Review

doi: 10.1111/joim.12508

The gut microbiota and metabolic disease: current

understanding and future perspectives
T. Arora1 & F. Backhed1,2
From the 1Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical
Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden; and 2Novo Nordisk Foundation Center for Basic Metabolic
Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen,
Denmark

Abstract. Arora T and B

ackhed F (University of
Gothenburg, Gothenburg, Sweden; University of
Copenhagen, Copenhagen, Denmark). The gut
microbiota and metabolic disease: current
understanding and future perspectives. (Review).
J Intern Med 2016; 280: 339349.
The human gut microbiota has been studied for
more than a century. However, of nonculturebased techniques exploiting next-generation
sequencing for analysing the microbiota, development has renewed research within the field during
the past decade. The observation that the gut
microbiota, as an environmental factor, contributes to adiposity has further increased interest
in the field. The human microbiota is affected by
the diet, and macronutrients serve as substrates
for many microbially produced metabolites, such
as short-chain fatty acids and bile acids, that may
modulate host metabolism. Obesity predisposes
towards type 2 diabetes and cardiovascular disease. Recently, it has been established that levels

Introduction
The human body is home to several distinct
microbial ecosystems colonizing all mucosal linings of the body [13]. Most studies have focused
on the gut microbiota, which is a dynamic
ecosystem shaped by a number of factors such
as genetics, diet and environment [4]. The adult
gut microbiota is dominated by taxa belonging to
two phyla, Bacteroidetes and Firmicutes [5], but
the relative proportions of these phyla differ
between populations (Fig. 1). Despite harbouring
bacterial genera from just a few phyla, the gut
microbiota shows a tremendous diversity at
lower taxonomic levels, for example species and
strains [5], which renders an individuals microbiota unique. However, a core gut microbiota
encompassing 160 bacterial taxa has been iden-

of butyrate-producing bacteria are reduced in

patients with type 2 diabetes, whereas levels of
Lactobacillus sp. are increased. Recent data suggest that the reduced levels of butyrate-producing
bacteria might be causally linked to type 2 diabetes. Bariatric surgery, which promotes long-term
weight loss and diabetes remission, alters the gut
microbiota in both mice and humans. Furthermore, by transferring the microbiota from postbariatric surgery patients to mice, it has been
demonstrated that an altered microbiota may
contribute to the improved metabolic phenotype
following
this
intervention.
Thus,
greater
understanding of alterations of the gut microbiota,
in combination with dietary patterns, may provide
insights into how the gut microbiota contributes to
disease progression and whether it can be
exploited as a novel diagnostic, prognostic and
therapeutic target.
Keywords: diet, germ-free, microbiome, microbiota,
obesity, type 2 diabetes.

tified [5]. Through an updated gene catalogue,

>10 000 000 genes have been identified in the
gut microbiome (genes encoded by the microbiota) [6]. Thus, the number of genes in the gut
microbiome exceeds that in the human genome
by almost three orders of magnitude, complementing our own genome by performing essential
functions such as xenobiotic metabolism, vitamin
production and metabolism of food components
[7]. The metabolites resulting from microbial
metabolism contribute to the hosts physiological
reactions to regulate host metabolism at different
levels.
Here, we will review how the microbiota is associated with metabolic diseases and identify some of
the remaining challenges in understanding the
mechanisms underlying this association.

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Review: Gut Microbiota and Metabolic Disease

HMP
Bacteroidetes
Firmicutes
Proteobacteria
Verrucomicrobia
Actinobacteria
Others

Others 0.3%

0.4%
Akkermansia 0.9%
Others 0.2%
Escherichia 0.8%

Sutterella 1.1%
Others 2.6%
Butyrivibrio 1.5%
Roseburia 1.5%
Dialister 2.3%
Faecalibacterium 3.5%

75.7%
20.5%

Ruminococcus 3.7%

Bacteroides 51.1%

Eubacterium 6.9%

Others 6.6%
Alisitpes 12.3%

Prevotella 5.7%

MetaHit
Bacteroides 21.8%

Alisitpes 8.6%

Others 0.5%

2.1%

Akkermansia 2.3%
Others 1.0%
Escherichia 1.0%
Sutterella 0.6%

45.8%
Prevotella 11.8%

Others 6.2%

Butyrivibrio 3.0%

46.8%
Others 3.6%

Roseburia 3.9%
Dialister 4.0%
Eubacterium 14.7%

Faecalibacterium 5.7%
Ruminococcus 6.0%

Establishment of the microbiota

Human infants acquire their first inoculum of
microbes from their mothers during birth. A major
factor that influences motherinfant transmission
is mode of birth, and accumulating data suggest
that the microbiota of vaginally born infants is
more similar to the vaginal and faecal microbiota of
their mother, whereas infants born via caesarean
section have a microbiota consisting of bacteria
from the mothers skin and the environment [8, 9].
The infants microbiota is thereafter exposed to a
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Fig. 1 Quantitative
comparison of faecal microbiota
in two healthy populations.
Relative taxonomic abundance
data from 139 healthy
individuals in the Human
Microbiome Project (HMP)
Consortium and 99 healthy
individuals in the
Metagenomics of human
intestinal tract (MetaHIT)
Consortium (25 patients with
inflammatory bowel disease
were excluded) representing
American and European
populations, respectively, were
extracted from http://
huttenhower.sph.harvard.edu/
metaphlan and analysed using
the metagenomic phylogenetic
analysis (MetaPhlAn) pipeline
[104]. The inner pie chart
indicates the proportions of
major phyla found in healthy
human gut. The outer pie chart
indicates the percentage of
major genera in the respective
phyla.

succession of bacterial species where the initial

more aerobic microbiota is replaced by anaerobic
bacteria [8, 9]. The microbiome of infants is
responsive to diet and is enriched in genes contributing to lactate degradation during the first
4 months of life when most infants consume
breastmilk [8, 10]. Cessation of breastfeeding and
the introduction of solid foods are important
determinants of the establishment of an adult-like
microbiota, which is rich in butyrate-producing
anaerobes [8]. Furthermore, after weaning, the
microbiome is enriched in genes involved in the

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Dietary modulation of the gut microbiota

The gut microbiome is particularly enriched in
genes encoding enzymes essential for metabolizing
several macronutrients, especially dietary complex
polysaccharides [13, 14]. However, the type of diet
we consume has a profound impact on the composition and gene expression of the gut microbiota.
For example, herbivores, omnivores and carnivores
form distinct groups based on their microbiota
[15]. Furthermore, expression of enzymes in the
microbiome of different mammals varies depending
on their diet, for example the microbiome of herbivores has a relatively increased abundance of
enzymes that hydrolyse plant polysaccharides
and synthesize amino acids, whereas the microbiome of carnivores is enriched in proteases to
facilitate digestion of proteins [16]. Similarly, vegetarians and vegans loose the capacity to metabolize L-carnitine, which is present in red meat [17].
Long-term food patterns modulate the gut microbiota [18]. The dietmicrobiota interaction is evident across globally distinct populations, where
communities consuming high levels of fibre have
an increased abundance of Prevotella, whereas fat
and protein intake correlate with an increased
abundance of Bacteroides (Fig. 2) [1922]. However, dramatic short-term changes in the diet can
promote shifts in the microbiota if diets are exclusively composed of animal or plant sources [23].
Lack of fibre in an animal-based diet leads to the
expansion of bile-resistant bacteria including Bacteroides, whereas plant-based diets promote bacteria with an enhanced capacity to ferment
polysaccharides (Roseburia sp., Eubacterium rec-

Fiber

Given that the microbiota originates from the

mother and that infants and children are exposed
to diets similar to those of their parents, it is not
surprising that even in adulthood the microbiota in
siblings and their mother is more similar than in
unrelated individuals [11]. A recent study analysing the microbiota of >400 twin pairs revealed
many microbial taxa, the abundance of which were
influenced by host genetics in addition to diet. It is
interesting that the family Christensenellaceae,
which was found to be the most heritable, cooccurred with other heritable bacteria as well as
with methanogenic Archaea and was associated
with a low body mass index [12].

Protein/fat

degradation of polysaccharides, which are highly

abundant in solid foods [8].

Bacte roides

Pr evotella

Fig. 2 Diet alters the gut microbiota. Dietary composition

alters the proportions of Bacteroides and Prevotella, both
of which belong to the phylum Bacteroidetes. Intake of an
animal-based diet rich in protein/fat promotes higher
Bacteroides levels, whereas intake of a plant-based diet
rich in fibre shifts the microbiota towards higher Prevotella
levels.

tale and Ruminococcus bromii) [24]. The relatively

fast alteration in the microbiota following a shift in
diet showed that fibre supplementation rapidly
promoted the expansion of Ruminococcus sp. and
E. rectale within 34 days in overweight men [24],
in agreement with the findings of David et al. [23].
Similarly, we recently demonstrated that supplementation with barley kernels over 3 days
increased the levels of Prevotella in those subjects
who responded with improved glucose metabolism
[25].
In addition to compositional alterations, gut bacteria have a profound capacity to regulate their
gene expression upon shifts in the diet [26]. Diets
lacking in plant polysaccharides promote localization of Bacteroides thetaiotaomicron from the
lumen of the gut to the mucus layer where expression of genes involved in mucus utilization is
induced [27, 28]. Furthermore, B. thetaiotaomicron
has the capacity to induce host fucosylation of the
intestinal mucosa, which can then be used as a
substrate [29]. Thus, there is a complex interaction
between the gut microbiota and the diet, whereby
the diet can modulate the microbiota, which in
turn also regulates its gene expression and metabolism in response to nutrient availability.
The gut microbiota as an environmental factor contributes to
increased energy harvest and adiposity
As described above, the microbiome has
profound capacity to degrade polysaccharides
the diet and accordingly, the gut microbiota
essential for efficient nutrient harvest from
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a
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polysaccharide-rich diet [30]. Germ-free (GF) mice

have reduced adiposity compared with conventionally raised mice. Of interest, colonization of GF
mice with caecal microbiota from conventionally
raised mice resulted in a >50% increase in adiposity in the resulting conventionalized mice (e.g. GF
mice that have been colonized with microbiota from
conventionally raised mice), normalizing adiposity
within 14 days to similar levels as observed in the
conventionally raised animals [31, 32]. The
reduced adiposity of GF mice fed a polysaccharide-rich chow diet was attributed to their reduced
capacity to harvest energy from the diet as the gut
microbiota is required for fermenting these food
components to short-chain fatty acids (SCFAs).
Importantly, the increased adiposity in conventionalized mice occurred despite reduced food
intake, further emphasizing the increased energy
harvest by the gut microbiota during consumption
of a polysaccharide-rich diet [31].
Fermentation of polysaccharides in the lower gut
in humans has been suggested to contribute 10%
of daily energy requirements [33]. However, Asian/
African diets have higher fibre content, which may
indicate a higher energy contribution from fibre
fermentation to the host. This was corroborated in
a study in pigs, which have similar intestinal
functions to humans, showing that an increase in
dietary fibre from 75 to 147 g kg 1 increased
energy contribution from 10.7% to 24.2% [34].
Thus, a slight increase in microbial fermentation
(1%) could provide 20 kcal day 1 extra energy
based on a diet of 2000 kcal day 1, resulting in
1 kg of weight gain per year [35]. In agreement
with these in vitro findings, fermentation of faeces
from obese donors with different nondigestible
carbohydrates was reported to produce higher
cumulative amounts of SCFAs compared with lean
donors [36].
The increased energy harvest in conventionally
raised mice is associated with reduced expression
of the lipoprotein lipase (LPL) inhibitor angiopoietin-like protein 4 (Angptl4; also known as fastinginduced adipose factor) [31]. The reduced level of
Angptl4 was associated with increased LPL activity
in the white adipose tissue, supporting increased
triglyceride incorporation into adipocytes. Using
GF and conventionally raised Angptl4-deficient
mice, we were able to demonstrate that Angptl4
was required for mediating microbiota-induced
adiposity [31]. The increased adiposity in conventionally raised and conventionalized mice is also
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Review: Gut Microbiota and Metabolic Disease

associated with enhanced inflammatory tone in the

white adipose tissue, which may be attributed to
increased influx of microbial pro-inflammatory
metabolites [32, 37, 38].
The gut microbiota and obesity
Obesity has increased worldwide and is attributed
to increased energy intake and reduced energy
expenditure. Comparisons between obese and lean
individuals have demonstrated that obese individuals have increased levels of Firmicutes and
reduced levels of Bacteroidetes [39]. Similar alterations were observed in obese versus lean mice
[40], suggesting that the microbiota may contribute
to the pathogenesis of obesity. Conflicting results
regarding the modulation of the proportions of
Firmicutes and Bacteroidetes in obese individuals
have also been reported [4145]; however, the
general consensus is that obesity is associated
with reduced microbial diversity [46, 47]. Metagenomic analysis has revealed increased harvest of
energy from indigestible carbohydrates in the
microbiome of obese mice, clarifying the role of an
altered microbiota in obesity [48]. Moreover, the
obese phenotype was transferrable from genetically
obese donor mice to GF recipients by gut microbiota transplantation [48]. Similar findings were
observed upon transfer of faecal samples from
twins discordant for obesity, and cohousing of lean
and obese recipient mice resulted in invasion of
Bacteroides sp. from the lean to the obese animals,
which prevented the development of obesity in a
diet-dependent fashion [49].
Accumulating evidence has suggested that early
perturbation of the microbiota may have longlasting effects on host metabolism. For example,
antibiotic administration within the first 6 months
of life in infants increased the risk of becoming
overweight at 7 years of age [50]. Similarly, antibiotic treatment of mice before weaning induced
obesity and metabolic disease in adulthood [51].
Thus, there may be an important time window
during which an individual is particularly sensitive
to microbial perturbations in relation to developing
metabolic diseases later in life.
The use of GF mice allows the interactions between
diet and the microbiota, and the underlying
mechanisms of the development of obesity, to be
investigated in detail. GF mice are resistant to
diet-induced obesity when fed a western diet,
which is rich in saturated fat and sucrose, despite

T. Arora & F. B
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a similar level of food intake compared to conventionally raised animals [5254]. The increased
resistance to obesity in GF mice may in part be
attributed to elevated levels of Angptl4 as discussed above [31]. Furthermore, phosphorylation
of AMP-activated kinase (AMPK) was increased in
GF mice [52]. However, it is still not clear whether
the increased phosphorylation of AMPK is a cause
of reduced adiposity or contributes to the lean
phenotype. Because the calorie-rich western diet
used in this study [52] is lacking in fermentable
fibre, the gut microbiota is also likely to contribute
to metabolic disease through additional pathways
other than harvesting nutrients from a polysaccharide-rich diet.

Review: Gut Microbiota and Metabolic Disease

type 2 diabetes may contribute to disease [59]. In a

landmark study, Vrieze et al. used faecal microbiota transplantation from lean donors to insulinresistant patients with metabolic syndrome and
demonstrated that faeces from lean subjects, but
not autologous transplantation, improved insulin
sensitivity and was associated with enhanced
numbers of butyrate-producing bacteria [60].
Thus, there are accumulating evidence to suggest
that the microbiome may directly modulate insulin
sensitivity in humans. However, how the microbiota modulates host glucose metabolism remains
unclear. Therefore, more mechanistic studies are
warranted.

Of note, the resistance to diet-induced obesity in

GF mice appears to be highly dependent on the
macronutrient composition of the diet; a high-fat
diet without sucrose promoted obesity in GF mice
[55]. Similarly, the origin of dietary fat is also
important; conventionally raised mice became
obese on a high-fat diet containing lard as the fat
source; however, they were protected against
obesity when the fat source was switched to fish
oil rich in polyunsaturated fatty acids [37]. It is also
noteworthy that the different fat sources markedly
affect the microbiota. It was shown that the altered
gut microbiota was directly associated with
improved metabolism, as continuous faecal transplants with fish oil microbiota to lard-fed mice
protected them against obesity [37]. These findings
demonstrate the importance of understanding the
interactions between the microbiota and diet.

Another bacterial species, Akkermansia muciniphila, which exhibits mucin-degrading properties

and has attracted considerable attention, was
found to be enriched in a Chinese cohort of
patients with type 2 diabetes [56]. However, this
finding was not corroborated in a European cohort
[57]. Instead, in a European population, it was
demonstrated that obese individuals with less
severe metabolic syndrome had increased levels
of A. muciniphila and this was associated with
increased microbial diversity compared with subjects with more impaired metabolic status [61].
Thus, there may be population-specific associations between A. muciniphila and type 2 diabetes.
Supplementation with A. muciniphila in dietinduced
obese
mice
reduced
circulating
lipopolysaccharide (LPS) levels and enhanced lipid
oxidation [62], and was associated with improved
glucose tolerance and reduced inflammation [63].

The gut microbiota and type 2 diabetes

Microbiota and cardiovascular disease

Obesity increases the risk of multifactorial diseases such as type 2 diabetes. Recently, we and
others found that type 2 diabetes in humans was
associated with a reduced abundance of butyrateproducing bacteria and an increased abundance of
Lactobacillus sp. [5658]. Moreover, computational
models based on the gut metagenome were able to
predict type 2 diabetes-associated phenotype in
patients with impaired glucose tolerance [57],
suggesting that the gut microbiome may constitute
a novel biomarker for prediction of type 2 diabetes.
Vancomycin treatment in patients with metabolic
syndrome reduced the abundance of Gram-positive bacteria, such as butyrate-producing bacteria;
this was associated with reduced insulin sensitivity, suggesting that the decreased levels of butyrate-producing bacteria observed in patients with

Bacteria and bacterial products have been associated with cardiovascular disease (CVD), and
atherosclerotic plaques contain bacterial DNA
and cells [64, 65]. Interestingly, we found that
several of the bacterial taxa observed in atherosclerotic plaques were also present in the oral cavity or
the gut of the same individuals [64], highlighting
the possibility that the microbial communities at
these sites may be a source of bacteria in the
plaque, which may contribute to plaque stability
and development of CVD. Metagenomic sequencing
of the stool microbiota from these subjects revealed
that the microbial ecology was altered in patients
with unstable plaques (e.g. patients with stroke),
associated with reduced levels of taxa belonging to
the genus Roseburia and increased capacity of the
microbiome to produce pro-inflammatory peptido 2016 The Association for the Publication of the Journal of Internal Medicine
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glycans and reduced production of anti-inflammatory carotenes [66]. Thus, the gut microbiome of
patients with CVD may be producing more proinflammatory molecules.
A series of studies have identified a microbederived metabolite, trimethylamine (TMA), which
is efficiently converted to trimethylamine-N-oxide
(TMAO) by the liver, as a biomarker and potential
causative factor for CVD [17, 67, 68]. Plasma
levels of TMAO were increased in subjects with
cardiovascular events compared to controls [67],
and it was demonstrated that microbial metabolism of dietary choline and L-carnitine increased
the levels of TMA, which was converted to TMAO
[17, 68]. Individuals exposed to antibiotics were
unable to convert L-carnitine to TMA and subsequently to TMAO [17], demonstrating that the
microbiota is essential for production of these
metabolites and is able to adapt to the macronutrient composition in the diet. A causal relationship between these microbial metabolites and
CVD has been established by supplementation of
TMAO in mice deficient in Apoe, a common model
for studying atherosclerosis, which increased
atherosclerotic lesions. TMA lyases have been
identified [69] and accordingly drugs inhibiting
these bacterial enzymes are attractive for preventing CVD.
Microbial signalling affects host metabolism
The gut microbiota has a vast capacity to produce
molecules that can affect host metabolism. Some
of these metabolites are structural components
such as LPS, the major component of membranes
of Gram-negative bacteria, which is known to
increase in type 2 diabetes and activate the innate
immune system (Fig. 3) [70]. A direct link between
LPS and metabolic impairment was demonstrated
by administering LPS for 4 weeks to chow-fed mice
[38]. Further, it was demonstrated that this signalling requires the LPS receptor CD14 and that
microbial activation of the innate immune signalling cascade in adipocytes promotes secretion
of the chemokine CCL2 [37, 71], which subsequently promotes accumulation of macrophages in
adipose tissue. LPS levels increased in human
subjects with type 2 diabetes [72, 73] and was
associated with increased risk of developing diabetes [74]. Administration of LPS in humans
induced insulin resistance by triggering inflammatory reactions [75], whereas in mice it enhanced
levels of hepatic pro-inflammatory lipid mediators
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causing liver injury [76]. Because LPS is produced

by Gram-negative bacteria in the gut microbiota,
altering the microbiota with soluble fibre [77] or
antibiotics [78, 79] reduced LPS-associated metabolic alterations. By contrast, it was shown that
gut-derived LPS enhanced macrophage recruitment to adipose tissue with no effect on glucose
metabolism [32].
Microbial interactions with the diet can also generate bioactive components such as SCFAs, of
which butyrate has been the most widely studied.
SCFAs can influence host metabolism through
several different effects either by supplying the
host with energy or as direct activators of G-protein
coupled receptors such as GPR41 and GPR43
(Fig. 3). Butyrate also acts as a histone deacetylase
(HDAC) inhibitor thus modulating gene expression
and contributing to epigenetic modulation [80]. It is
interesting that supplementation of butyrate in
mice prevented diet-induced obesity and insulin
resistance by enhancing thermogenesis and fatty
acid oxidation [81]. The effect was partially
explained by reduced activity of HDAC in muscle,
which could modulate expression of peroxisome
proliferator-activated receptor-gamma coactivator
1 alpha (PGC-1a) [81]. Some of the beneficial effects
of butyrate (and also of propionate) can be
attributed to its role as a substrate for intestinal
gluconeogenesis, which has important metabolic
effects [82]. However, additional studies are needed
to clarify the relative importance of these different
pathways and their relevance in humans.
The gut microbiota is also an important regulator
of bile acid metabolism; it is essential for synthesis
of secondary bile acids, but also regulates bile
acids synthesis through metabolism of a naturally
occurring FXR antagonist (Fig. 3) [83]. Of note, the
inhibition of FXR in the GF condition results in a
significantly increased bile acid pool and may also
contribute to the protection of diet-induced obesity
observed in GF mice [84]. Interestingly, secondary
bile acids such as lithocholic and deoxycholic
acids are agonists for the G-protein coupled receptor TGR5 [85]. TGR5 is expressed in Kupffer cells,
gall bladder, immune cells, brown adipose tissue
and enteroendocrine cells [86]. TGR5 has been
proposed as a putative target to improve metabolic
diseases. The widespread expression of TGR5 in
tissues suggests that it may regulate metabolism
through multiple pathways. Activation of TGR5 is
reported to stimulate GLP-1 secretion in L cells
[8790], promote thermogenesis in brown adipose

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Diet

Microbiota

Fiber

Structural
components

Bile acids

a) Butyrate, propionate
CA/
CDCA
c)
DCA/
LCA

b)
GPR43
GPR41
TGR5

d) LPS
tMCA
MCA
TLR4

TGR5

FXR

Energy
source

Ileum

HDAC
inhibition
Intestinal
gluconeogenesis

Metabolic
regulation

Proinflammatory
cytokines

FXR

GLP-1
release

Thermogenesis

Incretin effect
Appetite
Intestinal transit

Energy
expenditure

Bile acid synthesis

FA metabolism

Steatosis

Macrophage
recruitment
and polarisation

Inflammation

Fig. 3 Microbial metabolites regulate metabolism in different tissues. Fermentation of dietary fibre by the gut microbiota
produces short-chain fatty acids (SCFAs) such as butyrate, which serves as an energy source and promotes histone
deacetylase (HDAC) inhibition in enterocytes. (a) Propionate and butyrate also stimulate intestinal gluconeogenesis
facilitating metabolic regulation. In an enteroendocrine cell, SCFAs through G-protein coupled receptor 41 and 43 (a) and
microbiota-derived secondary bile acid lithocholic acid (LCA) and deoxycholic acid (DCA) through bile acid receptor TGR5 (b)
promote glucagon like peptide-1 (GLP-1) release, which enhances incretin response, suppresses appetite and reduces
intestinal transit. (b) LCA and DCA promote thermogenesis in brown adipose tissue (BAT) which increases energy
expenditure. (c) The gut microbiota promotes deconjugation of taurobetamuricholic acid (tbMCA), a natural farnesoid X
receptor (FXR) antagonist, which alleviates intestinal and hepatic FXR repression thus reducing bile acid synthesis and
altering fatty acid (FA) metabolism. (d) Lipopolysaccharide (LPS) a pro-inflammatory molecule derived from Gram-negative
bacterial membranes promotes macrophage recruitment and polarization in white adipose tissue inducing inflammation
through Toll-like receptor 4 (TLR4).

tissue (thus increasing energy expenditure [91,

92]) and reduce diet-induced obesity [93], showing
the potential of microbial-produced bile acids in
the regulation of metabolism (Fig. 3). TGR5
expression was enhanced in subcutaneous adipose tissue of obese subjects, but decreased after
weight loss and correlated positively with resting
metabolic rate [94], suggesting a link between
TGR5 and metabolism in humans. Comparison of
GF tissue-specific Tgr5 knockout mice may reveal
the relative contribution of microbial signalling in
different tissues.

Targeting the microbiome to treat metabolic disease

Probiotics
The encouraging evidence that faecal transfer of
the microbiota from lean donors improves metabolic outcome in patients with metabolic syndrome
[60] suggests that it may be possible to use
probiotics to improve metabolic features. In a
recent study, administration of Lactobacillus reuteri increased insulin secretion by promoting
incretin release in obese glucose-tolerant subjects
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[95]. However, a more direct approach based on the

use of bacterial species that are reduced in
metabolic diseases may be more attractive. Identification of reduced levels of Christensenellaceae in
obese subjects prompted Goodrich et al. [12] to
test the possibility that a member of this family,
Christensenella minuta, might have probiotic
effects and prevent obesity. Administration of
C. minuta altered the microbial ecology and protected mice from obesity [12]. Despite promising
results in mouse experiments, it is not clear how
these microbes may affect metabolism in humans
and the mechanism of action is yet to be determined.
Interestingly, bariatric surgery causes profound
alterations in the microbiota [9699]. Of note,
transfer of microbiota following Roux-en-y gastric
bypass (RYGB) from both mice [97] and humans
[98] to GF recipients reduced adiposity gain, suggesting that some of the beneficial metabolic effects
following bariatric surgery may be mediated by an
altered microbiota, which in turn may be important
for characterization of next-generation probiotics
to treat metabolic diseases.
Dietary fibre and prebiotics
Prebiotic administration is associated with alterations of the microbiota and improved metabolic
markers in obese mice [77] and increased insulin
sensitivity in healthy humans [100]. However,
prebiotic treatment in obese women did not show
similarly strong effects, which may be due to the
relatively lower dose administered in humans
compared with mice [101]. It has also been found
that not all humans respond to dietary changes in
a similar manner, and nonresponsiveness to either
a fibre-rich or weight loss diet was correlated with
increased bacterial diversity [102]. We recently
performed a dietary intervention study with barley
kernel bread, which is known to improve glucose
metabolism in humans [103], and were able to
identify responders and nonresponders to the
intervention based on the relative Prevotella/Bacteroides ratio [25]. By transferring the microbiota
from responders to GF mice, we were able to
demonstrate that the altered gut microbiota in
responders directly contributed to improved glucose metabolism in recipients; no such improvement was observed after transfer of nonresponder
faeces. Finally, we noted that administration of
Prevotella copri, the most abundant Prevotella
species in our study, improved glucose metabolism
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in a fibre-specific manner [25]. Taken together,

these findings suggest that individualized treatment programmes based on the microbiota may
provide novel treatment strategies for metabolic
diseases.
Conclusions
As the proposal that the microbiota should be
considered an environmental factor that contributes to adiposity and glucose metabolism [31]
and the demonstration that it is altered in obesity
[40], the number of studies exploring the impact of
the microbiota on metabolic diseases has dramatically increased. However, many of these studies are
cross-sectional and demonstrate associations
between an altered microbiota and a given disease.
To investigate whether the microbiota is altered
before the onset of disease, prospective studies are
required, which may further indicate that the microbiota contributes to rather than reflecting metabolic
disease. These results may provide the basis for
human intervention studies. However, given the
genetic and microbial diversity in the human
population and the complex microbiotadiet interactions, individualized treatment strategies are
likely to be required. Furthermore, mechanistic
studies demonstrating the underlying molecular
mechanisms are needed, which should be
supported by confirmation in human studies. In
conclusion, it has been established that the microbiota has an important role in metabolic disease, but
the future therapeutic potential of the gut microbiota remains to be demonstrated.
Conflict of interest statement
FB is founder and shareholder of Metabogen AB
and ProPrev AB.
Acknowledgements
We are grateful to Hao Wu for producing Fig. 1,
Anna Hall
en for assistance with Figs. 2 and 3 and
Valentina Tremaroli for critical comments on the
manuscript. Work in the authors laboratory is
supported by the Swedish Research Council, the
NovoNordisk Foundation, Torsten S
oderbergs
Foundation, Ragnar S
oderbergs Foundation,
Swedish Diabetes Foundation, Swedish Heart
Lung Foundation, G
oran Gustafssons Foundation,
IngaBritt and Arne Lundbergs Foundation, Knut
and Alice Wallenberg Foundation, the Swedish
Foundation for Strategic Research, the FP7

T. Arora & F. B
ackhed

sponsored programme METACARDIS and the

regional agreement on medical training and clinical
research (ALF) between Region V
astra G
otaland
and Sahlgrenska University Hospital. FB is a
recipient of an ERC Consolidator Grant (European
Research Council, Consolidator Grant 615362 METABASE).

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Correspondence: Fredrik B
ackhed, Wallenberg Laboratory, SU/
Sahlgrenska, Department of Molecular and Clinical Medicine,
Institute of Medicine, Bruna Str
aket 16 SE-413 45 G
oteborg,
Sweden.
(fax: +4631823762; e-mail: Fredrik.Backhed@wlab.gu.se).

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