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Microbes in the gastrointestinal tract are under selective pressure to manipulate host eating behavior to increase their fitness, sometimes at the expense of host fitness. Microbes may do this through two potential strategies: (i) generating cravings for foods that they specialize on or foods that suppress their competitors, or (ii) inducing dysphoria until we eat foods that enhance their fitness. We review several potential mechanisms for microbial control over eating behavior including microbial influence on reward and satiety pathways, production of toxins that alter mood, changes to receptors including taste receptors, and hijacking of the vagus nerve, the neural axis between the gut and the brain. We also review the evidence for alternative explanations for cravings and unhealthy eating behavior. Because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating.
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Prospects & Overviews
Is eating behavior manipulated by the
gastrointestinal microbiota? Evolutionary
pressures and potential mechanisms
Joe Alcock
1)
, Carlo C. Maley
2)3)4)
and C. Athena Aktipis
2)3)4)5)
Microbes in the gastrointestinal tract are under selective
pressure to manipulate host eating behavior to increase their
fitness, sometimes at the expense of host fitness. Microbes
may do this through two potential strategies: (i) generating
cravings for foods that they specialize on or foods that
suppress their competitors, or (ii) inducing dysphoria until
we eat foods that enhance their fitness. We review several
potential mechanisms for microbial control over eating
behavior including microbial influence on reward and satiety
pathways, production of toxins that alter mood, changes to
receptors including taste receptors, and hijacking of the
vagus nerve, the neural axis between the gut and the brain.
We also review the evidence for alternative explanations for
cravings and unhealthy eating behavior. Because microbiota
are easily manipulatable by prebiotics, probiotics, anti-
biotics, fecal transplants, and dietary changes, altering our
microbiota offers a tractable approach to otherwise
intractable problems of obesity and unhealthy eating.
Keywords:
. cravings; evolutionary conflict; host manipulation;
microbiome; microbiota; obesity
Introduction: Evolutionary conflict
between host and microbes leads to
host manipulation
The struggle to resist cravings for foods that are high in sugar
and fat is part of daily life for many people. Unhealthy eating is
a major contributor to health problems including obesity [1] as
well as sleep apnea, diabetes, heart disease, and cancer [2–4].
Despite negative effects on health and survival, unhealthy
eating patterns are often difficult to change. The resistance to
change is frequently framed as a matter of “self-control,” and
it has been suggested that multiple “selves” or cognitive
modules exist [5] each vying for control over our eating
behavior. Here, we suggest another possibility: that evolution-
ary conflict between host and microbes in the gut leads
microbes to divergent interests over host eating behavior. Gut
microbes may manipulate host eating behavior in ways that
promote their fitness at the expense of host fitness. Others
have hypothesized that microbes may be affecting our eating
behavior [6–8], though not in the context of competing fitness
interests and evolutionary conflict.
Conflict over resource acquisition and resource allocation
can occur as a result of conflict between different genetic
interests within an organism. For example, genetic conflict
between maternal and paternal genes is hypothesized to play
a role in the unusual eating behavior that characterizes the
childhood genetic diseases Beckwith–Wiedemann syndrome
and Prader–Willi syndrome. These syndromes are character-
ized by altered appetite and differences in infant suckling
that can result from overexpression of genes of paternal
or maternal origin, respectively [9, 10]. In parent-of-origin
genetic conflict, paternally imprinted genes are thought
to drive increased demands for extracting resources from
the mother, and maternally imprinted genes tend to resist
these effects. Metagenomic conflict between host and
microbiome can be considered an extension of this genetic
conflict framework, but one that includes other genomes (i.e.,
microbes in the gut) with genes that affect the physiology and
behavior of a host organism, potentially altering host eating
behavior in ways that benefit microbe fitness.
DOI 10.1002/bies.201400071
1)
Department of Emergency Medicine, University of New Mexico,
Albuquerque, NM, USA
2)
Center for Evolution and Cancer, Helen Diller Family Comprehensive
Cancer Center, San Francisco, CA, USA
3)
Department of Surgery, University of California San Francisco, San
Francisco, CA, USA
4)
Wissenschaftskolleg zu Berlin, (Institute for Advanced Study Berlin), Berlin,
Germany
5)
Department of Psychology, Arizona State University, Tempe, AZ, USA
*Corresponding author:
Carlo Maley
E-mail: carlo.maley@ucsfmedctr.org, cmaley@alum.mit.edu
940 www.bioessays-journal.com Bioessays 36: 940–949, ß 2014 The Authors. Bioessays published by WILEY Periodicals, Inc. This is an
open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
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Microbial genes outnumber human genes by 100 to 1 in the
intestinal microbiome, leading some to propose that it is a
“microbial organ” that performs important functions for the
host, such as nutrient harvesting and immune develop-
ment [11]. However, as with any complex and intimate
interaction, there is a mixture of common and divergent
interests with opportunities for mutual benefit [11] and
manipulation [12]. Fitness interests of gut microbes are also
often not aligned, because members of the microbiota
compete with one another over habitat and nutrients. This
means that highly diverse populations of gut microbes may be
more likely to expend energy and resources in competition,
compared to a less diverse microbial population. A less diverse
microbial population is likely to have species within it that
have large population sizes and more resources available for
host manipulation. Moreover, the larger a particular microbial
population is, the more power it would have to manipulate
the host through higher levels of factor production or other
strategies (see below) and large scale coordination of these
activities (e.g., through quorum sensing). Therefore, we
hypothesize that lower diversity in gut microbiome should
be associated with more unhealthy eating behavior and
greater obesity (i.e., decreased host fitness).
Evidence indicates many potential
mechanisms of manipulation
There is a selective influe nce of diet on
microbiota
Individual members of the microbiota, and consortia of those
microbes, have been shown to be highly dependent on the
nutrient composition of the diet. Prevotella grows best on
carbohydrates; dietary fiber provides a competitive advantage
to Bifidobacteria [13], and Bacteroidetes has a substrate
preference for certain fats [14]. Some specialist microbes, e.g.
mucin degrading bacteria such as Akkermansia mucinophila,
thrive on secreted carbohydrates provided by host cells. Other
butyrate producing microbes, e.g. Roseburia spp., fare better
when they are delivered polysaccharide growth substrates in
the diet. Specialist microbes that digest seaweed have been
isolated from humans in Japan [15]. African children raised
on sorghum have unique microbes that digest cellulose [16].
Many other examples exist [17]. Even microbes with a
generalist strategy tend to do better on some combinations
of nutrients than others, and competition will determine
which microbes survive [18, 19].
Microbes can manipulate host behavior
There is circumstantial evidence for a connection between
cravings and the composition of gut microbiota. Individuals
who are “chocolate desiring” have different microbial
metabolites in their urine than “chocolate indifferent”
individuals, despite eating identical diets [20]. There is also
evidence for effects of microbes on mood. A double-blind,
randomized, placebo controlled trial found that mood was
significantly improved by drinking probiotic Lactobacillus
casei in participants whose mood was initially in the lowest
tertile [21].
There are many other examples of microbes affecting their
hosts’ mood and behavior, mostly from animal studies (Fig. 1).
Butyrate, a short chain fatty acid largely produced by the
microbiota, has been shown to have profound central nervous
system effects on mood and behavior in mice [22]. Microbiota
transfer to germ free mice leads to timid behavior when fed
feces from mice with anxiety-like behavior. When germ-free
mice from an anxious strain were fed with a fecal pellet from a
control mouse, the inoculated mice exhibited behavior that
was more exploratory, and more like their fecal donors [23]. In
addition, a probiotic formulation with Lactobacillus helveticus
R0052 and Bifidobacterium longum R0175 alleviated psycho-
logical distress [24]. This effect can be altered by diet and
inflammation [25]. If one feeds Lactobacillus rhamnosus ( JB-1)
to mice, not only does it reduce their stress-induced
corticosterone hormone levels, but it also makes them more
dogged: L. rhamnosus (JB-1) fed mice swim longer than the
control fed mice when put in a glass cylinder filled with 15 cm
of water and no means of escape [26]. This effect disappeared
when the experimenters severed the vagus nerve, suggesting a
role for the vagus nerve in microbial manipulation of host
behavior. In contrast, severing the vagus nerve had no effect
on swimming behavior of control mice that were not fed
L. rhamnosus (JB-1) [26]. In a widely cited example of
microbes affecting behavior, Toxoplasma gondii suppresses
rats’ normal fear of cat smells, often to the detriment of the
rats, but to the benefit of the microbes that are ingested into
their new feline host. T. gondii infected rats are reported to
become sexually aroused by cat urine [27], a propensity that
promotes transmission of T. gondii at the expense of the fitness
of the rat.
Microbes can induce dysphoria that changes
feeding behavior
Although certain Lactobacillus appear to reduce anxiety,
colonization of the gut with the pathogen Campylobacter
jejuni increased anxiety-like behavior in mice [28], raising the
possibility that microbe-induced dysphoria might also affect
human behavior. Recent studies have linked the inconsolable
crying of infant colic with changes in gut microbiota including
reduced overall diversity, increased density of Proteobacteria
and decreased numbers of Bacteroidetes compared to
controls [29]. Colic has been reported to result in increased
energy delivery to infants, sometimes resulting in accelerated
weight gain [30]. If infant crying has a signaling function that
increases parental attention and feeding [31, 32], colic may
increase the resource delivery to the gut and hence microbial
access to nutrients.
One potential mechanism by which dysphoria can
influence eating involves bacterial virulence gene expression
and host pain perception. This mode of manipulation is
plausible because production of virulence toxins often is
triggered by a low concentration of growth-limiting nutrients.
Detection of simple sugars and other nutrients regulates
virulence and growth for a variety of human-associated
microbes [33–37]. These commensals directly injure the
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intestinal epithelium when certain nutrients are absent,
raising the possibility that microbes manipulate behaviors
through pain signaling. In accord with this hypothesis,
bacterial virulence proteins have been shown to activate pain
receptors [38]. Moreover, pain perception (nociception)
requires the presence of an intestinal microbiota in mice [39]
and fasting has been shown to increase nociception in rodents
by a vagal nerve mechanism [40].
Microbes modulate host receptor expression
One route to manipulation of host eating behavior is to alter
the preferences of hosts through changing receptor expres -
sion. One study found that germ-free mice had altered taste
recept ors for fat on their tongues and in their intestines
compared to mice with a normal mi crobiome [41]. In another
experiment, germ free mice preferred more sweets and
had greater numbers of sweet taste receptors in the gastro-
intestinal tract compared to normal mice [42]. In addi tion,
L. acidophilus NCF M, administered orally as a probiotic,
increased intestinal expression of cannabinoid and opioid
recept ors in mouse and rat intestines, and had similar
effects in human epithelial cell culture [43]. These results
suggest that microbes could influence food prefer ences by
altering receptor expression or transduction. Changes in
taste receptor expression and activity have been reported
after gastric bypass surgery, a procedure that also changes
gut microbiota and alt ers satiety and food preferences
(reviewed in [44]).
Microbes can influence hosts through neural
mechanisms
Gut microbes may manipulate eating behavior by hijacking
their host’s nervous system. Evidence shows that microbes
can have dramatic effects on behavior through the micro-
biome-gut-brain axis [6, 45, 46]. The vagus nerve is a central
actor in this communication axis, connecting the 100 million
neurons of the enteric nervous system in the gut [47] to the
base of the brain at the medulla. Enteric nerves have receptors
TOXINS
REWARD
VAGAL
CONTROL
RECEPTOR
ALTERATION
Negative mood
induced by toxins
[38,39] may increase
eating [109]
Microbes release
toxins in absence of
nutrients [33-37]
Taste receptors altered
by microbes, aect
eating behavior [41-44]
Microbes alter
cannabinoid and
opioid receptors
in gut [43]
Vagus nerve
interruption
leads to weight
loss [49,50]
Enteric receptors
respond to specic
bacteria [48]
High levels of
dopamine and
serotonin in gut [58,59]
Microbes have genes for human
neurotransmitters [8,55-57,60]
Figure 1. Like microscopic puppetmasters,
microbes may control the eating behavior of
hosts through a number of potential mecha-
nisms including microbial manipulation of
reward pathways, production of toxins that
alter mood (shown in pink, diffusing from a
microbe), changes to receptors including
taste receptors, and hijacking of neurotrans-
mission via the vagus nerve (gray), which is
the main neural axis between the gut and
the brain.
J. Alcock et al. Prospects & Overviews ....
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that react to the presence of particular bacteria [48] and to
bacterial metabolites such as short-chain fatty acids.
Evidence suggests that the vagus nerve regulates eating
behavior and body weight. For example, blockade or
transection of the vagus nerve has been reported to cause
drastic weight loss [49, 50]. On the other hand, vagus nerve
activity appears to drive excessive eating behavior in satiated
rats when they are stimulated by norepinephrine [51]. These
results suggest that gut microbes that produce adrenergic
neurochemicals (discussed below) may contribute to over-
eating via mechanisms involving vagal nerve activity.
Together these results suggest that microbes have
opportunities to manipulate vagus nerve traffic in order to
control host eating. Intriguingly, many practices that are
known to enhance parasympathetic outflow from the vagus
nerve, e.g. exercise, yoga, and meditation, are also thought to
strengthen willpower [52] and improve accuracy of food intake
relative to energy expenditure [53]. However, increased vagus
activity is not always associated with health. One study
linked parasympathetic vagus activity with weight loss in
patients with anorexia nervosa [54], suggesting that vagus
nerve signaling is important in regulating body weight, and
sometimes can lead to pathological anorexia.
Microbes can influence hosts through hormones
Microbes produce a variety of neurochemicals that are exact
analogs of mammalian hormones involved in mood and
behavior [8, 55–57]. More than 50% of the dopamine and the
vast majority of the body’s serotonin have an intestinal
source [58, 59]. Many transient and persistent inhabitants of
the gut, including Escherichia coli, [8, 55, 56] Bacillus cereus,
B. mycoides, B. subtilis, Proteus vulgaris, Serratia marcescens,
and Staphylococcus aureus [60] have been shown to
manufacture dopamine. Concentrations of dopamine in
culture of these bacteria were reported to be 10–100 times
higher than the typical concentration in human blood [60]. B.
subtilis appears to secrete both dopamine and norepinephrine
into their environment, where it interacts with mammalian
cells. Transplant of the microbiome from a male to an
immature female mouse significantly and stably increases
testosterone levels in the recipient [61]. In turn, host enzymes
are known to degrade neurotransmitters of bacterial origin.
For instance, mammals use monoamine oxidase to silence
exogenous signaling molecules, among other functions [62,
63]. This may be evidence for selection on hosts to counteract
microbial interference with host signaling.
Certain probiotic strains alter the plasma levels of other
neurochemicals. B. infantis 35624 raises tryptophan levels in
plasma, a precursor to serotonin [64]. The lactic acid
producing bacteria found in breast milk and yogurt also
produce the neurochemicals histamine [65] and GABA [66].
GABA activates the same neuroreceptors that are targeted by
anti-anxiety drugs such as valium and other benzodiazepines.
Appetite-regulating hormones are another potential avenue
for manipulation of mammalian eating behavior. In mice,
treatment with VSL#3, a dietary supplement consisting of a
mixture of Lactobacillus strains, reduced hunger-inducing
hormones AgRP (agouti related protein) and neuropeptide Y in
the hypothalamus [67]. Germ-free mice were also shown to have
lower levels of leptin, cholecystokinin, and other satiety
peptides [41], hormones that control hunger and food intake
partly by affecting vagus nerve signaling. Numerous commen-
sal and pathogenic bacteria manufacture peptides that are
strikingly similar to leptin, ghrelin, peptide YY, neuropeptide Y,
mammalian hormones that regulate satiety and hunger [68].
Moreover, humans and other mammals produce antibodies
directed against these microbial peptides, a phenomenon that
could have evolved as a mammalian counter-adaptation to
microbial manipulation. Anti-hormone antibody production
may be important in maintaining the fidelity of host signaling
systems. However, these antibodies also act as auto-antibodies
against mammalian hormones [68]. This autoimmune response
implies that microbes have the capacity to manipulate human
eating behavior (i) directly with peptide mimics of satiety
regulating hormones, or (ii) indirectly by stimulating produc-
tion of auto-antibodies that interfere with appetite regulation.
The antibody response to microbial analogs of human
hormones supports the hypothesis that conflict between host
and microbiota influences the regulation of eating behavior.
Mucin foraging bacteria control their nutrient
supply
Several commensal bacteria are known to induce their hosts to
provide their preferred nutrients through direct manipulation
of intestinal cells. For example, Bacteroides thetaiotaomicron
is found on host mucus, where it scavenges N-glycated
oligosaccharides secreted by goblet cells in the gut. B.
thetaiotaomicron induces its mammalian host to increase
goblet cell secretion of glycated carbohydrates [69, 70].
Investigators have shown that another mucin-feeding species,
A. muciniphila, also increases the number of mucus producing
goblet cells when inoculated in to mice [71]. On the other hand
Faecalibacterium prausnitzii, a non-mucus-degrading bacte-
rium that is co-associated with B. thetaiotaomicron, inhibits
mucus production by goblet cells [70]. These species provide a
proof of principle that gut bacteria can control their nutrient
delivery, involving a mechanism that is energetically costly for
the host [72].
Intestinal microbiota can affect obesity
Evolutionary conflict between the gut microbiome and host
may be an important contributor to the epidemic of obesity. In
a landmark paper, Backhed and colleagues showed that mice
genetically predisposed to obesity remained lean when they
were raised without microbiota [73]. These germfree mice were
transformed into obese mice when fed a fecal pellet from a
conventionally raised obese mouse [74]. Inoculation of germ-
free mice with microbiota from an obese human produced
similar results [75]. Mice lacking the toll-like receptor TLR5
became obese and developed altered gut microbiota, hyper-
phagia, insulin resistance, and pro-inflammatory gene expres-
sion [76]. Fecal pellets from these TLR5 knockout mice, when
fed to wild type mice, induced the same phenotype. The gut
microbes of obese humans are less diverse than the microbiota
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of their lean twins [77], consistent with the hypothesis that
lower diversity may affect eating behavior and satiety.
Probiotics are associated with weight loss
The addition of probiotics (i.e. purportedly beneficial ingest-
ible microbes) to the diet tends to decrease food intake,
consistent with the hypothesis that greater gut diversity may
limit microbial control over eating behavior. Some Lactoba-
cillus probiotics have been reported to reduce fat mass and
improve insulin sensitivity and glucose tolerance, although
these effects are not universally reported for all Lactobacillus
species [78, 79]. A recent study demonstrated that the
probiotic VSL#3 caused mice to decrease food intake [67].
Similarly, the probiotic Bifidobacterium breve inhibited weight
gain in mice given a high fat diet in a dose-dependent
manner [80]. Several studies suggest a role for probiotics in
weight loss in humans. In one trial, a probiotic yogurt
produced weight loss that was not due to change in energy
intake or exercise [81]. Similarly, yogurt was the food most
associated with reduced weight gain in a study that monitored
the diet and health of 120,000 nurses for over 12–20 years [82].
Further, a randomized, placebo-controlled trial found that
probiotic treatment in pregnancy, using L. rhamnosus GG and
Bifidobacterium lactis along with dietary counseling, reduced
abdominal fat at 6 months post-partum [83]. Together these
results demonstrate that probiotics can lead to weight loss and
regulate energy balance.
Predictions and experiments
Changing the microbiota composition will
change eating behavior
Prebiotics (i.e. non-digestible compounds that stimulate
growth of beneficial microbes), probiotics, antibiotics, fecal
transplant, and diet changes are potential strategies to alter
the microbiota. In addition to the proposal that microbiota
transplantation should result in adoptive transfer of food
preferences [84], we further predict that inoculation of an
experimental animal with a microbe that has a specialized
nutrient requirement, such as seaweed [15, 85], would lead to
preference for that novel food.
A consistent diet will select for microbial
specialists and lead to preference for those
foods
Raising an experimental animal on a simple diet with few
types of foods, should select for microbes that specialize on
those foods. Our hypothesis as to the microbial origin of food
preferences predicts that these microbes will influence their
host to choose the foods upon which they specialize. An
alternative hypothesis, that food cravings result from nutrient
shortages [86], predicts the opposite: preference for novel
foods rich in micronutrients that had been lacking in the
previous simple diet.
Cravings should be associated with lower
parasympathetic (vagal) tone, and blocking the
vagus nerve should reduce food cravings
If microbial control is mediated through the vagus nerve, then
microbial signals should interfere to some extent with the
physiological regulation coordinated by the vagus nerve.
Vagal tone can be easily measured through respiratory sinus
arrhythmia [87], the extent to which the heart rate changes in
response to inspiration and exhalation. We predict that people
experiencing cravings should have lower vagal tone. Further-
more, it is possible to block or sever the vagus, which we
predict would subdue microbial signaling via the vagus nerve,
and thereby alter food preferences. This would be consistent
with studies showing that blocking the vagus nerve can lead
to weight loss [49, 50].
Microbial diversity should affect food choices
and satiety
Certain features of microbial ecology, such as population size,
would be expected to influence a microbe’s capacity to
manipulate the host. Microbial communities with low alpha
(intrasample) diversity might be more prone to overgrowth by
one or more species, giving those organisms increased ability
to manufacture behavior-altering neurochemicals and hor-
mones. By comparison, in microbial communities with high
alpha diversity any single microbial species will tend to occur
at lower abundance. Highly diverse gut microbiotas tend to
be more resistant to invasion by pathogenic species than
less diverse microbiotas [88]. In addition, a phylogenetically
diverse community will likely contain competing groups
whose influences may counteract each other. Furthermore,
in a diverse microbial environment, microbes will likely
expend resources on competing and cooperating (e.g. via
cross-feeding), rather than on manipulating their host.
Supporting the hypothesis that a more diverse microbiota
causes fewer cravings, gastric bypass surgery has a twofold
effect: increasing alpha diversity in the gut microbiota as well
as reducing preference for high fat, high carbohydrate
foods [89–91]. Food preferences of germfree mice inoculated
with low versus high diversity microbial communities could
provide a test of this prediction. Similarly, probiotics that
increase microbiota diversity in humans are predicted to
reduce cravings more than control treatments that do not
increase diversity.
Excess energy delivery to the gut may reduce
microbial diversity
Besides affecting cravings for specific nutrients, conflict
between host and microbiota is expected to impact satiety and
overall calorie consumption because optimal energy intake is
likely to differ between the host and members of the gut
microbiota. Excess energy delivered to the gut, beyond what is
optimal for the host, might provide energy substrates for
microbial growth, permitting certain species to bloom,
potentially overwhelming inhibition by competitor organisms
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and the immune system. Energy excess is predicted to reduce
diversity as a result, leading to a vicious cycle of reduced
diversity, increased manipulation and chronic energy excess.
Such a positive feedback mechanism could drive long-term
changes in satiety, harming the host by causing obesity.
Experimental increases in gut microbiota diversity are
expected to change the satiety setpoint, favoring decreased
food intake by the host [92].
High gut diversity may inhibit density-dependent
microbial manipulation
One explanation for the health benefits of intestinal diversity
is the inhibition of quorum sensing microbes from achieving a
quorum. Quorum sensing is a cell–cell communication system
used by many gut bacteria to regulate density-dependent
conditional strategies, including virulence factor expression
and changes in growth. For instance, the common human
commensal and pathogen S. aureus uses the accessory gene
regulator system (AGR) of quorum sensing to regulate toxin
and other virulence genes. When S. aureus reaches high
density, AGR switches from expression of genes involved in
colonization and attachment to those involved in tissue
invasion [93]. Quorum sensing may be one route that microbes
can use to coordinate behavior in order to manipulate host
eating behavior and enhance resource delivery. It is in the
host’s interest to prevent bacteria from reaching the threshold
density for expression of virulence toxins and proteases. From
a translational perspective, treatments that increase microbial
diversity might prevent some microbe populations from
reaching the density required for a quorum, thus limiting
their capacity to manipulate host behavior.
Interrogation of host and microbiota genomes
should reveal a signaling arms race
There has been little work to study the co-evolution of the
microbiome and their host genomes [11, 94], and what there is
has tended to focus on mutualism rather than evolutionary
conflict between microbes and their hosts. We hypothesize that
there has been a genomic arms race in which microbes have
evolved genes to manipulate their hosts (particularly analogs of
human signaling molecules such as neuropeptides and
hormones) and corresponding host genes have evolved to
prevent that manipulation where it conflicts with the host’s
fitness interests. Comparative genomic analyses may reveal
such co-evolutionary patterns, and they have already identified
adaptations specific to obligate commensal microbes [95, 96].
Food preferences may be contagious
One intriguing implication of microbially induced cravings
is that preferences for certain foods may be contagious [97].
Both the fecal and oral microbiota are more similar among
cohabiting family members compared to non-cohabiting
individuals [98]. If the food preferences of one person in a
household influence the food consumption of the household,
any specialist gut microbes adapted to that diet would then
tend to flourish in the other household members. Even worse,
the obesity epidemic could be contagious as a result of
obesity-causing microbes transmitted from person to person.
A social network study of 12,067 people found that a person’s
chance of becoming obese increased by 57% if a friend had
become obese [99]. This raises up the possibility that cravings
and associated obesity might not be socially contagious (e.g.
through changes in norms) as the authors of the social
network study suggest [99], but rather truly infectious, like a
cold [75]. This proposition could be tested by experimentally
selecting for a microbiome that generates a particular food
preference in animals, as above. As others have proposed,
if food preferences are contagious, then co-housing those
manipulated animals with germ-free animals should lead to
transmission of food preference [7, 100].
Alternative hypotheses for unhealthy
eating and obesity
There are a number of existing hypotheses for the prevalence
of obesity and our cravings for unhealthy foods, including
addiction/lack of willpower, environmental mismatch, and
nutrient shortages. A microbial cause is not mutually
exclusive of other alternatives such as nutrient deprivation.
In this section, we review each of these alternative hypothe-
ses. We find that none of these hypotheses is completely
consistent with the data on cravings, food preferences, and
obesity.
Lack of willpower is not sufficient to explain
unhealthy eating
Conventional wisdom often blames unhealthy eating on a lack
of willpower. However, binge eating is not just a matter of
mental control [101]; food cravings are unlike other cravings.
Many other addictions, such as drugs and alcohol, require
ever-increasing doses to maintain the same mood-altering
effect. This habituation does not happen with food. For some
individuals, the more they indulge their food cravings, the
more enjoyment they get from them [102]. These results, and
recent work showing distinct mechanisms of food-reward and
morphine sensitization in mice suggest that overeating has a
different underlying mechanism from drug abuse, and is not
consistent with an addiction [103].
Mismatch with scarce resources in our ancestral
environment is not sufficient to explain unhealthy
eating
Food preferences are thought to arise from a complex
interaction between genes, environment, and culture. The
modern food environment is vastly different from that of our
evolutionary ancestors: the human ancestral diet is thought
to contain foods far lower in salt, simple carbohydrates,
and saturated fat than the typical Western diet [104]. This
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discordance, or environmental mismatch, has been cited as
the source of “diseases of civilization,” including obesity,
cancer, and cardiovascular disease [105]. Similar logic
postulates that past scarcity of calorie dense foods and
critical micronutrients has also shaped modern food prefer-
ences. The traditional diet of pre-agricultural humans relied
on low-carbohydrate plant foods and game, low in fat. Among
hunter gatherers, food acquisition efforts have been shown
to prioritize energy dense foods, gathered in a pattern that
maximizes energy capture relative to energy expenditure.
This strategy, described as optimal foraging theory, is fitness
enhancing in an environment where energy dense foods were
rare and hard to acquire [106]. Under this hypothesis, in the
modern food environment with abundant food and sedentary
lifestyles, once-adaptive physiologic mechanisms regulating
energy intake and expenditure have gone awry, leading to
overeating and obesity.
Despite the intuitive appeal of this hypothesis, a number
of food preferences and cravings are not in accord with its
predictions. For example, one of the most common modern
cravings involves a food that ancient hominids never knew
and which fulfills no nutritional requirement: chocolate [102].
The hypothesis that environmental mismatch explains
diseases caused by diet has also been criticized by others
as overly simplistic [86].
Nutrient deprivation is not sufficient to explain
unhealthy eating
A similar hypothesis proposes that cravings result from
nutrient shortage [84]. For instance, fruit flies seek out specific
nutrients after deprivation [107]. However, this hypothesis
does not explain many findings regarding cravings in humans.
Food cravings strike even in times of plenty [108, 109], and
often foods that would satisfy a supposed nutrient shortage
are not the ones that are craved [110]. Furthermore, fasting
reduces cravings [111–113] rather than increasing them, as
would be expected from the nutrient shortage hypothesis. The
same pattern holds for cravings of non-food items such as clay
and earth [114]. Young and colleagues subjected geophagy
(earth-eating) to a systematic review and concluded that
human geophagy is not driven by nutrient scarcity [114].
Conclusions
Modern biology suggests that our bodies are composed of a
diversity of organisms competing for nutritional resources.
Evolutionary conflict between the host and microbiota may
lead to cravings and cognitive conflict with regard to food
choice. Exerting self-control over eating choices may be partly
a matter of suppressing microbial signals that originate in the
gut. Acquired tastes may be due to the acquisition of microbes
that benefit from those foods. Our review suggests that one
way to change eating behavior is by intervening in our
microbiota.
It is encouraging that the microbiota can be changed by
many interventions, hence facilitating translation to the clinic
and public health efforts. Microbiota community structure
changes drastically within 24 hours of changing diet [14, 115]
or administration of antibiotics [116]. Fecal transplants have
shown efficacy in treating a variety of diseases [117]. The best
approaches to managing our microbiota are still open
questions. Many studies of the effects of gut microbes on
health have focused on identifying individual taxa that are
responsible for human diseases, an approach that has been
largely unsuccessful in generating predictive hypotheses.
Studies have identified conflicting different groups of
microbes associated with various diseases, including obesi-
ty [118, 119]. In other domains, it has proven useful to shift the
level of analysis from properties of the individual to properties
of the population, e.g. diversity [120]. Until we have a better
understanding of the contributions and interactions between
individual microbial taxa, it may be more effective to focus
interventions on increasing microbial diversity in the gut.
Competition between genomes is likely to produce a
variety of conflicts, and we propose that one important area,
impacting human health, is in host eating behavior and
nutrient acquisition. Genetic conflict between host and
microbiota selecting for microbes that manipulate host
eating behavior adds a new dimension to current view-
points, e.g. host-microbiota mutualism [11], that can explain
mechanisms involved in obesity and related diseases.
Acknowledgements
The authors thank A. Boddy, A. Caulin, R. Datta, and M.
Fischbach as well as A. Moore and the anonymous reviewers
for helpful feedback, suggestions, and discussions. This work
was supported in part by the Wissenschaftskolleg zu Berlin
(Institute for Advanced Study), a Research Scholar Grant
#117209-RSG-09-163-01-CNE from the American Cancer Socie-
ty, the Bonnie J. Addario Lung Cancer Foundation, and NIH
grants F32 CA132450, P01 CA91955, R01 CA149566, R01
CA170595, and R01 CA140657.
The authors have declared no conflict of interest.
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With the advancement of microbiome research, the requirement to consider the intestinal microbiome as the “last organ” of an animal emerged. Through the production of metabolites and/or the stimulation of the host’s hormone and neurotransmitter synthesis, the gut microbiota can potentially affect the host’s eating behavior both long and short-term. Based on current evidence, the major mediators appear to be short-chain fatty acids (SCFA), peptide hormones such as peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), as well as the amino acid tryptophan with the associated neurotransmitter serotonin, dopamine and γ-Aminobutyrate (GABA). The influence appears to extend into central neuronal networks and the expression of taste receptors. An interconnection of metabolic processes with mechanisms of taste sensation suggests that the gut microbiota may even influence the sensations of their host. This review provides a summary of the current status of microbiome research in farm animals with respect to general appetite regulation and microbiota-related observations made on the influence on feed intake. This is briefly contrasted with the existing findings from research with rodent models in order to identify future research needs. Increasing our understanding of appetite regulation could improve the management of feed intake, feed frustration and anorexia related to unhealthy conditions in farm animals.
... Gut microbes are under a constant selective force, naturally and artificially, to manipulate the hosts' behaviors to increase or decrease their fitness to surrounding environments [26]. Microbiota exhibit a driving role in ASD [27]. ...
... A decreased abundance of Lactobacillus and increased stress reactivity have been found in the infant rhesus monkeys experienced maternal separation [31]. Concerning the connection between gastrointestinal symptoms and neurodevelopmental disorders, including ASD, ADHD, and epilepsy [32][33][34][35], prenatal stresses (e.g., maternal malnutrition, drug administration, and disease) may perturb maternal-fetal microbe transmission and alter the gut microbiota composition and diversity in the progeny [36,37], by which it regulates the hosts' eating behaviors [26] and the nutrient supply for the development and activity of the MGB axis. Moreover, during postnatal life, endogenous influences and exogenous stimulations, including eating habits, disease, and medicinal history, alter the gut microbiome, the activity of the MGB axis and neuroendocrine system ( Figure 2) and consequentially affect the mental health and social decision making of individuals [38]. ...
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Nutrients and xenobiotics cross the blood–placenta barrier, potentially depositing in the fetal brain. The prenatal exposure affects the neuroendocrine and microbial development. The mechanism underlying maternal risk factors reprograming the microbiota–gut–brain axis with long-term effects on psychosocial behaviors in offspring is not clear. In humans, it is not possible to assess the nutrient or xenobiotic deposition in the fetal brain and gastrointestinal system for ethical reasons. Moreover, the maternal–fetal microbe transfer during gestation, natural labor, and breast-feeding constitutes the initial gut microbiome in the progeny, which is inevitable in the most widely utilized rodent models. The social predisposition in precocial birds, including chickens, provides the possibility to test behavioral responses shortly after being hatched. Hence, chickens are advantageous in investigating the ontogenetic origin of behaviors. Chicken embryos are suitable for deposition assessment and mechanistic study due to the accessibility, self-contained development, uniform genetic background, robust microbiota, and easy in vivo experimental manipulation compared to humans and rodents. Therefore, chicken embryos can be used as an alternative to the rodent models in assessing the fetal exposure effect on neurogenesis and investigating the mechanism underlying the ontogenetic origin of neuropsychiatric disorders.
... This perspective has failed to yield interventions that reliably lead to sustained weight gain and psychological recovery [27]. Attempts to describe and understand AN through evolutionary theories such as the suppression of reproduction or sexual competition theories, as well as the famine hypothesis [48,49], have also failed to provide a comprehensive understanding of AN development. ...
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Anorexia nervosa (AN) is a disabling, costly, and potentially deadly illness. Treatment failure and relapse after treatment are common. Several studies have indicated the involvement of the gut microbiota–brain (GMB) axis. This narrative review hypothesizes that AN is driven by malnutrition-induced alterations in the GMB axis in susceptible individuals. According to this hypothesis, initial weight loss can voluntarily occur through dieting or be caused by somatic or psychiatric diseases. Malnutrition-induced alterations in gut microbiota may increase the sensitivity to anxiety-inducing gastrointestinal hormones released during meals, one of which is cholecystokinin (CCK). The experimental injection of a high dose of its CCK-4 fragment in healthy individuals induces panic attacks, probably via the stimulation of CCK receptors in the brain. Such meal-related anxiety attacks may take part in developing the clinical picture of AN. Malnutrition may also cause increased effects from appetite-reducing hormones that also seem to have roles in AN development and maintenance. The scientific background, including clinical, microbiological, and biochemical factors, of AN is discussed. A novel model for AN development and maintenance in accordance with this hypothesis is presented. Suggestions for future research are also provided.
... The interaction between different types of intestinal flora can prevent certain strains of gut bacteria from reaching the level of manipulation of the host, thus further preventing the invasion of pathogenic bacteria. In our research, the diversity and composition of the microbiota in the HFD group have changed, with the Firmicutes increased and the Bacteroides and Proteobacteria decreased, which is similar to the situation of gut microbiota in obesity (Alcock et al., 2014). The increased abundance of Firmicutes is associated with the accumulation of lipid droplets, promoting fatty acid uptake at the onset of obesity and atherosclerosis (He and You, 2020). ...
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... Whether gut microbes influence fat loss via metabolism, or e.g. via eating behaviour [92], is an intriguing question. SCFAs, neurotransmitters and peptides produced by gut microbes are all hypothesized to regulate appetite [93]. ...
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Chapter
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Chapter
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Amino acid abnormalities have been suggested to be a key pathophysiological mechanism in schizophrenia (SZ). Recently, gut microbes were found to be critically involved in mental and metabolic diseases. However, the relationship between serum amino acid levels and gut microbes in SZ is rarely studied. Here, we analyzed serum amino acid levels in 76 untreated SZ patients and 79 healthy controls (HC). Serum levels of 10 amino acids were significantly altered in patients with SZ. We further classified the cut-off values for serum arginine, leucine, glutamine, and methionine levels to distinguish SZ patients from controls. These classifiers were shown to be effective in another validation cohort (49 SZ and 48 HC). The correlation between serum amino acids and clinical symptoms and cognitive functions was also analyzed. Arginine, leucine, glutamine, and methionine levels were significantly correlated with clinical symptoms and cognitive impairments in SZ patients. By metagenome shotgun sequencing of fecal samples, we found that patients with SZ with a low level of serum amino acids have higher richness and evenness of the gut microbiota. At the genus level, the abundances of Mitsuokella and Oscillibacter are significantly abnormal. At the mOTU level, 15 mOTUs in the low-level SZ group were significantly different from the HC group. In addition, Mitsuokella multacida was correlated with glutamine and methionine, respectively. Our research revealed that alterations in serum amino acid levels are critically related to changes in gut microbiota composition in SZ patients. These findings may shed light on new strategies for the diagnosis and treatment of SZ.
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The determinants of food choices made by hunter-gatherers have long been a topic of speculation and controversy. In this paper, we analyze the foraging behavior of the Aché of eastern Paraguay and conclude that it is consistent with predictions derived from optimal foraging models. We infer that these very general models will continue to prove useful in explaining variation in hunter-gatherer subsistence patterns throughout time and space. [Aché, hunter-gatherers, optimal foraging theory, South America, tropical forest]
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The concept that the gut microbiota serves as a virtual endocrine organ arises from a number of important observations. Evidence for a direct role arises from its metabolic capacity to produce and regulate multiple compounds that reach the circulation and act to influence the function of distal organs and systems. For example, metabolism of carbohydrates results in the production of short chain fatty acids (SCFAs), such as butyrate and propionate, which provide an important source of nutrients as well as regulatory control of the host digestive system. This influence over host metabolism is also seen in the ability of the prebiotic inulin is to influence production of relevant hormones such as glucagon like peptide-1 (GLP-1), peptide YY (PYY), ghrelin and leptin. Moreover, the probiotic L. rhamnosus PL60, which produces conjugated linoleic acid, has been shown to reduce body weight gain and white adipose tissue without effects on food intake. Manipulating the microbial composition of the gastrointestinal tract modulates plasma concentrations of tryptophan, an essential amino acid and precursor to serotonin, a key neurotransmitter within both the enteric and central nervous systems. Indirectly and through as yet unknown mechanisms, the gut microbiota exerts control over the hypothalamic-pituitary-adrenal axis (HPA). This is clear from studies on animals raised in a germ-free environment, who show exaggerated responses to psychological stress, which normalises following monocolonisation by certain bacterial species including B. infantis. It is tempting to speculate that therapeutic targeting of the gut microbiota may be useful in treating stress-related disorders and metabolic diseases.
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The development of the Emotional Eating Scale (EES) is described. The factor solution replicated the scale's construction, revealing Anger/Frustration, Anxiety, and Depression subscales. All three subscales correlated highly with measures of binge eating, providing evidence of construct validity. None of the EES subscales correlated significantly with general measures of psychopathology. With few exceptions, changes in EES subscales correlated with treatment‐related changes in binge eating. In support of the measure's discriminant efficiency, when compared with obese binge eaters, subscale scores of a sample of anxiety‐disordered patients were significantly lower. Lack of correlation between a measure of cognitive restraint and EES subscales suggests that emotional eating may precipitate binge episodes among the obese independent of the level of restraint. The 25‐item scale is presented in an Appendix (Arnow, B., Kenardy, J., & Agras, W.S.: International Journal of Eating Disorders, 17, 00‐00, 1995). © 1995 by John Wiley & Sons, Inc.
Book
We have built a world that no longer fits our bodies. Our genes - selected through our evolution - and the many processes by which our development is tuned within the womb, limit our capacity to adapt to the modern urban lifestyle. There is a mismatch. We are seeing the impact of this mismatch in the explosion of diabetes, heart disease and obesity. But it also has consequences in earlier puberty and old age. Bringing together the latest scientific research in evolutionary biology, development, medicine, anthropology and ecology, Peter Gluckman and Mark Hanson, argue that many of our problems as modern-day humans can be understood in terms of this fundamental and growing mismatch. It is an insight that we ignore at our peril.
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The prevalence of obesity has increased substantially over the past 30 years. We performed a quantitative analysis of the nature and extent of the person-to-person spread of obesity as a possible factor contributing to the obesity epidemic. We evaluated a densely interconnected social network of 12,067 people assessed repeatedly from 1971 to 2003 as part of the Framingham Heart Study. The body-mass index was available for all subjects. We used longitudinal statistical models to examine whether weight gain in one person was associated with weight gain in his or her friends, siblings, spouse, and neighbors. Discernible clusters of obese persons (body-mass index [the weight in kilograms divided by the square of the height in meters], > or =30) were present in the network at all time points, and the clusters extended to three degrees of separation. These clusters did not appear to be solely attributable to the selective formation of social ties among obese persons. A person's chances of becoming obese increased by 57% (95% confidence interval [CI], 6 to 123) if he or she had a friend who became obese in a given interval. Among pairs of adult siblings, if one sibling became obese, the chance that the other would become obese increased by 40% (95% CI, 21 to 60). If one spouse became obese, the likelihood that the other spouse would become obese increased by 37% (95% CI, 7 to 73). These effects were not seen among neighbors in the immediate geographic location. Persons of the same sex had relatively greater influence on each other than those of the opposite sex. The spread of smoking cessation did not account for the spread of obesity in the network. Network phenomena appear to be relevant to the biologic and behavioral trait of obesity, and obesity appears to spread through social ties. These findings have implications for clinical and public health interventions.
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The intestinal microbiota consists of a vast bacterial community that resides primarily in the lower gut and lives in a symbiotic relationship with the host. A bidirectional neurohumoral communication system, known as the gut-brain axis, integrates the host gut and brain activities. Here, we describe the recent advances in our understanding of how the intestinal microbiota communicates with the brain via this axis to influence brain development and behaviour. We also review how this extended communication system might influence a broad spectrum of diseases, including irritable bowel syndrome, psychiatric disorders and demyelinating conditions such as multiple sclerosis.