Review

The microbiota–gut–brain axis in obesity

Cristina Torres-Fuentes*, Harriët Schellekens*, Timothy G Dinan, John F Cryan

Changes in microbial diversity and composition are increasingly associated with several disease states including Lancet Gastroenterol Hepatol
obesity and behavioural disorders. Obesity-associated microbiota alter host energy harvesting, insulin resistance, 2017
inflammation, and fat deposition. Additionally, intestinal microbiota can regulate metabolism, adiposity, Published Online
August 24, 2017
homoeostasis, and energy balance as well as central appetite and food reward signalling, which together have
http://dx.doi.org/10.1016/
crucial roles in obesity. Moreover, some strains of bacteria and their metabolites might target the brain directly via S2468-1253(17)30147-4
vagal stimulation or indirectly through immune-neuroendocrine mechanisms. Therefore, the gut microbiota is *Joint first authors
becoming a target for new anti-obesity therapies. Further investigations are needed to elucidate the intricate APC Microbiome Institute,
gut-microbiota–host relationship and the potential of gut-microbiota-targeted strategies, such as dietary (C Torres-Fuentes PhD,
interventions and faecal microbiota transplantation, as promising metabolic therapies that help patients to maintain H Schellekens PhD,
a healthy weight throughout life. Prof T G Dinan MD,
Prof J F Cryan PhD), Department
of Psychiatry and
Introduction homoeostasis and the central appetite mechanism.10 Neurobehavioural Sciences
Hippocrates, the father of modern medicine, famously Thus, modulation of intestinal microbiota by dietary (Prof T G Dinan), and
said “all disease starts in the gut”. The past two decades interventions, including prebiotics, probiotics, or faecal Department of Anatomy and
Neuroscience (H Schellekens,
have seen an abundance of research supporting this microbiota transplantation (FMT), might provide Prof J F Cryan), University
concept. The human intestine hosts tens of trillions of potential novel anti-obesity strategies. Growing evidence College Cork, Cork, Ireland
microorganisms, including archaea, bacteria, viruses, suggests that the success of bariatric surgery is due to Correspondence to:
phages, fungi, protists, and nematodes, but is dominated its effects on the microbiota (panel 1; figure 1).11 These Prof John F Cryan, Department of
by bacteria from the phyla Firmicutes and Bacteriodetes. findings have important implications for society since Anatomy and Neuroscience,
University College Cork,
This gut microbiota ecosystem is established after birth obesity and its comorbidities (ie, type 2 diabetes, Cork T12 XF62, Ireland
following the transfer of maternal and environmental cardiovascular disease, and increased pro-inflammatory j.cryan@ucc.ie
bacteria, and continues to develop until adulthood.1 status), are serious and widespread health concerns
Despite being overlooked for years, the gut microbiota worldwide and urgently need to be addressed.14,15
is one of the largest components of our body, weighing
approximately 1–2 kg, and contains over 100 times more
genes than does the human genome.2 Commensal gut Panel 1: Bariatric surgery and the microbiome
bacteria have a crucial symbiotic relationship with the Bariatric surgery is an intervention indicated for severe obesity
human body throughout its evolution, protecting and and is the only treatment that leads to substantial and
supporting the structure of intestinal mucosa. Gut sustained weight loss. Different bariatric surgeries are
bacteria are therefore becoming increasingly recognised available, such as adjustable gastric banding, sleeve
as key regulators of host physiology and pathophysiology, gastrectomy, Roux-en-Y gastric bypass (RYGB), and
and undeniably have a role in health and disease.3 biliopancreatic diversion.11 Results from human and animal
Alterations in the composition of the human gut studies show that RYGB reduces adiposity, improves
microbiota occur in metabolic disorders such as obesity, hormonal (increased glucagon-like peptide-1 and peptide YY)
diabetes,3 and eating disorders, as well as stress-related and inflammatory status, and increases the pool of bile acids,
neuropsychiatric disorders including depression4 and as well as improving insulin sensitivity (figure 1).11 RYGB also
anxiety,5 which are also characterised by changes in affects the composition of the gut microbiota, leading to
eating behaviour. Moreover, gut microbiota regulate fat increased diversity.1 For example, although with variation
storage6 and can harvest energy from the diet.7 Several across studies, after bariatric surgery, patients and mice have
studies have found that intestinal microbiota also affect an increased abundance of Gammaproteobacteria and
inflammation, insulin, and glucose metabolism, as well Verrucomicrobia (Akkermansia) and a decreased abundance of
as hepatic lipid metabolism.8 Furthermore, gut bacteria Firmicutes.11,12 Moreover, faecal microbiota transplantation
can directly affect the CNS via modulation of endocrine from mice that had RYGB into germ-free mice resulted in
signalling pathways of the microbiota–gut–brain axis weight loss and decreased fat mass in the recipient animals,
such as, glucagon-like peptide-1 (GLP-1) and peptide YY potentially due to altered microbial production of short-chain
signalling, or activation of reward pathways.9 fatty acids, increased propionate levels, and decreased acetate
A healthy gut microbiota is crucial for proper levels.13 Therefore, bariatric surgery leads to specific changes in
metabolic function and homoeostasis, which sub­ the gut microbiota, causing changes in the composition of
stantially benefits the host in exchange for living and short-chain fatty acids and thus influencing host metabolism,
proliferating in the intestinal habitat. Alterations in the including gut hormone secretion and insulin sensitivity.
composition of the microbiota, especially early in These effects might be central to the success of RYGB in
life, might cause obesity and diabetes by substantially treating obesity, metabolic syndrome, and diabetes.11,12
modifying the host’s metabolism and affecting

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 Review

Nutrients
Roux-en-Y gastric bypass

↓Ghrelin
↓Appetite

↑Insulin sensitivity GPR43

Bile acids pool
↓Adiposity
↓Inflammation
↓Leptin
↑Proteobacteria
↑Verrucomicrobia (Akkermansia)
↑Diversity

↓Firmicutes/Bacteroidetes GPR41 GPR43

SCFAs
Butyrate
↓Acetate
↑Propionate

↓GLP-1/PYY/CCK

↑Satiety

GLP-1

Figure 1: Effects of Roux-en-Y gastric bypass surgery on the gut microbiota and its metabolic outcomes
SCFAs=short-chain fatty acids. GLP-1=glucagon-like peptide 1. PYY=peptide YY. CCK=cholecystokinin. GPR41=G-protein coupled receptor 41. GPR43=G-protein
coupled receptor 43.

In addition to metabolic changes, obesity is a disorder of
the brain with altered food intake behaviour. Research is
focusing on whether the microbiome can affect brain
processes and modify the homoeostatic and hedonic
control of food intake.16 We review the gut microbiota as a
key regulator of host metabolism, central appetite, and
food reward, and its role in metabolic disorders such as
obesity, summarise the literature on potential mechanisms
of gut–brain axis signalling, review how some bacterial
strains might contribute to, or protect against, metabolic
disease, and address how FMT, bariatric surgery, and
dietary interventions might be novel metabolic therapies
in clinical practice in obesity management.
Obesity-associated microbiota
One of the earliest key findings implicating a role for
intestinal microbiota in energy balance originated from
germ-free mice, which completely lack intestinal
microbiota from birth. These mice were protected against
obesity and were significantly leaner than were control
mice, despite consuming more calories.6 Furthermore,
these germ-free mice had altered plasma lipid metabolic
markers and lower concentrations of ghrelin and leptin,
which are indicative of an energy deficit.17 Conversely,
specific alterations in gut microbial composition have
been linked with obesity; a wider variety of Bacteroidetes,
which break down plant starches and fibres for energy,
was found in individuals with normal body-mass index
than in obese individuals, in whom an increase in the
abundance of Firmicutes was found.18 Despite large
variations in composition among individuals, changes in
an overall core human microbiome were associated
with obese individuals.19 The obese phenotype was
transmittable via intestinal microbiota alone in germ-free
mice20 and human beings21 and was reversed in germ-free
mice following co-housing with mice transplanted
with the lean microbiota.21 These findings show the
transmissible, rapid, and modifiable nature of inter­
actions between diet and the microbiota in obesity and
metabolic syndrome.
More recently the link between the microbiota and
obesity was tested in a meta-analysis in which datasets
from ten previous studies were pooled using a random-
effect model; no significant associations were observed
for the ratio of Bacteroidetes to Firmicutes or their
individual relative abundance.22 The researchers showed

2 www.thelancet.com/gastrohep Published online August 24, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30147-4

 Review

Circulation

Hypothalamus
NTS
Satiety ARC
Vagal afferent B cells
NPY/AgRP CART/ Bacterial neuroactives Gut peptides Cytokines
GABA POMC nerve
(GLP-1, PYY, CCK)

Adipose tissue Enteric Enteric nervous

muscles system neuron
↑Leptin GLP-1
↑Insulin sensitivity DC
↓Ghrelin EEC
Pancreas
FXR
SCFAs
FFAR

Taste receptor Toll-like TGR5

GLP-1 LPS receptor
Conjugated
Metabolites bile acids
SCFAs, GABA, 5-HT, NTs
Bile acids
Nutrients Microbiota

Figure 2: Microbiota-driven mechanisms of metabolism and appetite regulation

Intestinal microorganisms convert dietary nutrients into metabolites such as short-chain fatty acids (SCFAs), γ-aminobutyric acid (GABA), serotonin (5-HT),
and other neurotransmitters (NTs), which have different peripheral and central effects modifying host metabolism and central regulation of appetite directly via
vagal stimulation or indirectly through immune–neuroendocrine mechanisms. Enteroendocrine cells (EECs) are activated by these microbial-derived metabolites via
activation of different receptors (eg, fatty acid receptors [FFARs] and taste receptors), leading to the production of gut hormones such as glucagon-like peptide-1
(GLP-1), peptide YY (PYY), and cholecystokinin (CCK). These gut hormones signal from the gut to the nucleus tractus solitarius (NTS) in the brain via the vagus nerve
and direct secretion into the circulatory system. Information from the NTS is distributed to the arcuate nucleus (ARC) in the hypothalamus, where appetite and
energy balance is regulated. The ARC contains neuropeptide Y (NPY), agouti-related protein (AgRP), anorexigenic peptides, cocaine amphetamine-regulated
transcript (CART), and pro-opiomelanocortin (POMC) neurons. Moreover, gut microorganisms might also use bile acids and their conjugates, activating farnesoid X
receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5) and increasing GLP-1 secretion by EECs. GLP-1 in the gut is also essential for glucose tolerance and
insulin sensitivity. Moreover, microbial-derived metabolites might also lead to other peripheral effects such as increased leptin production by adipose tissue or
decreased ghrelin production in the stomach. Additionally, gut microbiota has been associated with inflammation via release of lipopolysaccharide (LPS), which leads
to activation of immune cells, such as B cells or dendritic cells (DCs), and cytokine production.

that, after a power analysis, most studies have a large
interpersonal variation and insufficient sample sizes,
and do not have sufficient power to detect a 5% difference
in the diversity of microbiota.
Complex interactions between environmental factors,
host genetics, and the gut microbiota play an
essential part in the pathophysiology of obesity and
diabetes. Alterations in the gut microbiota following
environmental reprogramming ameliorates the develop-
ment of metabolic syndrome in different strains
of mice (obesity/diabetes-prone C57Bl/6J, obesity/
diabetes-resistant 129S1/SvImJ, and obesity-prone but
diabetes-resistant 129S6/SvEvTac mice).23 Moreover,
a twin study24 found that host genetics affect the
composition of the gut microbiota as well as host
metabolism; monozygotic twins had a more similar gut
microbiota composition than did dizygotic twins and gut
microbiota were enriched in particular taxa including
Christensenellaceae minuta. Furthermore, an obesity-
associated microbiome enriched with C minuta and
transplanted to germ-free mice reduced weight gain and
altered the microbiome of recipient mice.24 More recently,
a metagenome-wide association study found a decreased
abundance of a glutamate-fermenting commensal bacteria
in obese individuals, which was inversely correlated with
serum glutamate concentration. This abundance was
increased after bariatric surgery, which highlights further
unknown links between intestinal microbiota alterations,
circulating amino-acids, and obesity.25
Metabolism and appetite regulation
Although the gut microbiota is a contributing and
potential causal factor for obesity and metabolic
syndrome, the exact mechanisms underlying this
relationship are unclear. Nevertheless, the intestinal
microbiota produce bioactive metabolites in a
diet-dependent manner, including short-chain fatty
acids and conjugated fatty acids.26 These microbiota-
derived metabolites have peripheral effects but also
modulate the brain via direct or indirect mechanisms,
which modifies host metabolism and the central
regulation of appetite and food intake (figure 2).9,16

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 Review
Peripheral metabolic signalling
Intestinal microbiota can affect peripheral metabolic
function. Metagenomics and biochemical analysis in
genetically obese mice (ob/ob, leptin-deficient mice)
revealed that an obesity-associated microbiota increases
the efficiency of calorie uptake from ingested foods and
affects energy balance by influencing energy use
and storage.7 Thus, an obesity-associated microbiota
provides more energy to the host from otherwise
indigestible carbohydrates and proteins than does a
lean-associated gut microbiota, via increased production
of different primary fermentation enzymes and nutrient
transporters.27 However, the proportions of Firmicutes
and Bacteroidetes are unrelated to markers of energy
harvesting, highlighting that this relationship might be
more complex than previously considered.28
Furthermore, the gut microbiota can affect other
obesity-associated factors such as hyperglycaemia and
insulin resistance.29 Germ-free mice have resistance to
these high-fat-diet-induced metabolic complications,30
which is lost after FMT from conventionally raised mice.6
The gut microbiota changes the composition and relative
abundance of bile acid species, which might explain
its effect on glucose and insulin homoeostasis.31
A reduced bile acid concentration in the gut has been
associated with bacterial overgrowth and inflammation.31
Additionally, some gut bacteria metabolise bile acids and
their conjugates for a source of energy, causing activation
of bile acid receptors farnesoid X receptor (FXR) and
Takeda G-protein-coupled receptor 5 (TGR5), which are
essential receptors for maintaining glucose tolerance and
insulin sensitivity, in the intestine and liver (figure 2).32,33
Activation of TGR5 improves liver function and glucose
tolerance in obese mice by regulating intestinal GLP-1
production,32 whereas FXR deficiency in leptin-deficient
mice protects against obesity and improves insulin
sensitivity.33 Obese patients and those with type 2 diabetes
have altered bile acid metabolism,34 and administration
of bile acids, in both human and animal studies, led to
improved glycaemic control.35 Furthermore, the effect of
the gut microbiota on serotonin metabolism might also
influence host glucose homoeostasis;36 pharmacological
stimulation of 5-HT1B or 5-HT4 receptors increased
plasma active GLP-1 concentrations independent of
feeding and improved glucose tolerance under dipeptidyl
peptidase-4 inhibition in mice.37
The gut microbiota might also affect fat storage and
hepatic lipid metabolism. Bäckhed and colleagues6
showed that the fasting-induced adipocyte factor,
a circulating lipoprotein lipase inhibitor, is selectively
suppressed by intestinal bacteria, inducing triglyceride
deposition in adipocytes.6 Moreover, gut bacteria affect
the bioavailability of choline, an essential nutrient for
synthesis of very-low-density lipoproteins, which affects
triglyceride storage in the liver.38 Furthermore, gut
microbiota-mediated activation of the bile acid FXR
receptor increases adiposity.39
4 www.thelancet.com/gastrohep Published online August 24, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30147-4
The gut microbiota is also associated with inflammation
in obesity. Increased plasma levels of lipopolysaccharide,
an endotoxin in the cell wall of Gram-negative
bacteria, causes metabolic endotoxaemia, inducing a
strong immune system response and contributing to
obesity-related low-grade inflammation.40 Dietary fat is
crucial in this process because it inc­reases intestinal
lipopolysaccharide absorption through in­corpor­ation
into chylomicrons. Moreover, impaired intestinal barrier
integrity might also contribute to this metabolic
endotoxaemia.40 However, some gut bacteria could
prevent this endotoxaemia by protecting intestinal
barrier integrity via a different mechanism, which leads
to thickening of the mucus layer or upregulating tight
junction protein expression.41
Microbiota and obesity—from gut to brain
Appetite, food intake, and energy balance are centrally
regulated by a complex network of neuroendocrine
factors and their receptors, which mediate the
bidirectional communication between the gastro­
intestinal tract and the brain (figure 2).16 The presence
of nutrients in the gastrointestinal tract after meal
ingestion causes complex neural and hormonal signalling
to the brain to inform of the ongoing change in nutritional
status. This signalling is mediated by afferent nerve fibres
from the autonomic nervous system, such as the vagus
nerve, that project information from the gut to the
nucleus tractus solitarius (NTS) as well as by effector
fibres that project to the smooth muscles of the gut.
Information from the NTS is then distributed to the
hypothalamus, which regulates energy balance, appetite,
and food intake in the neurons of the arcuate nucleus
(ARC).42 The ARC contains orexigenic neuropeptide Y,
agouti-related protein, and anorexigenic peptides, as well
as cocaine amphetamine-regulated transcript, and pro-
opiomelanocortin neurons (figure 2).42 This central role of
the vagus nerve in appetite signalling is supported by
studies that show that vagotomy in animal models causes
a reduction in anorexigenic hormone signalling and
subsequent increases in food intake and weight gain.43,44
However, results from human studies are more
contradictory and the mechanism by which vagal nerve
stimulation affects eating behaviour remains unclear.45
Additionally, gut peptide secretion from enteroendocrine
cells also contributes to this signalling from the gut to the
brain via afferent nerve fibres as well as by direct secretion
into the circulatory system.16 Some bacterial strains can
modify gut hormone secretion, including peptide YY,
GLP-1, leptin, and ghrelin, and thus affect appetite and
satiety via hypothalamic neuroendocrine pathways
(figure 2).46,47 Microbiota-derived metabolites, such as
short-chain fatty acids, can bind to receptors on
enteroendocrine cells, modifying the release of enteric
hormones into the systemic circulation.48,49 Hence,
fermentation of non-digestible carbohydrates by the
intestinal microbiota has been shown to increase the

production of short-chain fatty acids and secretion of gut
hormones in animal and human studies.46
Acetate, the main short-chain fatty acid secreted by
intestinal bacteria, directly suppresses appetite via central
hypothalamic mechanisms.50 However, an increase in
acetate concentration caused by altered microbiota leads
to activation of the parasympathetic nervous system,
promoting glucose-stimulated insulin secretion, increased
ghrelin secretion, and obesity.51 Moreover, absence of a
microbiota in germ-free mice substantially decreased
expression of intestinal satiety peptides.17 These germ-free
mice also had increased expression of the oral fat taste
receptor, fatty acid translocase receptor, resulting in an
increased calorie intake from fats.17 These oral receptors
transmit information from the taste papillae via nerve
fibres to the NTS in the brainstem.52 Moreover, in
enteroendocrine cells, different taste receptors (eg, sweet,
fat, bitter, and umami receptors) are expressed and their
activation leads to secretion of GLP-1, cholecystokinin,
and ghrelin.52 Hence, modulation of taste receptors might
also be involved in the effect of the gut microbiota on the
host’s appetite control. Another study53 in germ-free mice
showed alteration in the intestinal sweet signalling
protein, T1R3, which led to increased con­sumption of
nutritive sweet solutions.53
Gut bacteria produce neuroactive metabolites, including
serotonin and γ-aminobutyric acid (GABA),54 which affect
the central control of appetite.55,56 Serotonin mediates its
appetite-suppressant effects by modulating melanocortin
neurons, which control bodyweight homoeostasis.57,58
GABA, the main inhibitory neurotransmitter in the central
nervous system and one of the main neurotransmitters
involved in hypothalamic synaptic transmission, stimulates
feeding, and its synaptic release by agouti-related
protein-expressing neurons in the hypothalamic ARC is
required for normal regulation of energy balance.56
Pathways related to mood, reward, and feeding
In addition to the mechanisms mentioned previously, gut
microbiota might also affect host feeding behaviour by
modulating reward pathways and altering mood. Some
bacterial species might interact with host metabolism
through stimulation of systems outside of the
gastrointestinal tract such as the endocannabinoid
system, which affects gut barrier function, host
metabolism,59 and the homoeostatic and hedonic control
of appetite and food intake.60 Brain reward signalling is
mediated by the dopaminergic mesolimbic system and
has been postulated to play a major part in the
development of obesity.61 A human imaging study found
that increased colonic propionate, one of the main
short-chain fatty acids secreted by gut bacteria, reduces
anticipatory reward responses to high-energy foods via
striatal pathways.62 Gut bacteria might also affect this
reward system by modulating gut hormone secretion.62
Gut microbiota affects mood and behaviour via different
mechanisms such as vagal nerve stimulation, immune
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Review
activation, and production of microbial metabolites.4
Depression-like and anxiety-like behaviours substantially
affect food intake, and different associations exist between
obesity and affective psychiatric disorders.61 Increases in
psychological stress augment the risk of developing
anxiety and depression and activate the hedonic signalling
pathway, stimulating intake of calorie-dense so-called
comfort foods.61 Interestingly, FMT from either anxious or
obese mice, or patients with depression, produces an
anxious phenotype in the recipient rodent.63–65 Moreover,
germ-free mice have exaggerated responses to stress66 and
alterations in neurodevelopment and behaviour.67 Further­
more, modifi­cation of the gut microbiota via prebiotic
administration has anxiolytic-like and antidepressant-like
effects.68 The vagus nerve links mood to feeding and plays
a key part in coordinating feeding behaviours45 and the
behavioural effects modulated by gut bacteria.69 Overall,
gut microbiota might clearly affect mood and ultimately
affect brain circuits linked to feeding behaviours.
Diet as modifiable factor of microbiota in obesity
The composition of the intestinal microbiota and its
function are established by the host’s genetic background
and external factors, including the mode of birth,
environmental elements, exercise, and nutrition.70 Most
notably, the key determinant affecting the composition
and activity of the gut microbiota is diet; changes in diet
could explain 57% of structural variations in total gut
microbiota.71 Different dietary components directly shape
the gut microbiota,16 and long-term dietary habits have
profound effects on the composition of the intestinal
microbiota in human beings.72 Western diets, especially
those associated with low levels of microbiota-accessible
carbohydrates found in dietary fibre, have possibly
reduced the diversity of microbiota over generations.
By contrast, populations with traditional diets that are
high in fibre and low in sugar and fat, will have increased
microbiota diversity.73
Diet-induced obesity in mice following a high fat and
high sugar western-style diet was associated with an
increase in some Firmicutes, possibly caused by their
competitive advantage in processing simple sugars, and
a substantially lower abundance of Bacteroidetes.74 These
changes in microbiota were diminished by subsequent
dietary manipulations that limit weight gain and
adiposity, reinforcing the interaction between diet and
the composition of the distal gut microbiota in metabolic
function. The composition of the microbiota changes
substantially with age, from early life colonisation, to
ageing-mediated decline in diversity. Altered gut
microbiota is particularly relevant for health in ageing
because the microbiota might modulate age-related
changes in innate immunity, sarcopenia, and the decline
in cognitive function, all of which are elements of frailty.75
Moreover, these factors are modified by diet, with
decreased diversity in microbiota associated with
increased frailty and markers of inflammation.76
 Review
Thaiss and colleagues77 found that the microbiome
contributes to accelerated post-dieting weight regain.
An intestinal microbiome signature that persisted after
successful dieting in obese mice and contributed to
reduced post-dieting flavonoid concentrations and
energy expenditure showed that flavonoid-based
post-biotic inter­vention ameliorates excessive secondary
weight regain. The recognition that diet is a key
determinant in short-term and long-term composition,
diversity, dynamics of the intestinal microbiota, and sub­
sequent microbiota-driven host metabolic functioning,
has generated interest in designing diets that enhance
the growth of specific beneficial anti-obesity gut
microbiota. The table shows the diet’s effects on gut
microbiota and host metabolism. Fibre is one of the
main dietary components affecting the gut microbiota
and consists of indigestible carbohydrates, which are
fermented by gut bacteria, causing secretion of beneficial
metabolites (eg, short-chain fatty acids).78 High-fibre diets
are associated with different positive metabolic effects
and a diverse, healthy microbiota.16 Dietary fat might also
indirectly modulate the gut microbiota through bile acid
secretion and composition.79 Bile acids have selective
antimicrobial activity and could therefore mediate the
fat-induced effects on the gut microbiota.79 In fact,
reduced concentrations of bile salt are associated
with bacterial overgrowth in the gut, particularly
Gram-negative members, including lipopolysaccharide
pro­ducers and pathogens, leading to increased
inflammation, whereas increased bile salt concentrations
promote growth of Gram-positive bacteria such as
Firmicutes.31 Saturated and unsaturated fats have
different health effects; although saturated fats are not
beneficial for obesity treatment, unsaturated fats have
anti-obesity effects (table).83 Similarly, polyphenols are
also gaining prominence as positive modulators of the
gut microbiota because of their positive effects on
Interaction with the gut microbiota
Fibre or Principal carbon and energy source for Increase in Bifidobacterium spp,
carbohydrates16,72,78,80,81 colonic microorganisms; fermented to Bacteroidetes, Akkermansia muciniphila,
beneficial metabolites such as
short-chain fatty acids
Proteins16,82 Major source of nitrogen for the gut
microbiota, and essential for their
assimilation of carbohydrates, gases,
and putrefactive fermentation products
Saturated fats16,19,74,81–83 Indirect modulation of the gut
microbiota via bile acid metabolism
Unsaturated Indirect interaction with the gut
fats16,19,74,81–83 microbiota via effects on bile acid
secretion and composition
Polyphenols84–86 Act as an energy substrate for some
beneficial bacteria and inhibit the
growth of pathogenic bacteria
Table: Effects of the diet on the gut microbiota and host metabolism
6 www.thelancet.com/gastrohep Published online August 24, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30147-4
obesity84 and metabolic syndrome, including reduction in
body-mass index, waist circumference, blood pressure,
and blood glucose, as well as improved lipid metabolism.85
However, only 5–10% of dietary polyphenols are absorbed
in the small intestine, whereas the remaining 90–95%
accumulate in the large intestine and act as energy
substrates for some beneficial bacteria while inhibiting
the growth of pathogenic bacteria.86 Thus, owing to their
low bioavailability, this prebiotic effect on the gut
microbiota is believed to be crucial for polyphenol-
mediated health effects.77,86 Dietary proteins are essential
nutrients and are integral for a balanced diet. They are
the major source of nitrogen, which is essential for
fermentation of carbohydrates and production of
beneficial products such as short-chain fatty acids.87 The
effect of dietary proteins on the gut microbiota requires
investigation; for example, although a high-protein diet
seems to lead to weight loss, it can also cause detrimental
health effects, such as increased risk of colonic diseases,
especially when combined with low dietary fibre intake
(table). Animal-based diets, which contain more protein
than do plant-based diets, can increase the abundance of
bile-tolerant microorganisms (Alistipes spp, Bilophila spp,
and Bacteroides) and decrease that of Firmicutes that
metabolise dietary plant polysaccharides (Roseburia spp,
Eubacterium rectale, and Ruminococcus bromii).88 Overall,
a high-fibre diet low in saturated fat leads to beneficial
anti-obesity effects (table). However, the precise mech­
anisms by which nutritional factors and dietary strategies
modulate the intestinal microbiota and affect host
metabolic signalling need further investigation.
Additionally, the composition of the gut microbiota
might also be altered by various other factors such as
antibiotics, processed food, sweeteners, stress, and even
mode of birth (panel 2). These factors negatively affect
intestinal microbiota, causing dysbiosis and ultimately
affecting host physiology and metabolism.
Gut microbiota changes Health effects
Enhanced intestinal barrier integrity, insulin
sensitivity, and intestinal motility; decreased
Clostridium spp, and Prevotella spp inflammation; improved lipid metabolism;
enhanced intestinal motility; and increased satiety
Increase in Bacteroidetes and a Weight loss and increased risk of atherosclerosis
decrease in Bifidobacterium spp and colonic diseases
Increase in Firmicutes, Proteobacteria, Increased endotoxaemia, bodyweight, and
and Bilophila spp, and a decrease in adiposity, and reduced insulin sensitivity
Bacteroidetes and Bifidobacterium spp
Increase in Bifidobacterium spp, Decreased inflammation and adiposity
Lactobacillus spp, and Akkermansia
muciniphla
Increase in Bacteroides spp, Lactobacillus Reduced body-mass index, waist circumference,
spp, Bifidobacterium spp, and blood pressure, and blood glucose; and improved
Akkermansia muciniphila, and a decrease lipid metabolism
in Clostridium spp

Therapeutic strategies
With consideration of the gut microbiota’s key role
in regulation of the host’s metabolism, energy homo­
eostasis, and central appetite regulation, it is not surprising
that the microbiota is now a target to combat metabolic
disorders such as obesity. Gut-microbiota-based treatments
have subsequent effects on the host’s metabolism.
However, advances in the field are needed before gut-
microbiota-based treatment can be used as a therapeutic
tool to curb appetite and food intake, and restore metabolic
imbalances in metabolic disorders such as obesity.
Probiotics
Western diet is driving obesity via different mechanisms in
which changes in gut microbiota play a key part. Hence,
western diet, preservatives, and emulsifiers are causing an
increase in the Firmicutes-to-Bacteroidetes ratio, which is
characteristic in obese individuals.74,90 Thus, strategies to
reverse this obesity-induced change in composition are of
crucial pharmacological and nutritional interest in the
management of obesity and obesity-related disorders.
Dietary intervention by probiotic administration might be
one of the approaches to modulate and maintain a healthy
microbiota. Probiotics are defined as “live microorganisms
that, when administrated in adequate amounts, confer
beneficial health effects on the host”.98 Studies highlight
the potential role of probiotics in the treatment of
obesity. Hence, different bacterial strains have shown
beneficial anti-obesity effects such as reduction of tissue
inflammation, endotoxaemia, adiposity, bodyweight, leptin
levels, and energy intake.47 However, most studies have
used rodent models and, therefore, more studies in human
beings are needed to support the use of these probiotic
strains to treat or prevent obesity. The most common
probiotic species that have shown these anti-obesity effects
are Bifidobacterium and Lactobacillus spp. More recently,
Akkermansia muciniphila has emerged as one of the main
gut bacteria affecting host metabolism, with the capability
to reverse high-fat diet-induced metabolic effects such as
fat-mass gain, metabolic endotoxaemia, adipose tissue
inflammation, and insulin resistance.99 Beneficial bacteria
interact with different components of the diet, mainly
insoluble fibre, releasing bioactive metabolites that signal
to the host via the gut–brain axis.81 Further studies are
poised to elucidate the mechanism by which specific
probiotics can harvest energy from food and nutrients.
Prebiotics
In addition to the direct administration of live bacteria in
probiotics, prebiotics might promote the growth of
beneficial bacteria over unfavourable commensal species
in the gut. Prebiotics have been redefined as non-digestible
compounds that, through their meta­ bolism by gut
microorganisms, modulate com­position, activity, or both,
of the gut microbiota, which thus confers a beneficial
physiological effect on the host.80 Although dietary
carbohydrates, such as oligosaccharides (eg, insulin),
www.thelancet.com/gastrohep Published online August 24, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30147-4 7
Review
Panel 2: Negative modulators of gut microbiota
Antibiotics
Overuse of antibiotics and exposure to antibiotics maternally or via the food chain,
especially during early life, can have a large effect on the gut microbiota, with substantial
disturbances caused to its composition and functionality, which can subsequently disrupt
gut barrier function and lead to influx of bacterial fragments into the circulation.
The resulting low-grade chronic inflammation and metabolic endotoxaemia can greatly
affect host metabolism and insulin resistance. This microbiota alteration in early life has
long-lasting effects on bodyweight in adulthood. Epidemiological studies show that
exposure to antibiotics early in life is associated with increased risk of obesity and related
metabolic disorders.89
Emulsifiers
These components of processed foods are used to improve food texture and extend their
shelf life. Dietary emulsifiers affect the gut microbiota, promoting colitis and metabolic
syndrome in mice. Emulsifier-induced metabolic syndrome was associated with
alterations in the microbiota and increased pro-inflammatory potential. Alterations in the
composition of gut microbiota included reduction in microbial diversity, a reduced
abundance of Bacteroidales, an increased abundance of mucolytic bacteria (including
Ruminococcus gnavus), bloom in Verrumicrobia (especially in Akkermansia muciniphila),
and enriched Proteobacteria. These changes were sufficient for low-grade inflammation
and metabolic syndrome development, as shown in germ-free mice and using faecal
transplants in mice.90
Sweeteners
Non-caloric artificial sweeteners (NASs) are among the most widely used food additives
worldwide. Although their consumption has been considered safe and beneficial because of
their low-calorie content, NAS consumption can lead to development of glucose intolerance
through compositional and functional alterations in the intestinal microbiota.
These alterations include increased abundance of Bacteroides spp and decreased abundance
of Lactobacillus reuteri. NAS-mediated metabolic effects were prevented by antibiotic
treatment, and were transferrable to germ-free mice upon faecal microbiota transplantation
from NAS-consuming mice, or from microbiota anaerobically incubated in the presence of
NAS. Similar NAS-induced dysbiosis and glucose intolerance were also seen in healthy
human participants.91
Caesarean section
Mode of birth is crucial for development of a healthy microbiota. Dominguez-Bello and
colleagues92 showed that delivery mode establishes the acquisition and structure of the
initial microbiota in newborn babies. Hence, babies born by caesarean section have a
microbiota composition more similar to that of their mother’s skin, dominated by
Staphylococcus, Corynebacterium, and Propionibacterium spp, whereas vaginally delivered
infants acquired bacterial communities more similar to that of their mother’s vaginal
microbiota, dominated by Lactobacillus, Prevotella, or Sneathia spp. These alterations in the
composition of the gut microbiota in early life might affect host physiology and metabolism
later in life. Epidemiological studies93–96 have reported associations between caesarean
section delivery and increased risk of obesity, asthma, allergies, and immune deficiencies.
Stress
Hypothalamus–pituitary–adrenal axis activity associated with stress affects the composition
of the gut microbiota. Thus, early exposure to stress leads to decreased diversity in gut
microbiota and might have long-term effects on its composition. Moreover, chronic stress
in adulthood affects the composition of the intestinal microbiota, with a decrease in
Bacteroides and Clostridium spp, and also leads to increased inflammation, which is
indicative of immune activation. Furthermore, chronic stress alters the integrity of the
intestinal barrier, increasing circulating concentrations of immunomodulatory bacterial cell
wall components such as lipopolysaccharide.97
 Review
Search strategy and selection criteria
The aim of this Review was to identify studies investigating
the effects of the gut microbiota on host metabolism and
central appetite regulation in obesity. Thus, we searched
PubMed, Google Scholar, and Web of Science for the terms
“obesity”, “microbiota”, “microbiome”, “metabolic syndrome”,
and “appetite” between Jan 1, 2000, and April 5, 2017. Only
papers published in English were reviewed. The final reference
list was generated on the basis of the relevance to this Review.
fructo-oligosaccharides, and galacto-oligosaccharides, are
the most commonly used prebiotics, other compounds,
such as polyphenols might also fit this definition.80
Administration of fibre-rich diets increases the abundance
of beneficial bacteria in the gut, such as some
Bifidobacterium and Lactobacillus spp, causing anti-obesity
effects, including reduction of endotoxaemia and
enhanced intestinal barrier function caused by increased
expression of tight junction proteins and decreased
circulating pro-inflammatory cytokines.47 A lower number
of beneficial bacteria have been found in patients with
obesity and type 2 diabetes than in healthy individuals.47
However, most of the studies are based on correlations
and do not establish a causal link between modulation of
the gut microbiota and the observed beneficial metabolic
and physiological effects. Therefore, more studies are
needed to elucidate the potential mechanisms involved in
beneficial prebiotic-mediated effects.80
FMT
A promising new strategy to alter the composition of
the gut microbiota is FMT from healthy donors into
the patient’s intestinal tract, typically by colonoscopy
or duodenal endoscopy, resulting in the restoration
of normal gut microbial community structure and
functionality.100 Donor microbial strains in human beings
can colonise the recipient gut microbiota and persist for
at least 3 months after FMT.101 However, donor–recipient
compatibilities are important for successful establish­
ment of the donor’s microbial strains in the recipient’s
gut, with a greater chance of prospering if the species
were already present in the recipient.101
FMT has successfully been used to treat Clostridium
difficile infections with greater than 90% efficacy.102 Such a
high efficacy is a hopeful indication of the ability of FMT to
modify the gut microbiota and, therefore, of its potential as
a therapeutic intervention for other diseases in which
gut microbiota dysbiosis is involved, such as ulcerative
colitis, irritable bowel syndrome, chronic constipation, and
Crohn’s disease. However, no conclusive results yet exist
and more studies need to be done to draw conclusions
about the efficacy of FMT as a therapeutic intervention for
these gastrointestinal disorders.100 Additionally, evidence is
increasing that FMT might also have potential to treat
obesity and associated disorders such as type 2 diabetes.
8 www.thelancet.com/gastrohep Published online August 24, 2017 http://dx.doi.org/10.1016/S2468-1253(17)30147-4
Transfer of gut microbiota through a duodenal tube from
healthy donors with a normal body-mass index to obese
individuals diagnosed with type 2 diabetes increased
insulin sensitivity, faecal microbiota diversity, and butyrate-
producing intestinal bacteria from the Clostridium
cluster XIVa, and decreased faecal short-chain fatty acids.103
Moreover, a case study104 reported that a woman successfully
treated with FMT for Clostridium difficile developed
new-onset obesity after receiving stool from a healthy but
overweight donor. This finding is controversial, as it is only
a case report; nevertheless, this finding is consistent with
observations in animal models, in which the obesity
phenotype was transferred to germ-free mice by FMT
from obese donors.21 FMT might also pose some potential
risks such as the spread of transmissible disease. However,
although there have been some mild effects such as
diarrhoea and fever, no side-effects have been reported.105
Conclusions
Host–microbe interactions are key for optimal health.
Commensal bacteria exert many structural and protective
effects on intestinal mucosa, but also affect host
metabolism. Accumulating evidence from both human
and rodent studies highlights the central role of the gut
microbiota in the gut–brain axis and its implication on
central appetite modulation. Moreover, the association
between the composition of the intestinal microbiota and
metabolic dysfunction or obesity is becoming clear and
has been extensively reported. Therefore, modulation of
the gut microbiota might be a potential therapeutic target
for the treatment of obesity and other metabolic diseases,
such as diabetes. Although use of prebiotics and probiotics
is one of the most widely used strategies to modulate the
gut microbiota and hence improve metabolic imbalances,
other strategies, including other dietary components such
as polyphenols and interventions such as bariatric surgery
and FMT, should also be considered.
Contributors
All authors contributed to the concept, structure, and writing of
the manuscript.
Declaration of interests
We declare no competing interests.
Acknowledgments
We are supported in part by a grant from Science Foundation Ireland
(Alimentary Pharmabiotic Centre grant number SFI/12/RC/2273) and
received funding from the European Community’s Seventh Framework
Programme “MyNewGut” (grant agreement number FP7/2007–2013).
The Alimentary Pharmabiotic Centre Microbiome Institute has done
studies in collaboration with several companies including Nutritia,
4D Pharma, Cremo, Suntory Wellness, and Mead Johnson.
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