with those of their mothers (n ¼ 46), using a com-
bination of traditional 16S rRNA gene clone libraries and
high-throughput metagenomic analyses of the micro-
biome. Fecal samples were obtained from the majority
of participants at an initial time point and then again
2 months later. Comparisons between all 154 participants
showed obesity to be associated with reduced bacterial
diversity and reduced representation of the Bacteroi-
detes. Furthermore, the microbiome differed between
obese and lean hosts in much the same way it had in the
obese mouse model, with obese host microbiomes
enriched in gene categories involved in carbohydrate
and lipid metabolism.
Varied patterns of microbial ecology in relation to
weight
This and other patterns of fecal microbial ecology in
relation to body weight in humans have been reported
recently [4,5,6–9,10,11,12,13,14], and these are
summarized in Table 1. In studies that examine the
effect of weight loss on the abundance of Bacteroides-
related taxa, the relationship has been reported as
positive [12], neutral [9], and negative [11]. It is note-
worthy that rather than using broad 16S rRNA gene
surveys or metagenomics to assess the composition of
microbial communities, these studies enumerated
specific taxa using probes, which can differ between
studies (e.g., [11] vs. [9]). Thus, the varying patterns
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
of association between microbial taxa and host weight
raise the question of how much impact the differences in
methodology can have on the patterns observed. Biases
are inherent to all of the methods employed in studies of
microbial ecology, and the degree of bias can vary
between samples within a study. For instance, several
of the studies listed in Table 1 use fluorescent in-situ
hybridization (FISH) with group-specific oligonucleotide
probes targeting the ribosomal RNA as a starting point to
enumerate (by microscopic counts or cell sorting) cells
belonging to specific microbial taxa. FISH reveals a
limited fraction of cells (roughly 20–30% of bacterial
cells in a given sample cannot be stained with FISH
[6,9]) either due to cell permeability or probe mismatch
issues. In addition, any method that relies on specific
oligonucleotide probes (e.g., qPCR and FISH) is inher-
ently limited by the fact that without a 16S rRNA gene-
based survey of the overall diversity within a sample, the
specificity of the selected probes will be uncertain.
Indeed, each time a new participant’s microbiota is
surveyed, novel diversity is described: the overall diver-
sity of humanity’s microbial diversity is far from circum-
scribed. It would be highly informative for all of these
common methods to be applied together within a single
study so that we can begin to understand how they relate.
In addition, researchers are calling for standardized
approaches for sample processing [15,16].
Animal vs. human studies
In contrast to studies performed in humans, studies of gut
microbial ecology and obesity conducted in animals tend
to have less variable outcomes. Studies in rats and pigs
have reported greater abundances of Bacteroidetes
associated with the lean state [16–18,19], as observed
in ob/ob mice. In a systems-biology approach, Waldram
et al. [20] studied a rat model of obesity, characterizing
gut microbiotas in parallel with metabolites. Results
broadly support patterns of greater Firmicutes/Bacteroi-
detes ratios observed in other animal studies. In addition,
specific bacteria were associated with the obese phenotype
(Halomonas and Sphingomonas), as were lower total bac-
terial counts and lower Bifodobacterial counts; further-
more, differences in microbial community composition
correlated with differences in metabotypes [20].
Is the variation in outcomes of human studies related to
the complexity of the human lifestyle? In animal studies,
diet can be controlled precisely – this precludes any
potentially modulating effects of variations in diet
between participants (e.g., see [21] where specific
microbial taxa respond to changes in a diet’s content of
specific carbohydrates). Yet, average human diets that
are not designed for weight loss may add noise to data
rather than skew results one way or another. Indeed, in a
comparison of human vegetarians and omnivores allowed
to eat their normal diet, Tap et al. [22] did not note any
 Obesity and the human microbiome Ley 7

Table 1 Human studies of gut microbial ecology in relation to body weight

Author Participants Method (sample type) Finding

Ley et al. [2] 12 obese participants on one
of two diets, carbohydrate or
fat-reduced, for 1 year;
two lean controls
Turnbaugh et al. [5] 154 participants, MZ and DZ twins
and mothers, obese or lean
Schwiertz et al. [6] 30 lean, 35 overweight, 33 obese
participants
Collado et al. [7] Women before and during pregnancy, FISH/flow cytometry
18 overweight participants
and 36 controls
Sotos et al. [8] 8 obese and overweight adolescents
during weight loss
Duncan et al. [9] Participants on weight loss diets
over 8 weeks vs.
weight maintenance
Kalliomaki et al. [10] Obese and overweight children
(n ¼ 25) and normal
weight children (n ¼ 24);
prospective study
Santacruz et al. [11] 36 adolescents on diet and physical
activity, 10 weeks
Nadal et al. [12] 39 adolescents on diet and physical
activity, 10 weeks
Sabate et al. [13] 137 obese patients, 40 healthy
controls
Zhang et al. [14] 3 lean, three obese, and three
postgastric bypass
participants
DZ, dizygotic; FISH, fluorescent in-situ hybridization; MZ, monozygotic.
16S rRNA surveys by
Sanger sequencing (feces)
16S by Sanger and 454
pyrosequencing,
metagenomics (feces)
qPCR for Bacteroidetes,
Actinobacteria, Archaea
(feces)
and qPCR (feces)
FISH (feces)
FISH counts (feces)
qRT-PCR and FISH/flow
cytometry (feces)
qPCR (feces)
qPCR (feces)
Glucose-hydrogen breath test
(for H2) and liver biopsy
(breath, liver)
Sanger and 454 sequencing of Firmicutes more abundant in lean participants,
16S rDNAs, qPCR (feces)
Proportion of Bacteroidetes sequences
increased over time, on average, and
correlated with weight loss. No difference
between diets
Reduced levels of diversity, and reduced
levels of Bacteroidetes in obese participants;
metagenomes of obese participants enriched
in energy-harvesting genes
More Bacteroidetes in overweight and obese
vs. lean participants, and more
Methanobrevibacter in lean participants
Higher levels of Bacteroidetes and S. aureus in
overweight, positive correlation between
Bacteroides levels and weight gain over
pregnancy
Enterobacteriaceae and sulfate-reducing
bacteria reduced in group with greatest
weight loss. Reduced levels of
Roseburia–Eubacterium in those with
less weight loss
No difference in Bacteroidetes levels between
groups; reduced levels of Roseburia
and Eubacterium, and increased levels of
Clostridium spp., correlate with reduced
carbohydrate intake
Children remaining lean at age 7 had higher
levels of Bifidobacteria and lower levels of
S. aureus, as infants
Bacteroides fragilis abundance correlated
with carbohydrate intake. Levels of
Bacteroides and Lactobacillus increased
with weight loss
Clostridium histolyticum and E. rectale–C.
coccoides reduced with weight gain;
increase in Bacteroides–Prevotella in
high weight loss group
Bacterial overgrowth in small intestine
more common in obese vs. lean participants
lowest after gastric bypass. Gamma-
Proteobacteria and Verrucomicrobia enriched
after gastric bypass; higher Archaea in obese
participants; overall communities of gastric
bypass and obese participants more similar
to each other than to lean participants

major differences between gut microbiotas for the two
diet groups. Rather than the composition of the diet,
another factor that may be important to consider is how
the food is ingested throughout the day, for instance, how
long the fasting periods last. Fasted mice have been
shown to harbor a greater proportion of Bacteroidetes
in their ceca compared with unfasted mice with equiv-
alent body fat [23]. Thus, the frequency with which food
enters the bowel and its transit time may be important
factors to control for, or at least note, when comparing
studies in humans.
Prospective studies
The question of whether or not a microbial community
can predispose a host to weight gain or loss has been
addressed in animal models and human studies. One
approach to this question has been to control the com-
position of the initial microbial community directly. This
is accomplished by administering whole microbiotas of
known composition by oral gavage straight into the
stomach of germ-free (usually mouse) recipients housed
in asceptic isolators. As mentioned above, the result of
such ‘transplantation’ of the gut microbes from obese
(genetic or diet-induced models) to lean germ-free reci-
pient mice is greater weight gain for mice that received
obese-microbiotas [3,19]. Although these transplan-
tation experiments are highly artificial, they show that
a microbiota can predispose the host to greater weight
gain, and recent studies have shown these findings to be
relevant to human health. Kalliomaki et al. [10] com-
pared groups of children over time and observed that
those who became overweight by age 7 had had lower

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 8 Gastrointestinal infections
levels of Bifidobacteria and higher levels of Staphylococcus
aureus as infants compared with those that kept a healthy
weight. These researchers had banked samples over time
and were able to go back to interrogate the microbiota of
the same individuals prospectively. In shorter-term
study, Santacruz et al. [11] found that the response of
overweight adolescents to a diet and exercise weight-loss
program was dependent on the initial microbiota prior to
the treatment. Both of these studies demonstrate that the
microbiota are differentiated between people prior to the
change in weight, which suggests that therapeutic inter-
ventions aimed at reshaping the gut microbiota may be
beneficial for weight loss as well as preventive against
weight gain.
Other body habitats
Clearly, obesity can be associated with a dysbiosis of the
microbiota from the lower intestinal tract; recently,
researchers have extended this observation to other parts
of the body. In a study of the oral microbiota, Goodson
et al. [24] show differences in the diversity and abun-
dances of salivary bacteria between overweight and
healthy weight people. Specifically, they found that
Prevotellas (a group within the Bacteroidetes phylum)
were in greater abundance in the overweight and Sele-
nomonas was present only in the overweight individuals,
suggesting that these taxa could be biomarkers for excess
adiposity. Traveling further down the gastrointestinal
tract, bacterial overgrowth in the small intestine has been
shown to be more common in morbidly obese patients
than in healthy weight individuals [13]. Although pre-
liminary, these studies indicate that obesity may be
associated with a dysbiosis of the normal microbiota
throughout the body.
Mechanisms linking the microbiota to obesity
Obesity is associated with a number of chronic con-
ditions, including inflammation, insulin resistance, type
II diabetes, hepatic steatosis, and cardiovascular disease.
A number of recent studies have focused on the mechan-
istic links between gut microbes and specific conditions
associated with obesity (for more in-depth reviews see
[25,26]). Combining studies of host–microbial inter-
actions relevant to obesity with studies of microbial
diversity should lead to a more comprehensive under-
standing of which microbes, or microbial products, are the
best targets for interventions (such as pharmaceutical
mimicry) aimed at improving health, aiding weight loss,
or preventing weight gain.
Gut microbes and host metabolism
The microbiota can influence host adiposity through
energy extraction from the diet, with variable efficiency
depending on community composition; furthermore, the
microbiota can also affect host adiposity by influencing
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metabolism throughout the body. Germ-free mice raised
in asceptic isolators are significantly leaner than conven-
tionally raised mice despite their considerably greater
food intake, and, in addition, they are resistant to diet-
induced obesity and insulin resistance [27,28]. Presence
of a microbiota increases serum levels of glucose and
SCFAs, which can induce triglyceride production in the
liver, and is associated with greater adiposity and reduced
glucose tolerance [28].
Bäckhed et al. [27] showed that the gut microbiota
regulates an important gut-derived regulator of host
lipid metabolism, angiopoietin-like protein 4 (Angptl4),
also known as Fiaf, or fasting-induced adipose factor.
Angptl4 regulates fatty acid oxidation in both muscle
and adipose tissue [29]. When a normal mouse microbiota
is administered to germ-free mice, Angptl4 production is
suppressed in the intestine and a greater proportion of
triglycerides are deposited in adipose tissue. Further-
more, germ-free mice lacking Angptl4 are no longer
protected against diet-induced obesity [27]. The
relevance of these findings to human health is under-
scored by population genetic and metabolic studies in
humans. Functional variants of the ANGPTL4 gene
were found to be more prevalent in individuals with
comparatively low triglyceride levels [30]. In addition,
in a study of 108 participants, ANGPTL4 plasma levels
correlated with fasting fatty acid levels and adipose tissue
lypolysis [31]. Thus, ANGPTL4 may be an important
regulator of lipid metabolism in humans as well, and
research that investigates the role of the gut microbes
in regulating its expression in the human intestine
is warranted.
Gut microbes, inflammation, and insulin resistance
Low-grade metabolic inflammation is recognized as an
important component of obesity and metabolic syndrome
[32]. Metabolic systems are integrated functionally and
molecularly with immune responses, for instance, the
increase in pro-inflammatory cytokines, such as tumor
necrosis factor-a (TNF-a), typical of obesity-related
inflammation, has been shown to result in insulin resist-
ance [33]. Recent work has shown that gut bacteria can
initiate the inflammation and insulin resistance associ-
ated with obesity.
One of the ways bacteria can impact inflammation and
insulin resistance is through the activity of lipopolysac-
charide (LPS), an essential component of the cell walls of
Gram-negative bacteria such as the Bacteroidetes. Cani
et al. [34] have shown that subcutaneous infusion of LPS
can cause weight gain and insulin resistance in mice
without altering energy intake. In accordance with this,
mice lacking Toll-like receptor 4 (TLR4), which recog-
nizes LPS, are resistant to diet-induced obesity and
insulin resistance [35].

In addition to insulin resistance, Cani et al. [34] showed
that LPS also induces inflammation in mice and that mice
lacking CD14 (a co-receptor of TLR4) are resistant to the
development of inflammation. One type of inflammatory
molecule that appears to be induced by LPS are the
serum amyloid A (SAA) proteins, which exhibit increased
levels in the serum of obese persons [36]. The mouse
isoform SAA3 is the most abundant in adipose tissue [37].
Reigstad et al. [38] assessed the effects of the presence
of microbes on SAA3 levels in germ-free, conventionally
raised and Myd88/ mice. Results showed that SAA3 is
elevated in adipose tissue and colonic tissue in the
presence of microbes. Decreased levels of SAA3 in
Myd88-deficient mice compared with controls and
increased levels of TNF-a in colonic tissue in conven-
tionalized vs. germ-free mice indicate that microbiota can
partially mediate SAA3 through LPS-mediated TLR/
Myd88/NF-kB signaling.
Evidence suggests that a high-fat diet can trigger the
steps that lead to metabolic inflammation by aiding
transport of LPS out of the gut. A diet rich in energy
can increase levels of plasma LPS in humans [39] and
mice [34]. Furthermore, SAA3 is upregulated in the
adipose tissue of mice fed a high-fat diet [37]. Myd88-
deficient mice fed a high-fat diet are leaner than wild-
type controls, further supporting the role of LPS-TLR
signaling in SAA3 production [38]. The link between a
high-fat diet, LPS, and inflammation was made by
Ghoshal et al. [40], who showed that a high-fat diet can
increase LPS absorption. Dietary fat is transported from
the gut after its incorporation as triglycerides into
chylomicrons, which also have a high affinity for LPS.
Thus, triglycerides form chylomicrons that move LPS
from gut cells into the circulation.
A high-fat diet may also modulate plasma LPS levels and
inflammation through changes in the gut microbiota. A
high-fat diet has been shown in mice to alter the proportion
of Bacteroides-related bacteria both positively and nega-
tively [19,41] (these studies used different enumer-
ation methods), as well as to promote a bloom in Mollicutes
(phylum Firmicutes [19]), but perhaps most importantly
to reduce the numbers of Bifidobacteria (Gram-positive,
phylum Actinobacteria) [41]. The effect of a decrease in
Bifidobacterial levels may be inferred by the inverse:
augmenting levels of Bifidobacteria in the gut, either
directly as an ingested probiotic or indirectly with bifido-
genic prebiotics, has been shown to reduce inflammation
and improve glucose tolerance [42,43]. Greater levels of
Bifidobacteria have also been associated with reduced gut
leakiness, allowing less LPS to translocate to the serum
[44]. Thus, a high-fat diet is thought to modulate the
composition of the gut bacteria (notably by reducing levels
of Bifidobacteria), which increases gut permeability and
allows higher LPS plasma levels [26].
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Obesity and the human microbiome Ley 9
In humans, plasma LPS levels correlate positively with
total energy intake in healthy individuals [39]. Plasma
LPS levels are also higher in participants with type II
diabetes [45]. At this time, the effect of energy intake and
diabetes on the gut microbiota is not known in humans,
but based on the results in mice, it is likely that a
dysbiosis exists under these conditions.
Gut microbes and endocrine cells
The gut communicates with the brain using endocrine
signals to coordinate energy intake and expenditure.
Enteroendocrine cells respond to nutrient intake by
secreting incretin hormones, including glucagon-like
peptides 1 and 2 (GLP-1 and GLP-2). GLP-1 stimulates
insulin release from the pancreas, slows gastric emptying,
and promotes satiety and weight loss [25]; GLP-2 stimu-
lates intestinal glucose transport and reduces gut per-
meability [46]. An earlier report indicated that gut micro-
biota can regulate enteroendocrine cells and influence
the release of gut hormones [47]. Furthermore, the pre-
sence of microbes is necessary for the full complement of
enteroendocrine cells to be present in zebrafish [48]. In a
series of studies, Cani et al. [49] have shown a connection
between gut microbes and levels of both GLP-1 and
GLP-2. In rats, oligofructose treatment (which increases
the proportion of Bifidobacteria) has been associated with
a greater number of GLP-1 secreting enteroendocrine
cells (L cells) in the colon. Ob/ob mice treated with
prebiotic carbohydrates had altered gut microbiotas
and increased levels of GLP-1 and GLP-2 [44]. Thus,
enteroendocrine cells represent a direct signaling path-
way from gut microbes to host metabolism.
In yet another distinct pathway, gut microbes have been
shown to stimulate gut hormones. Samuel et al. [50]
recently showed that enteroendocrine cells express a
receptor for SCFAs, GPR41, which is necessary for the
full metabolic effect of these microbial metabolites. Mice
lacking Gpr41 had reduced levels of the gut hormone
PYY, greater gut transit time, lower recovery of SCFAs
from the diet, and lower fat accumulation in fat pads.
SCFAs are products of bacterial fermentation of carbo-
hydrates from the diet: thus, they function both as an
energy source and as a signaling molecule, and their
abundance and type (e.g., butyrate, propionate, acetate)
are directly related to the species composition of the
microbiota and their syntrophic interactions. Again, it will
be interesting to see whether other signaling pathways
(such as through the SCFA receptor GPR43 for example)
are similarly involved in host energy balance and whether
different microbial communities interact differently with
these molecules.
Anecdotal evidence suggests that the gut microbes also
affect gut hormones in humans. Gut hormones are
 10 Gastrointestinal infections
implicated in the reduction of appetite and weight after
Roux-en-Y gastric bypass surgery (RYGP) [51,52]. In
RYGP, a small gastric pouch is created from the prox-
imal stomach and the distal stomach and proximal small
intestine are bypassed. In a study of the effects of
RYGP on the fecal microbes, Zhang et al. [14] showed
that members of the Gamma-Proteobacteria (and Ver-
rucomicrobia) were enriched after gastric bypass, com-
pared with lean and obese participants. In addition, the
stomach chambers formed in RYGP surgery are colo-
nized by bacteria to a greater extent than the normal
stomach [53]. Interestingly, the administration of pro-
biotic microbes after the procedure has been shown to
accelerate weight loss [54], supporting the notion that
the gut bacteria may be modulating gut hormones.
Conclusion
An increasing number of studies relate imbalances in the
composition of the gut microbiota to obesity and its associ-
ated diseases. The approaches used to characterize gut
microbiotas vary widely, which might explain in part why
the specific alterations in the microbiota associated with
excess body fat, or weight loss, can also vary between
studies. To compare studies will require some standard-
ization of approaches or use of a variety of approaches
within single studies. However, irrespective of the specific
changes observed in microbial communities with respect
to body fat, evidence suggests that microbes do indeed
respond and contribute to host energy balance. They may
do this using a number of different and possibly interactive
signaling mechanisms involving innate immune
responses, endocrine cells, and epithelial cells. An integ-
ration of mechanistically based investigations and
microbial ecology studies using high-throughput sequen-
cing will provide insights into how best to reshape host–
microbial interactions to promote health.
Acknowledgement
Fredrik Bäckhed and Lars Angenent provided helpful comments on
the manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 71–72).
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