The Journal of Nutrition

Critical Review

Microbiota-Gut-Brain Axis: Modulator of Host

Metabolism and Appetite1,2
Marcel van de Wouw,3,4 Harriët Schellekens,3,4 Timothy G Dinan,4,5 and John F Cryan3–5*
3
Department of Anatomy and Neuroscience, 4 APC Microbiome Institute, and 5 Department of Psychiatry and Neurobehavioural
Science, University College Cork, Cork, Ireland

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Abstract
The gut harbors an enormous diversity of microbes that are essential for the maintenance of homeostasis in health and
disease. A growing body of evidence supports the role of this microbiota in influencing host appetite and food intake.
Individual species within the gut microbiota are under selective pressure arising from nutrients available and other
bacterial species present. Each bacterial species within the gut aims to increase its own fitness, habitat, and survival via
specific fermentation of dietary nutrients and secretion of metabolites, many of which can influence host appetite and
eating behavior by directly affecting nutrient sensing and appetite and satiety-regulating systems. These include
microbiota-produced neuroactives and short-chain fatty acids. In addition, the gut microbiota is able to manipulate
intestinal barrier function, interact with bile acid metabolism, modulate the immune system, and influence host antigen
production, thus indirectly affecting eating behavior. A growing body of evidence indicates that there is a crucial role for
the microbiota in regulating different aspects of eating-related behavior, as well as behavioral comorbidities of eating
and metabolic disorders. The importance of intestinal microbiota composition has now been shown in obesity, anorexia
nervosa, and forms of severe acute malnutrition. Understanding the mechanisms in which the gut microbiota
can influence host appetite and metabolism will provide a better understanding of conditions wherein appetite
is dysregulated, such as obesity and other metabolic or eating disorders, leading to novel biotherapeutic
strategies. J Nutr 2017;147:727–45.

Keywords: nutrition, microbiota, obesity, metabolism, behavior

Introduction
The role of the gut microbiota in the regulation of physiology in
both health and disease is becoming increasingly recognized
(1, 2). These trillions of intestinal occupants form an integral
evolutionary-driven relation with the host in maintaining
homeostasis (3). The gut microbiota is comprised of archaea,
viruses, protozoa, and mostly bacteria, the quantity of which
exceeds that of the eukaryotic cells in the human body (4, 5).
More startling is the fact that the cumulative amount of unique
genes in the gut microbiota, the microbiome, is 100-fold higher
than that of the human genome, further indicating its signifi-
cance (6). Accumulating data also show that the gut microbiota
significantly affects the bidirectional communication between
the gastrointestinal tract and the brain, which has been coined
1 (12, 25, 26). It is important to note that the gut microbiota has a
Supported by Science Foundation Ireland (SFI) grant nos. 07/CE/B1368 and
12/RC/2273; the Irish Health Research Board; the Department of Agriculture, Food,
and the Marine; and Enterprise Ireland (all to JFC). Also supported by SFI grant no.
SFI/12/RC/2273 and by the Health Research Board through Health Research Awards
(grant nos. HRA_POR/2011/23, HRA_POR/2012/32, and HRA_POR/2014/647) and
through EU grant 613979 (MYNEWGUT FP7-KBBE-2013-7) (all to TGD).
2
Author disclosures: M van de Wouw, H Schellekens, TG Dinan, and JF Cryan,
no conflicts of interest.
*To whom correspondence should be addressed. E-mail: j.cryan@ucc.ie.
ã 2017 American Society for Nutrition.
Manuscript received December 23, 2016. Initial review completed February 6, 2017. Revision accepted February 21, 2017.
First published online March 29, 2017; doi:10.3945/jn.116.240481.
the microbiota-gut-brain axis (7–9). Moreover, the gut micro-
biota is now being implicated in various aspects of disease
(10, 11).
In particular, the influence of the microbiome on host energy
metabolism and thus metabolic and eating-related disorders is
becoming increasingly established (12, 13). For instance, altered
intestinal microbiota composition has been demonstrated for
obesity (14–16), anorexia nervosa (17–19), and forms of severe
acute malnutrition such as kwashiorkor (20). In addition, the
gut microbiota and its metabolites are subsequently altered after
interventions that address some of these conditions, such as
bariatric or Roux-en-Y gastric bypass surgery (21–23) and
dietary interventions (24). Thus, accumulating evidence indi-
cates the potential of targeting the gut microbiota as an effective
therapeutic option for mitigating metabolic and eating disorders
key regulatory role in both host metabolism and central appetite,
which together can modify host eating behavior in metabolic
disorders and eating disorders such as obesity and malnutrition
(27–29).
The homeostatic control of energy balance is highly regulated
by a complex neuronal network wherein the hypothalamus
plays a key role connecting to the brainstem and various
727
forebrain regions (30). There are various peripheral anorexi-
genic hormones, such as glucagon-like peptide 1 (GLP-1)6,
peptide YY (PYY), insulin, and leptin, that increase satiety,
whereas ghrelin is able to induce hunger (31). Within the
hypothalamus, pro-opiomelanocortin (POMC) and cocaine-
and amphetamine-regulated transcript–containing neurons reg-
ulate satiety, whereas neurons that contain neuropeptide Y and
those that contain agouti-related peptide are involved in hunger
signaling (30). These hypothalamic neurons project to other
brain circuits such as the mesolimbic rewards circuit, which is
highly involved in food reward, addiction, and impulsive choice
(32). As such, signaling of the previously mentioned peripheral
hormones has also been implicated in both addiction (33) and
impulsivity (34). This additionally highlights the involvement of
physiologic and/or psychological components in eating disorders
(35, 36). Importantly, the influence of the microbiota-gut-brain
axis is becoming increasingly recognized in psychological and
psychiatric disorders (37, 38), indicating that this axis could
play a role in the physiologic and/or psychological components
of metabolic and eating disorders.
This review focuses on the diverse mechanisms through
which the gut microbiota influences host metabolism, feeding
behavior, and appetite as a crucial piece of the puzzle in
conditions wherein food intake and body weight are dysregu-
lated. To focus on these, we first provide a brief overview of
various food-related disorders in which the gut microbiota is
involved. Then we further introduce the role of the gut
microbiota in metabolic and eating disorders, with particular
emphasis on obesity. After that, we discuss the involvement of
gut microbial metabolites in the microbiota-gut-brain axis.
Special emphasis is laid on SCFAs and the diverse mechanisms
by which these are able to regulate host energy metabolism and
appetite. In addition, we examine the interplay between the gut
microbiota, intestinal barrier permeability, immune system
functionality, and gut microbial mimicry. Further, we discuss
mechanisms by which the gut microbiota could influence host
nutrient and taste sensing throughout the gastrointestinal tract.
Finally, we briefly emphasize the multifaceted nature of eating
disorders in regard to their food-related behavioral components,
other behavioral comorbidities such as anxiety and depression,
and the role that the gut microbiota plays herein.
Metabolic and Eating Disorders
The role of the gut microbiota in host metabolism and appetite
has been primarily investigated in regard to obesity and
metabolic syndrome. As such, less work has been done with
other eating disorders associated with a positive energy balance,
such as binge-eating disorder and drug-induced obesity, or with
eating disorders associated with a negative energy balance, such
as anorexia nervosa, cachexia, and infant malnutrition. It is
crucial to note that, even though a dysfunctional energy balance
is common between all mentioned disorders, each disorder has
other specific malfunctioning physiologic and psychological
factors. As such, each metabolic and eating disorder is discussed
separately in the following section to emphasize their particu-
larities and our current knowledge.
6
Abbreviations used: ClpB, caseinolytic protease B; CNS, central nervous
system; FFA2, FFA receptor 2; FFA3, FFA receptor 3; FXR, farnesoid X receptor;
GABA, g-aminobutyric acid; GF, germ-free; GIP, gastric inhibitory polypeptide;
GLP-1 glucagon-like peptide 1; GPCR, G protein–coupled receptor; MSH,
melanocyte-stimulating hormone; POMC, pro-opiomelanocortin; PYY, peptide
YY.
728 van de Wouw et al.
Obesity and metabolic syndrome. Obesity and related met-
abolic syndrome have become one of the most prominent health
concerns in developed countries worldwide (39), with the WHO
estimating that nearly 600 million people worldwide are obese
(40). Obesity is characterized by excessive adipose tissue, an
imbalance between energy intake and expenditure favoring a
positive energy balance, and it is associated with low-grade
inflammation (41) and insulin resistance (42). As such, obesity is a
risk factor for numerous medical conditions, such as cardiovascu-
lar disease, nonalcoholic fatty liver disease, endocrine and meta-
bolic disorders, as well as certain cancers (43). Considerable focus
is being put on the contribution of overeating and a positive energy
balance to body weight gain. In addition, obesity is associated with
an increased prevalence of compulsive food behavior (32), as well
as food-related impulsivity (44). There is a growing realization that
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there is involvement of the gut microbiota in obesity, especially
considering that gut microbiota features could be used to predict
glucose responses, enabling personalized dietary interventions (45).
Notably, the gut microbiota is regarded as an important factor
contributing to nonalcoholic fatty liver disease, which is often
associated with obesity (46). For #25% of all nonalcoholic fatty
liver disease patients, this condition progresses into a progressive
form of liver disease called nonalcoholic steatohepatitis, potentially
resulting in cirrhosis, hepatocellular carcinomas, and liver dys-
function (47). The importance of the gut microbiota in obesity is
also emphasized by the fact that interventions targeting this
disorder, including bariatric surgery, and Roux-en-Y gastric bypass
surgery in particular, induce substantial weight loss and are
associated with alterations in gut microbiota composition (21–23,
48). This is particularly important in regard to the mechanisms of
actions, including changes in gut hormones, bile acid, and lipid
metabolism, and neuronal signaling (49).
Binge-eating disorder. Binge-eating disorder is characterized
by excessive, out-of-control, and rapid food intake (50, 51), and is
recognized as a distinct eating disorder by the Diagnostic and
Statistical Manual of Mental Disorders—Fifth Edition (52). It is
the most common eating disorder, with an estimated lifetime
prevalence of 1.9–2.8% in US adults, yet it often goes unrecog-
nized (50, 53). Enhanced food-related impulsivity and compul-
sivity plays a critical role in the maintenance of this disorder (44).
Binge-eating disorder is not only associated with obesity and
metabolic syndrome, but also with gastrointestinal disorders,
asthma, and, among women, menstrual dysfunction, pregnancy
complications, intracranial hypertension, and polycystic ovary
syndrome (54, 55). Even though the role of gut microbes in host
eating behavior is being elucidated at a rapid rate (28), the link
between binge-eating disorder and the gut microbiota currently
remains unclear, and more research is warranted.
Drug-induced obesity. A change in body weight is often a side-
effect of various medications. Atypical antipsychotics represent
the mainstay of treatment for schizophrenia and bipolar
disorder, and they are known for their various side-effects,
such as weight gain and metabolic dysfunction (56–58). In
particular, the drug olanzapine is known for its weight gain–
inducing effects (59, 60). Rodents receiving olanzapine also have
an altered gut microbiota composition (61, 62). In addition, rats
that also received an antibiotic cocktail had reduced olanzapine-
induced body weight gain and various markers of metabolic
dysfunction, further highlighting the involvement of the gut
microbiota (61). Another medication is the second-generation
antipsychotic risperidone, often used to treat bipolar disorder
and schizophrenia in children and adolescents (63). Chronic
risperidone treatment results in altered gut microbial composi-
tion, with enriched pathways that have been implicated in
weight gain (64). Furthermore, mice receiving risperidone
treatment displayed altered gut microbiota composition and
body weight gain, which was primarily attributed to decreased
energy expenditure (65). In addition, this trait was transmissible
via fecal matter transplantation and via treatment with phage
isolated from risperidone-treated microbiota (65).
Anorexia nervosa. Anorexia nervosa is characterized by a
distorted body image leading to restricted food intake and
subsequently severe weight loss, which in addition is associated
with hyperactivity and hypothermia (66). Anorexia nervosa has
the highest mortality rate among psychiatric illnesses and
significantly affects quality of life (67, 68). There is currently
no clear understanding of its etiology, nor is there any medica-
tion present. The role and involvement of the gut microbiota is
largely unclear in this disorder, even though current evidence
indicates that it could represent a potent intervention target (25).
Cachexia. Cachexia is a metabolic condition caused by severe
illness that is characterized by the loss of skeletal muscle mass,
both dependent of and independent of fat mass loss (69). Fifty
to eighty percent of all cancer patients are affected by this
condition, and it ultimately reduces quality of life and survival
(70). Central elements in the pathophysiology of cancer cachexia
are a reduced food intake and an abnormal metabolism
leading to a negative protein and energy balance (71). These
are primarily driven by the central nervous system (CNS) and
inflammatory pathways (69). Even though the role of the gut
microbiota in cancer cachexia is unclear, the former does play a
role in both CNS and immune system regulation (72, 73),
indicating that it may be a potential therapeutic target (26). In
particular, appetite-related signaling might be of interest here,
with the novel ghrelin-receptor agonist anamorelin recently
having demonstrated that it increases lean body mass, as well as
quality of life, in patients with cachexia (74, 75).
Infant malnutrition. A mature gut microbiota configuration
resembling that of an adult is reached after the first 2–3 y of age
(76). Disturbances within this critical time period can result in an
immature gut microbiota (77). Of note, the consequences of having
an immature gut microbiome in later life in will be discussed in the
section Key Determinants of the Adult Gut Microbiota Composi-
tion in Metabolic and Eating Disorders. In early life, gut microbiota
maturity is a crucial contributory factor to the prevalence and
severity of kwashiorkor, an enigmatic form of severe acute
malnutrition that affects millions of children (20). Notably, this
condition is transferrable by gut microbiota transplantation,
highlighting its importance (78, 79). In addition, a recent study
by Wagner et al. (80) demonstrated that gut microbiota transplan-
tation from undernourished 24-mo-old Bangladeshi children into
mice resulted in drastic weight loss, which was transmissible from
the dams to their offspring. The importance of the gut microbiota is
emphasized by the fact that antibiotics such as amoxicillin and
cefdinir reduce mortality in children with kwashiorkor (81, 82).
The Gut Microbiota as a Key Player
in Obesity and Metabolic and
Eating-Related Disorders
One of the early and pivotal experiments demonstrating the key
role of the gut microbiota in host energy metabolism showed that
mice with an absent microbiota [i.e., germ-free (GF) mice], had
dramatically decreased body fat despite having higher food
intake, both of which were normalized after colonization with
a conventional gut microbiota (83). Shortly after this, it was
discovered that there was a different gut microbial ecology
associated with obesity (84, 85), and that the gut microbiota
connected with obesity was associated with an increased capacity
for dietary energy harvest (86). Indeed, colonization of GF mice
with a gut microbiota originating from an obese human resulted
in a substantial increase in total body fat compared with a lean gut
microbiota (86). Nonetheless, even though a tremendous body of
evidence indicates that the gut microbiota plays a key role in
metabolic disorders, it was shown recently that a high-fat diet was
able to drive obesity in mice, regardless of the gut microbial
composition (87). In addition, a recent meta-analysis demon-
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strated that the association between the gut microbial composi-
tion found in human feces and obesity is relatively weak (88).
The majority of the composition of the gut microbiota is
composed of the phyla Firmicutes (including Lactobacillus,
Clostridium, and Enterococcus) and Bacteroidetes (including
Bacteroides), with less from the phyla Actinobacteria (Bifi-
dobacteria), Proteobacteria (Escherichia coli), Fusobacteria,
Verrucomicrobia, and Cyanobacteria (6, 89). Recently, 2
population-based gut microbiome analysis studies demonstrated
that the core microbiota within human populations is consid-
erably robust (90, 91). Nonetheless, distinct compositional
differences have been demonstrated in individuals with obesity
(14, 16), anorexia nervosa (17–19, 92, 93), and kwashiorkor
(20). In regard to obesity, phylum-level changes, such as
increased Actinobacteria (14) and Firmicutes and decreased
Bacteroidetes, have been reported (84), as well as genus-level
changes (16). Notably, the changes in Firmicutes and Bacter-
oidetes have not consistently been reported (94, 95). Interest-
ingly, anorexia is also associated with decreased Bacteroidetes
and increased Actinobacteria and Verrucomicrobia levels (19).
In addition to compositional differences, studies have
reported a decrease in gut microbial diversity in obesity (14),
and anorexia nervosa (17–19). Interestingly, a recent study
reported that weight gain in anorexia nervosa did not result in
the recovery of intestinal microbiota composition perturbations,
but did lead to increased microbial richness (19). This decreased
gut microbial diversity could play a key role in the associated
dysregulation of appetite, metabolism, and food-related behaviors.
Alcock et al. (27) hypothesized that decreased microbial diversity,
which tends to be associated with larger populations of the same
species, results in individual species having more energy and
resources and a higher capacity for host manipulation, because
fewer resources are spent on competition. This, combined with the
fact that many microbes are specialized in the use of specific
nutrients, may result in the possibility that microbes influence the
host to consume their preferred nutrients, or to influence host
eating behavior in general (96). This concept is in agreement with
the work of Fetissov (28), who showed that bacterial components
and metabolites are able to influence intestinal satiety pathways,
thus controlling host appetite and satiety.
Key Determinants of the Adult Gut
Microbiota Composition in Metabolic
and Eating Disorders
Gut microbial composition, especially in early life, is determined
by various factors (97, 98). Perturbation of the gut microbiota in
the form of severe acute malnutrition during this period is
Microbiota and eating behavior 729
associated with persistent relative microbiota immaturity (77),
and this could also result in alterations in the development of
organs, tissues, and/or body systems (99), which may subse-
quently increase the predisposition to various diseases at an
older age (100). Indeed, it is postulated that microbiota
immaturity could be causally related to the neurologic abnor-
malities associated with child malnutrition (100). It is likely that
this could also affect the neuroendocrine systems associated with
appetite, food intake, and body weight both during this
developmental phase and later in life. Notably, perturbation of
the gut microbiota by antibiotic exposure during this period
increases the risk of being overweight or obese later in childhood
(101–104), whereas probiotics have been postulated to have
beneficial effects on both offspring at risk of chronic disease and
offspring who are healthy (105).
Furthermore, various other factors, such as host genetics and
day-to-day diet, play a crucial role (106). In regard to diet, it is
important to note that specific nutrients are correlated with an
increase in microbes that have the ability to utilize them (107–
109). For example, the genus Bacteroides is associated with
increased consumption of a high-carbohydrate, high-glycemic
index diet, as well as with an increased long-term consumption
of dietary protein and animal fat (110, 111). Conversely, the
genus Prevotella is associated with an increased long-term
carbohydrate intake (110). Bifidobacteria have the capacity
to use host-indigestible complex carbohydrates, which subse-
quently can stimulate their proliferation and metabolic activity
(111–113). A recent study also demonstrated that host-
microbiome interactions were particularly influenced by nitro-
gen intake, of which dietary reduction was associated with
health (114). It is also interesting to note that consumption of the
noncaloric artificial sweetener saccharin alters both gut micro-
biota composition and functionality, ultimately resulting in
glucose intolerance (115). Nutrient-microbe interactions also
include more specific food products and bacterial strains. For
instance, children in a rural African village in Burkina Faso who
are often raised on a polysaccharide-rich diet were found to
harbor unique microbes associated with an increased capacity to
digest cellulose (116). In addition, the gut microbiota of Hadza
hunter-gatherers is more enriched in bacteria associated with the
breakdown of dietary fibers, resulting in an enhanced ability to
digest and extract nutrients from fibrous plant foods (117, 118).
Furthermore, marine bacterial-derived enzymes have been
discovered in the gut microbiota of healthy Japanese individuals,
which was linked to increased local seaweed consumption (119,
120). It is important to note that specialized taxa can be driven
into low abundance from decreased consumption of the nutri-
ents they thrive on, potentially resulting in the extinction of such
taxa (121).
The interplay between appetite, metabolism, and gut micro-
biota is not only restricted to what is being eaten, but is also
influenced by when food is consumed, and thus host circadian
rhythm. It is long known that the circadian clock facilitates the
anticipation of regularly timed periodic events such as food
consumption, resulting in optimized energy supply and demand,
and thus maximized metabolic fitness (122). The disruption of
behavioral and molecular circadian rhythms in diet-induced
obese mice suggests that the circadian clock is an important part
of understanding the mechanisms behind obesity and other
metabolic disorders (123). This disruption is not limited to the
hostÕs endogenous circadian rhythm, but also disrupts the daily
oscillations in gut microbiota composition and function (124–
126). Interestingly, restricting feeding to a specific period of time
(i.e., time-restricted feeding) results in a period of fasting and
730 van de Wouw et al.
potentially ketosis and alleviates these cyclical fluctuations in the
gut microbiota (125). In addition, time-restricted feeding and
fasting reverses numerous features of the metabolic syndrome
(125, 127–129).
Overall, there is a growing body of evidence linking the gut
microbiota with nutrition, host metabolism, appetite, and
circadian rhythm. As such, influencing one of these factors will
most likely result in alterations in the others, making the gut
microbiota easily accessible and manipulable for targeting host
metabolism and appetite control.
Gut Microbiota and Its Metabolites as a
Therapeutic Target in Host Metabolism
and Appetite Control
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There are $4 primary means by which the gut microbiota can be
modulated: 1) the administration of live beneficial bacterial
strains (probiotics), 2) the administration of host-indigestible
dietary fibers, which undergo bacterial fermentation and subse-
quently stimulate the growth of certain types of bacteria
(prebiotics), 3) the administration of targeted antibiotics, and,
finally, 4) fecal microbiota transplantation (Table 1). Both pro-
and prebiotics have already been demonstrated to represent a
potent strategy to significantly improve metabolism in overweight
and obese individuals (12, 130). Conversely, the effects of pre- and
probiotics on undernourished individuals have been relatively
poorly studied, even though current evidence indicates that these
could improve therapeutic outcomes (26, 140). Rodent studies
have demonstrated that probiotic supplementation enhances
recovery from starvation (141–143). Nonetheless, much is still
unknown about the underlying mechanisms under which pre- and
probiotics influence host physiology and behavior. The study of
gut microbiota–host interactions is therefore crucial for the
development of effective therapeutics targeting the gut micro-
biota. Since the development of next-generation sequencing-based
metagenomics, our understanding of the composition, diversity,
and role of the gut microbiota in human health and disease has
greatly expanded. However, gut microbial composition provides
little insight into the interactions between the microbiota and its
host. Research is therefore moving away from just compositional
analysis toward a more functional metabolomic parsing of
microbiota-host interactions (144). In regard to diet and
microbiota-gut-brain axis interactions, human brain imaging in
particular is a crucial tool to elucidate microbiota-host interac-
tions (100, 145). This approach will help us understand how the
microbiota influences brain function, and will likely identify
underlying microbiota-gut-brain axis mechanics (145).
Microbial metabolites can affect host metabolism through
a variety of pathways, including direct interactions with the
gastrointestinal tract and peripheral tissues (Figure 1). These
interactions include influencing host gene expression through
epigenetic mechanisms (146), affecting the enteric nervous
system and directly inducing vagus nerve signaling (147, 148),
altering bile acid signaling (149), and affecting central appetite
pathways integrating host energy status (150). It is also worth
noting that individual gut microbes can influence the overall gut
microbiota composition and its metabolites. Interestingly, this
particularly plays an important role in SCFA production
through a process called bacterial crossfeeding, wherein one
species of bacteria provides nutrients for another species (151).
The mechanisms described above are mostly mediated through
gut microbial metabolites, which include, but are not limited to,
SCFAs (152), bile acids (153), and various neuroactives.
TABLE 1 Means of gut microbial modulation and their impact in host appetite and energy metabolism

Method of microbial modulation Rationale General findings References

Probiotic administration
Prebiotic administration
Live beneficial bacterial strains secrete strain-
dependent metabolites and cause shifts in the
microbial composition of the small intestine and,
to a lesser extent, the colon. Notably, most
probiotics do not colonize the hostÕs gut, and
continuous consumption often is necessary to
achieve lasting effects.
Host-indigestible dietary fibers pass through the
stomach and small intestine and are subsequently
fermented, stimulating the growth of certain types
of bacteria.
Particular bacterial strains can affect body weight or 130–132
symptoms associated with being overweight or
obese, such as metabolic endotoxemia, insulin
resistance, and cardiometabolic disorders.
These increase satiety and affect postprandial 133, 134
glucose and insulin concentrations. They also
have been inconsistently reported to be associ-
ated with decreased energy intake, body weight,

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Antibiotic administration
Fecal microbiota transplantation
Antibiotics have been the cornerstone for treating
infectious disease. They deplete specific gut
microbial taxa, depending on the particular
antibiotic given, resulting in long-term alterations
in gut microbial composition.
This procedure normally is used after antibiotic
treatment results in microbiota depletion, or in
studies of germ-free animal models, since fecal
microbiota transplantation provides an elegant way
to demonstrate gut microbial–dependent effects.
insulin secretion, and circulating lipids and
inflammatory markers.
Prenatal exposure to antibiotics affects birth weight, 103, 104, 135–139
obesity, and related metabolic sequelae later in
life and increases the risk of childhood overweight
and obesity when administered at an early age.
Antibiotics interfere with the gut microbiota–
immune interaction, resulting in immune system
perturbations, and are associated with
Clostridium difficile infection when consumed
later in life.
Transplantation of an ``obese`` gut microbiota in 20, 86
mice results in a transfer of obesity-associated
symptoms; similar results are obtained in studies
of kwashiorkor.

One of these gut microbial neuroactives is g-aminobutyric acid
(GABA), which is produced by several Lactobacillus and Bifido-
bacterium strains (154). L. reuteri is able to produce histamine
(155, 156), and acetylcholine is produced by both bacteria and
fungi (157, 158). In addition, tryptophan decarboxylase enzymes
have been detected in the human gut microbiota, suggesting that
the gut microbiota could produce the neurotransmitter trypta-
mine (159). Furthermore, gut microbial b-glucuronidase activity
can increase concentrations of catecholamines as noradrenaline
and dopamine (160). Interestingly, close to one-half of the
dopamine formed in the human body is produced in the
gastrointestinal tract (161). Finally, indigenous spore-forming
gut bacteria are able to modulate local and peripheral host
serotonin production (162). Much research is still needed to
identify how local elevations in the gut of these transmitters can
affect host metabolism and even brain function, if, indeed, they
can. Interestingly, with regard to serotonin-modulating bacteria,
they have been demonstrated to affect host physiology, modu-
lating gastrointestinal motility and platelet function (162).
As for bile acids, the gut microbiota has a dynamic interplay
with bile acid metabolism, conversion, and subsequent signal-
ing (149, 163). When food is consumed, primary bile acids stored
in the gall bladder are secreted in the duodenum, after which these
can be deconjugated by gut microbes (i.e., removal of the glycine
or taurine conjugate), preventing reuptake in the small intestine.
These deconjugated bile acids subsequently enter the colon and
are metabolized into secondary bile acids. At this level, the gut
microbiota is able to influence primary bile acid synthesis in the
liver, both the deconjugation of these bile acids and conversion
into secondary bile acids in the colon (164), and finally the
reabsorption of primary bile acids in the ileum (165, 166). The
production of bile acids is highly regulated through the nuclear
farnesoid X receptor (FXR) by negative feedback inhibition (167),
through which bile acids are able to signal as both agonists and
antagonists (149). GF and antibiotic studies highlight the impor-
tance of the gut microbiota in bile acid metabolism and FXR
signaling (168–171), both of which are crucial for host metab-
olism and appetite (169, 172). In addition, Takeda G protein–
coupled receptor 5 is highly expressed in enteroendocrine L cells,
which, upon activation, results in the peripheral release of the
anorexigenic hormones GLP-1 and PYY (173, 174). As such,
enhancing the production of secondary bile acids through the
increase of bacterial bile salt hydrolase enzymes results in reduced
weight gain, serum cholesterol, and liver TGs (175). It is also
interesting to note that bile acids influence gut microbial
composition, indicating a bidirectional interaction (149). This is
highlighted in FXR-deficient mice, which have an altered
microbiota and bile acid composition (169).
The impact of the gut microbiota is not only restricted to the
periphery, but can also influence central metabolites. For
instance, GF mice have decreased hypothalamic histamine
concentrations (176). In addition, assessment of the cerebral
metabolome of GF mice demonstrated that 38 of the 196
metabolites were significantly altered (177). As such, the
administration of specific bacterial strains can result in altered
CNS metabolites. For instance, Bifidobacteria infantis is able
to reduce 5-hydroxyindoleacetic acid concentrations in the
frontal cortex and a decrease in 3,4-dihydroxyphenylacetic
acid in the amygdaloid cortex (178). These findings indicate
that specific gut microbes might influence appetite through
serotonergic signaling (179), or could affect the dopaminergic
mesolimbic rewards circuit, which is highly involved in food
Microbiota and eating behavior 731
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FIGURE 1 Gut microbial metabolite pathways to host appetite and metabolism control. Ingested nutrients are used by gut microbes,
thereby resulting in altered microbiota composition and functionality. These gut microbes influence bile acid metabolism and are able to
manufacture various metabolites, including SCFAs, neuroactives, small protein sequences, and toxins. Several of these gut microbial
metabolites are able to exert their effects through direct interaction with receptors in the gut on enteroendocrine L cells or the vagus nerve, or
by translocating through the intestinal epithelium into the peripheral circulation. Stimulation of L cells by bile acids or SCFAs results in the
release of anorexigenic hormones PYY and GLP-1, and can increase concentrations of peripheral hormones, such as insulin, leptin, and
ghrelin. Signaling mediated by these hormones can be affected by Ig, which in turn can be stimulated or interact with gut microbial–derived
small protein sequences as ClpB. The impact of such protein sequences, as well as gut microbial–derived toxins such as LPS, are highly
influenced by intestinal barrier integrity. LPS is also able to evoke an immune response, possibly leading to a decrease in taste receptor cell
differentiation and decreased taste detection. These pathways cumulatively affect appetite and metabolism, highly regulated by anorexigenic
pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript and orexigenic neuropeptide Y and agouti-regulated peptide–
containing neurons in the hypothalamus, ultimately affecting eating behavior, eating-related behaviors (e.g., cognition and impulsivity), and
behavioral comorbidities associated with disorders in which appetite and metabolism are dysfunctional (e.g., anxiety and depression). Ach,
acetylcholine; ClpB, caseinolytic protease B; DA, dopamine; GABA, g-aminobutyric acid; GLP-1, glucagon-like peptide 1; HI, histamine; NA,
noradrenaline; PYY, peptide YY; TRP, tryptamine; 5-HT, serotonin.

reward, addiction, and impulsive choice (32). In addition, the
gut microbiota plays a role in the regulation of brain-derived
neurotropic factor (180–182), a key player in the support of the
survival of existing neurons, the growth and differentiation
of new neurons, and the formation of new synapses (183).
Regulation of central receptor expression has also been
reported. For instance, Lactobacillus rhamnosus is able to
regulate central GABA receptor expression in a vagus nerve–
dependent manner (184), and it was recently shown to increase
central GABA concentrations (185). Notably, the role of
GABAergic neurotransmission is becoming increasingly recog-
nized in host energy metabolism (186). Thus, bacterial strains
producing or altering these neurochemicals could provide a
potent therapeutic for neurological diseases, and could most
likely play a pivotal role in influencing appetite and energy
metabolism via modulation of the CNS (187, 188).
732 van de Wouw et al.
Gut Microbial SCFAs and Their Impact on
Host Appetite and Metabolism
SCFAs are perhaps the most extensively studied molecules with
respect to how the gut microbiota influences host energy
metabolism and appetite (Figure 2). Numerous studies have
reported that overweight and obese individuals have increased
SCFA concentrations (86, 95, 189, 190), even though this is not
always consistently reported (191). It is also interesting to note
that the previously mentioned second-generation antipsychotic
risperidone, known to induce weight-gain in children and
adolescents, also increases gut microbial–derived SCFA con-
centrations (64). Conversely, individuals with anorexia nerv-
osa have been demonstrated to have decreased concentrations
of both acetate and propionate (18), which were not al-
tered after weight gain (19). SCFAs are generated by the
fermentation of nonhost-digestible dietary fibers by the gut
microbiota and can provide #10% of total daily caloric intake
(86, 192). As such, the ‘‘obese’’ gut microbiota has an increased
capacity for energy harvest through SCFA production (86).
Nonetheless, SCFA supplementation tends to result in a reduc-
tion in body weight in both humans (193) and rodents (194–
196), and ameliorates gut microbial alterations found in mice
with diet-induced obesity to a more lean phenotype (196). In
addition, GF mice are resistant to diet-induced obesity, and even
though they have drastically lower SCFA concentrations (197–
199), this has not been attributed directly to SCFA concentra-
tions (197).
Over 95% of gut microbial–derived SCFAs are made up of
acetate, propionate, and butyrate (200). With respect to their
use as an energy source, butyrate is highly used by colonocytes
butyrate and propionate are reported to be in the circulation at
5- to 20-mmol/L concentrations, whereas acetate tends to be
within a range of 100–200 mmol/L (205–207). In addition, a
recent study demonstrated that systemic availability of colonic-
administered acetate, propionate, and butyrate was 36%, 9%,
and 2% respectively (208).
SCFA-induced signaling. SCFAs have many effects at the
cellular level, one of which is the regulation of histone
acetylation and methylation, resulting in altered gene expression
(209). This is likely mediated through the facilitation of histone
acetyltransferase availability and inhibition of histone deacetylase
(210–212). In particular, acetate increases histone acetyltransfer-
ase availability (213), whereas butyrate is the most potent
inhibitor of histone deacetylase classes I and IIa (211, 214).

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(201–203), and propionate is primarily used by hepatocytes
in the liver (204). As such, only acetate is thought to reach
the peripheral circulation at relatively high amounts (205),
resulting in a SCFA concentration gradient. In line with this
theory are studies investigating SCFA concentrations in human
subjects during surgery and sudden-death victims, in whom
In addition, acetate is converted to acetyl-CoA, after which it is
integrated into the citric acid cycle (Krebs cycle), and finally used
as a mitochondrial energy source (215). Notably, this increase in
cellular energy also boosts the mechanistic target of rapamycin,
which is known to be an ATP sensor and thus a homeostatic
cellular energy sensor (216).

FIGURE 2 Gut microbial–derived SCFAs and their impact on host appetite and metabolism. SCFAs are the product of microbial fermentation in the
colon, in which they are able to induce histone deacetylase inhibition, increase histone acetyltransferase availability, increase serotonin synthesis, and
activate various GPCRs. Activation of these receptors results in the release of anorexigenic hormones, such as GLP-1 and PYY, into the peripheral
circulation. In addition, SCFAs increase concentrations of leptin and insulin. SCFAs are also able to pass through the intestinal epithelium to the portal vein,
in which portal nerves express FFA3, where they are able to induce vagus nerve signaling. In regard to their concentrations in the circulation and brain, only
acetate reaches high concentrations because of both colonic and hepatic clearance. Nonetheless, propionate is able to induce a decreased anticipatory
reward response through currently unknown mechanisms. All these factors cumulatively affect both short- and long-term host energy homeostasis and
appetite. FFA2, FFA receptor 2; FFA3, FFA receptor 3; GLP-1, glucagon-like peptide 1; GPCR, G protein–coupled receptor; GPR109A, niacin receptor 1;
HAT, histone acetyltransferase; HDACi, histone deacetylase inhibition; Olfr78, olfactory receptor 78; PYY, peptide YY; 5-HT, serotonin.

Microbiota and eating behavior 733

 Locally in the gut, SCFAs are able to enhance colonic
serotonin production and secretion (217–219), as well as
facilitating the secretion of the anorexigenic hormones GLP-1
and PYY from L cells in the gastrointestinal tract into the
circulation (220). These effects are largely mediated through the
G protein–coupled receptors (GPCRs) FFA receptor 2 (FFA2/
GPR43) and FFA receptor 3 (FFA3/GPR41) (194, 221, 222).
The SCFAs receptors FFA2 and FFA3 are also expressed in
adipocytes, where they increase the expression and secretion of
the anorexigenic hormone leptin in vitro (223–226). Notably,
FFA3 expression has not been consistently reported in adipo-
cytes (223, 224, 227). The importance of these receptors was
particularly emphasized by a recent study in which it was
demonstrated that supplementation with all individual SCFAs,
in addition to with a mix of all 3 principal SCFAs, in mice with
diet-induced obesity resulted in an attenuation of the obesity-
associated decrease in FFA2 and FFA3, which subsequently
correlated with various biomarkers of obesity (196). In addition,
mice overexpressing FFA2 specifically in adipose tissue remained
lean even on high-fat diets, whereas FFA2-deficient mice were
obese while on a normal diet (228).
In regard to the nervous system, FFA3 in particular is
expressed in the enteric nervous system (229) and vagal afferents
(230) and throughout the peripheral nervous system (227, 231).
In addition, butyrate is able increase the proportion of cholin-
ergic enteric neurons through epigenetic mechanisms, indicating
that the effects of SCFAs on the nervous system are not limited to
neuronal activation (232). Importantly, de Vadder et al. (230)
demonstrated that signaling through FFA3 expressed on portal
nerves by propionate resulted in increased activity in the dorsal
vagal complex, which receives inputs from the vagus nerve and
the hypothalamus, a key brain region in the control of appetite
and metabolism.
SCFAs have also been reported to exhibit potent immuno-
modulatory properties (233, 234). These include the regulation
of the chemotaxis and inflammation of neutrophils (235–237)
and the suppression of inflammatory cytokine production of
monocytes and macrophages (238, 239), as well as T regulatory,
T helper 1, and T helper 17 cell differentiation and subsequent
cytokine production (240–243). Moreover, SCFAs alleviate
blood-brain barrier permeability and microglia immaturity in
the CNS in GF mice (244, 245). It is important to note that
several of these anti-inflammatory effects have also been
demonstrated in mice with diet-induced obesity, indicating the
multifaceted role of SCFAs in conditions with disordered
metabolism and appetite (195, 196).
Even though many of the previously mentioned effects can be
induced by all SCFAs, there are distinct differences between the
principal gut microbial–derived SCFAs in the manner in which
they affect their host that are important to keep in mind: 1) not
all SCFAs are increased or decreased to the same extent in
different pathophysiological conditions; 2) only acetate reaches
the circulation at high concentrations, also resulting in the
suggestion that only gut microbial–derived acetate will induce
the GPCR signaling of FFA2 and FFA3, whenever SCFAs are
required to travel through the peripheral circulation before
GPCR activation; 3) only acetate directly increases histone
acetyltransferase availability, and butyrate is the most potent
histone deacetylase inhibitor, indicating that the effects of the
individual SCFAs via epigenetic means might differ; and 4) even
though all SCFAs activate FFA2 and FFA3, various GPCRs are
specific to 1 or 2 of the principal SCFAs as olfactory receptor 78,
which is only activated by acetate and propionate (246), and
niacin receptor 1, which is activated by butyrate (247).
734 van de Wouw et al.
Acetate. The word acetate comes from the Latin word for
vinegar, ‘‘acetum,’’ in which it is very abundant. Other dietary
means of increasing endogenous acetate are alcohol consump-
tion (248), and gut microbial production of acetate. The latter is
mediated by the acetyl-CoA or the Wood-Ljungdahl pathway
(249), after which a part is converted into butyrate by bacterial
crossfeeding (250, 251). In regard to the effects of acetate on
host metabolism, dietary acetate supplementation in obese mice
does not significantly affect cumulative food intake, but does
ameliorate body weight gain, TG concentrations, fasting insulin,
and leptin (194, 196). This is without affecting fasting glycemia
and oral glucose tolerance, all of which were completely restored
when either propionate or butyrate were administered (194). In
addition, acute oral administration of acetate does not alter
GLP-1, PYY, insulin, gastric inhibitory polypeptide (GIP), or
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amylin concentrations (194). Acute acetate injection does,
however, decrease circulating concentrations of FFAs (252),
result in appetite suppression, and suppress hypothalamic
neuronal activation patterning, as well as inducing a change in
the expression profile of regulatory neuropeptides, favoring
appetite suppression (253). In addition, acetate infusions into
the distal colon of overweight or obese men increase postpran-
dial glucose and insulin concentrations and fat oxidation (254).
Interestingly, a recent study showed that rats with diet-induced
obesity had an increased whole-body acetate turnover, as well as
increased plasma and fecal acetate concentrations (255). It was
subsequently demonstrated that acetate increased glucose-
stimulated insulin secretion, ghrelin secretion, hyperphagia,
and obesity through the parasympathetic nervous system (255).
These data indicate that acetate may have a causal role in obesity
(256). This is contrary to data demonstrating that acetate could
improve metabolic variables associated with obesity (194, 196,
253, 254). As such, Bindels and Leclercq (257) recently
discussed the current acetate controversy and stressed the
importance of location within the gastrointestinal tract as a
contributing factor for the differential effects of acetate on
host metabolism (i.e., proximal or distal colon).
Propionate. Propionate is widely used in Europe (European
food additive codes: E280–E282) as a food additive because
of its antifungal properties (258, 259). Its formation by gut
microbes is mediated via the succinate, acrylate, and propane-
diol pathways (260, 261). With respect to its effects on host
metabolism, dietary propionate supplementation ameliorates
body weight gain, oral glucose tolerance, TG concentrations,
and fasting insulin and leptin in mice (194, 196). In addition,
acute oral administration increases GIP, insulin, and amylin
without significantly altering PYY and GLP-1 (194). This could
be due to the fact that oral propionate would most likely not
reach the colon, where PYY- and GLP-1–containing L cells are
located. This is in line with the fact that intracolonic adminis-
tration of propionate does result in increased concentrations of
PYY and GLP-1 in the circulation (222). Furthermore, acute
administration of inulin-propionate ester, which delivers propi-
onate directly to the colon, leads to an increase in plasma
propionate, PYY, and GLP-1, and a decrease in energy intake
and appetite compared with inulin alone in healthy adults (193,
262). This intervention also decreases caudate and nucleus
accumbens activity, indicating that colonic propionate could
attenuate reward-based eating behavior via striatal pathways.
However, this study did not detect any alterations in GLP-1,
PYY, or serum propionate, which were found in the former study
(263). This does indicate that the observed effects on caudate
and nucleus accumbens activity were independent of GLP-1 and
PYY and are more likely mediated through currently unknown
mechanisms. Long-term supplementation for 24 wk with this
inulin-propionate ester in overweight adults did not significantly
affect overall body weight, but did result in decreased body
weight gain, without altering basal PYY and GLP-1 concentra-
tions (193). As such, these conflicting results call into question
the therapeutic potential of propionate in the regulation of
metabolism and host appetite, and further research is warranted.
Butyrate. Butyrate, which is infamous for its strong smell of
rancid butter and milk (264), has its etymologic roots in the
Greek word for butter. Butyrate is also widely known for its
potent histone deacetylase inhibitory effects, which, combined
with its ability to cross the blood-brain barrier, has resulted in
butyrate being studied extensively as a neuropharmacologic
agent (at somewhat supraphysiological doses) to investigate
epigenetic mechanisms in brain and behavior research (265).
Nonetheless, research performed on butyrate from this perspec-
tive has limited relevance to the effect of gut microbial–derived
butyrate, with many of the studies being focused on the
administration of acute, systemic, and high doses. The produc-
tion of butyrate by gut microbes is mediated through the enzyme
butyryl-CoA:acetate CoA transferase (266). Interestingly, both
this enzyme and butyrate have a diurnal variation, which is
ablated in mice with diet-induced obesity (126). This also
appeared to be the case for the less-pronounced diurnal variation
of propionate, whereas no variation at all was demonstrated for
acetate (126). In regard to butyrateÕs effect on host metabolism,
dietary butyrate supplementation ameliorates body weight gain,
TG concentrations, oral glucose tolerance, and fasting insulin, as
well as leptin in mice (194, 196). In addition, acute oral
administration increases GIP, insulin, amylin, PYY, and GLP-1
(194). Oral administration of tributyrin, a TG that contains 3
butyrate moieties, reduces body weight gain in mice with diet-
induced obesity, likely because of increased energy expenditure,
which is accompanied by an attenuation in glucose and insulin
tolerance (195).
The fact that obesity and metabolic syndrome seem to be
associated with increased SCFA concentrations (86, 95, 189,
190), whereas supplementation with SCFAs tends to decrease
acute food intake and markers associated with these disorders
(193–196), highlights the fact that much is still unknown about
the role and impact of SCFAs on long-term energy homestasis
and metabolism. In addition, much is still unclear about the
mechanisms in which gut microbial–derived SCFAs can influ-
ence host appetite and metabolism. In particular, the impact of
SCFAs in peripheral nervous system signaling remains largely
understudied. Nonetheless, current evidence indicates that
SCFAs represent a potential therapeutic strategy for diseases
with alterations in metabolism and appetite.
The Interplay between Gut Microbiota and
the Immune System on Host Appetite
and Metabolism
Gastrointestinal barrier functionality and permeability are
highly affected by the gut microbiota (267). This barrier not
only regulates the absorption of nutrients, electrolytes, and
water, but also prevents toxic substances and pathogens from
entering the circulation from the lumen, which makes intestinal
barrier functionality a crucial player in the influence of the gut
microbiota on its host (268). Barrier function and permeability
are affected by several stimuli, including pathogens, commensal
bacteria, and bacterial products (267, 269). Low-level translo-
cation of substances or microbes across the tight junctions of
these luminal antigens is normal and shape a proper adaptive
immune system (270). Nonetheless, excessive intestinal perme-
ability, often colloquially referred to as ‘‘leaky gut,’’ is associated
with the development of low-grade chronic inflammation and
sepsis, in which inflammatory mediators are thought to exacer-
bate intestinal permeability (271). Interestingly, decreased
intestinal permeability has been reported in individuals suffering
from anorexia nervosa (272), whereas increased intestinal
permeability has been observed in obesity (273, 274) and
protein-energy wasting (for in-depth discussion see (275). Of
note, SCFA supplementation has been demonstrated to improve
deficits in intestinal permeability (276–278). Obesity-associated
increases in intestinal permeability can lead to an increased
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translocation of Gram-negative bacterial-derived LPS into the
circulation, resulting in chronic low-grade systemic inflamma-
tion (273, 279, 280), in a condition called metabolic endotox-
emia (281–283). Interestingly, administration of the antibiotics
ampicillin and neomycin decreases cecal LPS content and
metabolic endotoxemia in both mice with diet-induced obesity
and ob/ob mice, further emphasizing the role of the gut
microbiota in metabolic endotoxemia (284).
Increased intestinal permeability can facilitate the transloca-
tion of gut microbial metabolites into the peripheral circulation.
Some of these gut microbial metabolites have a structure similar
to the hostÕs own molecules that is divergent enough to be
recognized as foreign by the hostÕs immune system, in a
phenomenon known as molecular mimicry (285).
Various gut microbes have the capacity to produce protein
sequences of $5 amino acids that share a sequence that is
identical to various appetite-regulating peptides, and can thus
trigger the production of Ig (286, 287). Ig has the ability to
reduce the rate of degradation of gut-derived hormones and
neuroendocrine factors, which was demonstrated to be the case
for the orexigenic hormone ghrelin (288), or can initiate an
autoimmune response. Coadministration of the hunger hormone
ghrelin, together with IgG from obese individuals or ob/ob mice,
increased food intake in rodents, whereas IgG from anorectic
patients or control animals did not (288). In addition, GF rats
have increased concentrations of IgG directed at the orexigenic
hormone ghrelin, and decreased concentrations of IgA directed
at the anorexigenic neurotransmitter agouti-related peptide and
the anorexigenic melanocyte-stimulating hormone (MSH)
(286).
Moreover, a rat model of intestinal inflammation and
anorexia induced by the chemotherapeutic agent methotrexate
has been reported to have decreased concentrations of a-MSH
IgG, which likely plays a role in observed changes in food intake
and body weight (289). Acute administration of a-MSH Ig
results in increased food intake (290), even though long-term
effects may actually potentiate a-MSH–mediated signaling
(291). Importantly, E. coli, a prominent inhabitant of the gut
microbiota, is able to produce a small protein sequence and
antigen-mimetic of a-MSH called caseinolytic protease B (ClpB)
(290, 292, 293). ClpB is elevated in a variety of eating disorders
associated with inadequate food intake (i.e., anorexia nervosa,
bulimia nervosa, and binge-eating disorder), and its concentra-
tions have been correlated with various psychopathologic traits
(294). Interestingly, E. coli produces relatively more ClpB in the
stationary phase of proliferation than in its exponential growth
phase, indicating that E. coli induces a more potent anorexigenic
effect whenever nutrients for E. coli stabilize. In addition,
systemic administration of E. coli in the stationary phase also
Microbiota and eating behavior 735
increases c-Fos expression in POMC neurons of the arcuate and
ventromedial nucleus of the hypothalamus generally associated
with decreased food intake (293). Notably, this study harvested
E. coli proteins by means of centrifugation, meaning that the
observed effects were not necessarily ClpB-mediated (293).
Nonetheless, the administration of ClpB-producing E. coli
results in a short-term reduction in body weight and food intake
compared with the administration of ClpB-deficient E. coli
(290). In addition, ClpB induces neuronal firing in POMC
neurons in the arcuate nucleus of the hypothalamus, which is
associated with a decrease in food intake (293). It is also worth
noting that female rats exhibit increased concentrations of and
affinity for a-MSH IgG in response to acute oral E. coli
administration, whereas males had increased a-MSH IgM
concentrations indicating sex-specific differences (292).
The Gut Microbiota in Host Nutrient and
Taste Sensing
The ability to sense and taste nutrients throughout the gastro-
intestinal tract plays a crucial role in the maintenance of nutrient
balance, the rewarding aspects of consuming food, and the
identification of spoiled food. Interestingly, animal models have
demonstrated that specific signaling mechanisms affect the
responsiveness of different tastes (i.e., sweet, bitter, salty, sour,
and umami). As such, modulation of these signaling mechanisms
by gut microbes could influence the host to eat specific nutrients,
therefore increasing their food substrates and survival. One can
therefore expect that individuals with eating disorders have an
altered taste responsiveness corresponding with their phenotype.
Indeed, obesity is associated with a lowered responsiveness to
sweet and fatty tastes, resulting in a shift toward liking foods
with higher concentrations of these tastes (295). In addition,
individuals with anorexia nervosa have impaired taste percep-
tion (296, 297), which has been shown to improve with weight
gain (298, 299).
Signals conveying taste are detected by taste receptor cells
on the tongue that are subsequently transmitted through the
solitary tract into the thalamus, signaling to other brain regions
(300, 301). These taste receptor cells also express the anorex-
igenic hormones GLP-1, PYY, and cholecystokinin, indicating
a peripheral signaling pathway via gastrointestinal hormone
secretion, resulting in decreased appetite (302–305). Interest-
ingly, PYY knockout mice have a decreased behavioral response
to both fat- and bitter-tasting compounds (306). Subsequent
reconstitution of salivary PYY concentrations in these mice
improves their response to fat, but not bitter taste (306). In
addition, higher concentrations of circulating TNF-a, insulin-
like growth factor 1, and leptin have been detected in individuals
with increased taste-responsiveness, indicating that these par-
ticular circulating hormones could play a role in taste perception
(307).
To our knowledge, few studies have investigated the role of
the gut microbiota in host nutrient and taste sensing. A recent
study by Lyte et al. (308) demonstrated with the use of the
selectively bred occidental low- and high-saccharin–consuming
rat model that rats innately more prone to saccharin consump-
tion have a gut microbiota composition that is different from
those less prone to saccharin consumption. In addition, studies
in GF mice suggest that the gut microbiota is able to influence
taste receptors and, subsequently, taste. For instance, an increase
in intestinal sweet taste receptors, such as type 1 taste receptor 3,
a-gustducin, and sodium-glucose luminal transporter 1, as well
736 van de Wouw et al.
as increased sucrose preference, has been reported in GF mice
(309). Furthermore, GF mice have an increased oral preference
for and expression of lingual FA translocase (CD36), but
decreased intestinal expression of the FA receptors GPR40,
FFA3, FFA2, and GPR120, indicating decreased fat signaling
(310).
Current knowledge about the impact of the gut microbiota
on nutrient and taste sensing and, thus, gustatory function
suggests that these effects could be modulated through the
immune system by affecting the continual supply of differenti-
ated taste-receptor cells. These cells are essential in the detection
of taste compounds and transmit subsequent signals either
directly or indirectly via taste bud cells, resulting in oral taste
perception (301, 311). Continual supply of differentiated taste
receptor cells is crucial for normal taste function, and disruption
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of this supply can be detrimental to taste signaling (312).
Activation of the immune system results in decreased cell
renewal and lifespan in both taste receptor and taste bud cells on
the tongue (313–315), which is potentially mediated through
mammalian toll-like receptors and type-I and -II IFN receptors,
as these are localized in taste cells (314–316). Several studies
furthermore have pointed to the involvement of immune system
functionality in taste. For instance, IL-10–knockout mice have a
reduced number of taste buds and taste receptor cells and have
an increased inflammatory response to LPS-induced inflamma-
tion (317). In addition, TNF-knockout mice have a decreased
response to various bitter compounds, but not to other tastes
(318).
Interestingly, systemic administration of the bacterial-derived
toxin LPS results in an inflammatory response in the tongue,
combined with decreased taste cell lifespan and decreased taste
preference (313, 314, 319–323). Furthermore, prolonged oral
LPS administration in mice results in decreased sweet taste
receptor expression and a decreased response to sucrose (324).
Notably, LPS administration also results in sickness behavior,
which includes both anhedonic and anxiogenic components, and
it could therefore be a confounding factor when investigating
behavior in vivo (325, 326). However, LPS administration
decreases c-Fos expression in the lingual taste epithelium,
indicating that there is local inhibited cellular activity (314). In
addition, subcutaneous injection of LPS to the ventral surface
of the tongue results in leukocyte recruitment and inhibits
sodium-induced taste signaling via the chorda tympani, a
primary sensory afferent nerve (327). Cumulatively, these
results indicate that the gut microbiota could influence host
nutrient and taste signaling, and thus gustatory function,
through immune system regulation, of which LPS is a potential
mediator.
The Microbiota-Gut Brain Axis in
Eating-Related Behavior
It is highly likely that other eating-related behaviors besides
gustatory function are influenced by the gut microbiota and its
metabolites. Although direct links with the gut microbiota
have not been investigated extensively yet, it is likely that
olfactory function, food-related cognitive processing, food-related
impulsivity and compulsivity, and the social aspects of food intake
are susceptible to microbiome regulation. Interestingly, the gut
microbiota has recently been hypothesized to play a key role in
addiction (328), which could have particular relevance to the
controversial concept of food addiction. In addition, the gut
microbiota has already been linked to cocaine use in mice (329)
and alcohol-dependence in humans (330). It is also interesting
to note that the administration of the principal psychoactive
constituent of cannabis, D9-tetrahydrocannabinol, alleviates the
high-fat diet–induced increases in fat mass and body weight that
are associated with an altered gut microbiota, although it is
unclear whether the altered gut microbiota composition in
conjunction with D9-tetrahydrocannabinol treatment played a
causative role in this reduction in fat mass and body weight (331).
Overall, much is still unknown about the role of the gut
microbiota in food addiction, and other eating-related behaviors
in particular, and additional research is warranted for a more
comprehensive picture of the role of the gut microbiota in eating-
related behavior.
The Microbiota-Gut-Brain Axis in Metabolic
and Eating Disorder Comorbidities
Eating and metabolic disorders are often associated with other
behavioral comorbidities, such as anxiety and depression (35,
36), and it is thus conceivable that there is a strong bidirectional
interplay with these behaviors. It is therefore also likely that
microbes or microbial-derived metabolites that affect these
food-related behaviors will invariably alter the hostÕs appetite
and metabolism (Figure 1). Importantly, the influence of the
microbiota-gut-brain axis is also becoming increasingly recog-
nized in behaviors such as anxiety and depression (37, 38,
144, 332–334). As such, findings in regard to anxiety, stress,
depression, sociability, and other behaviors are pivotal for a
comprehensive understanding of eating and metabolic disorders.
Importantly, a recent study indeed demonstrated that the gut
microbiota composition and diversity in individuals with ano-
rexia nervosa at inpatient admission is correlated with levels of
depression, anxiety, and eating disorder psychopathology (17).
In addition, many food-related behavioral findings in regard to
the microbiota-gut-brain axis are often mediated through
pathways similar to the ones involved in gut microbiota
interactions with host metabolism and appetite, including
modulation of the immune system (37), vagus nerve signaling
(184, 335), and the production of neurochemicals (336).
Conclusion
It is clear that the gut microbiota is a key regulator of host
appetite and metabolism. However, the majority of research has
been focused on obesity and its comorbidities. As such, less is
known about other disorders wherein appetite and metabolism
are dysregulated, such as binge-eating disorder, drug-induced
obesity, cachexia, anorexia nervosa, and infant malnutrition.
Nonetheless, mechanisms in which the gut microbiota influences
the hostÕs appetite and metabolism are being elucidated at a
rapid rate, providing a better understanding of its role in
disorders with both a positive and negative energy balance. Such
information will be crucial for elucidating in which instances
alterations in gut microbiota composition and function are
causative, or merely correlative, because many studies up until
now have only identified associations. In this article, we have
portrayed many of these direct and indirect mechanisms. Gut
microbes are able to secrete various substrates and metabolites,
affecting appetite- and metabolism-regulating systems and the
hostÕs ability to sense and taste nutrients, as well as eating-
related behaviors and other behavioral comorbidities. This
information, cumulatively contributing to a greater understand-
ing of the gut microbiota and its metabolites in appetite and
energy metabolism, will therefore ultimately result in better
therapeutic strategies for obesity and eating disorders.
Acknowledgments
We thank Mahendra De Silva and Lilani De Silva for their
generous financial assistance to MvdW. MvdW wrote the
manuscript; and HS, TGD, and JFC significantly contributed to
the manuscript concept and structure. All authors read and
approved the final manuscript.
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