Figures
The relationship between the microbiota-gut-brain axis and social behavior. The bidirectional pathway between the gut microbiota and the central nervous system, the microbiota-gut-brain axis, influences various complex aspects of social behavior across the animal kingdom. Some animals have evolved their own unique relationship with their gut microbiota that may assist them in interacting with conspecifics. The relationship between the gut microbiota and social behavior may help to explain social deficits observed in conditions such as autism spectrum disorders (ASDs) and could potentially lead to the development of new therapies for such conditions.
Fig. 1 Social behavior is governed by multiple interconnected limbic brain regions. Preclinical and clinical imaging studies have helped delineate the neurocircuitry underlying social behavior in humans and other mammals. Social interaction is governed by several subcortical forebrain structures such as the prefrontal cortex (PFC), anterior cingulate cortex (ACC), amygdala (AMG), hippocampus (Hipp), and hypothalamus (paraventricular nucleus, PVN), which form part of an integral interconnected network to facilitate this complex behavior. Damage or dysfunction to any one of these brain regions can give rise to perturbations in social behavior. Indeed, the neurobiology of regions such as the AMG and PFC have been shown to be altered in disorders of the social brain such as autism spectrum disorders (ASDs).
Fig. 2 Biological pathways underlying the regulation of social behavior by gut microbiota. There are numerous pathways through which the gut microbiota may influence behavioral processes such as sociability. Although additional unidentified metabolites and pathways connecting gut microbiota and the brain may exist, much focus has been on the bidirectional communication mediated via neural immune and metabolic routes. Bacterial fermentation and metabolism in the gastrointestinal tract lead to the production of metabolites such as neurotransmitters and short-chain fatty acids (SCFAs). SCFAs may be indirectly capable of influencing brain physiology and behavior through binding to and activating free fatty acid receptors (FFARs) expressed on the vagus nerve. Additionally, their ability to inhibit histone deacetylases locally within the gastrointestinal system may indirectly influence signaling of various mediators to the brain. Vagotomy studies have provided empirical evidence that the vagus nerve is an additional route through which the microbiota can communicate with the brain. The association between the gut microbiota and the immune system is another highly explored pathway through which commensal bacteria can exert their influence on brain physiology and behavior. Bacterial peptidoglycan expressed on the cell wall of Gram-negative and Gram-positive bacteria is capable of influencing the development of social behavior through the activation of specific pathogen recognition receptors, such as PGLYRP2, expressed in the brain (central nervous system inset). The microbiota can also influence social interaction through the excretion of metabolites that act as olfactory pheromones. Trimethylamine secreted in mouse urine can facilitate social cohesion of mouse conspecifics through the activation of olfactory receptors (olfactory system inset). Through these various pathways, the gut microbiota has been shown to modulate multiple central physiological processes such as neuroinflammation, serotonin turnover, myelination, and the secretion of the prosocial hormone oxytocin, thereby providing mechanistic insights into how gut bacteria influence social behavior. After exposure to a stressor, adrenocorticotropic hormone (ACTH) is released from the anterior pituitary gland (pituitary gland inset) and stimulates the release of stress hormone glucocorticoids (cortisol in humans, bears, ruminants, fish, and some rodents; corticosterone in rats, mice, birds, and reptiles). Glucocorticoids influence metabolism and mediate immune activation, among other systemwide effects. Exposure of commensal bacteria to glucocorticoids has been shown to decrease their relative abundance. Moreover, under conditions of chronic stress, increased release of glucocorticoids is associated with a reduction in gut microbiota diversity and richness.
Fig. 3 The social brain is influenced by multiple biological and environmental factors. Social behavior is governed by multiple interconnected brain regions such as the hypothalamus, amygdala, cingulate cortex, and prefrontal cortex that are influenced by multiple extrinsic and intrinsic factors such as sex, genetic and epigenetic mechanisms, and the environment. Each of these factors may influence social behavior directly. However, they may also act in combination with one another to shape such behaviors. For instance, host genetics can influence the composition of the host gastrointestinal microbiota, thereby influencing the relative contribution of enteric bacteria toward social behavior. Moreover, extrinsic factors such as diet, psychotropic medication and environment can also affect the composition of the microbiota to indirectly modify behavior (17, 116, 132, 139, 148, 149). PFC, prefrontal cortex; vmPFC, ventromedial prefrontal cortex; ACC, anterior cingulate cortex; AMG, amygdala; PVN, paraventricular nucleus of the hypothalamus.
Tables
- Table 1 The relationship between microbiota and social behavior across the animal kingdom.
Examining the microbiota composition of social and nonsocial species reveals that the same bacterial phyla are present in many animal species. However, different species use their associated microbiota in various ways to facilitate various forms of social interaction. For each animal, gut bacterial phyla are ranked in terms of the most to least abundant. For each study cited, the microbiota analysis was performed on fecal samples with the exception of the termite and honey bee studies, in which proctodeal segments were analyzed.
Species Behavior Ranking of dominant
phyla in the microbiotaRelationship between
social behavior and microbiotaReference Honey bee
(Apis
mellifera)This eusocial invertebrate species
exists within colonies consisting
of a queen bee along with
worker and soldier bees.
Worker and soldier bees interact
in a cooperative manner to
ensure maintenance and
survival of the colony.1. Firmicutes
2. Actinobacteria
3. ProteobacteriaSocial interaction facilitates
horizontal transmission of
microbiota that confers
immune resistance
against pathogens.(51) Desert locust
(Schistocerca
gregaria)Desert locusts can shift from
solitary to gregarious behavior
depending on the environment
and other factors. During the
gregarious phase, locusts exist
in large swarms, which aids in
protecting them from predators.Proteobacteria Volatile fatty acids produced
by the proteobacterium
Pantoea agglomerans
facilitate social cohesion
of locust swarms.(66, 140) Firebrat
(Thermobia
domestica)Although they lack any known form
of long-distance communication,
firebrats gather around
conspecific feces and former
firebrat shelters. Moreover, these
insects are capable of locating
mates in their environment,
presumably through
odor detection.1. Proteobacteria
2. FirmicutesThe bacterium Enterobacter
cloacae present in the feces
of firebrats mediates
aggregation of conspecifics.
The aggregation leads to
the horizontal transmission
of microbiota.(67, 68) Termite
(Mastotermes
darwiniensis)Termites are an eusocial insect
species existing within a colony
of multiple queens along with
soldier and worker termites.
Worker termites undertake
the most work in the colony,
cooperating in food storage
as well as brood and
nest maintenance.1. Spirochaetes
2. Bacteroidetes
3. FirmicutesSocial interaction facilitates
the horizontal transmission
of microbiota that aids in
food digestion.(62, 63) Zebrafish
(Danio rerio)This species of fish aggregates into
large groups, known as shoals.
They can also exhibit aggression
toward conspecifics, which
typically arises as a result of
territoriality. These fish can
exhibit anxiety-like behavior when
under threat from other animals.1. Fusobacteria
2. Proteobacteria
3. FirmicutesModulation of the microbiota
has been shown to influence
shoaling behavior of zebrafish.
Antibiotic treatment reduces
shoaling behavior. Conversely,
probiotic supplementation
can increase shoaling behavior.(136, 141) Zebra finch
(Taeniopygia
guttata)The zebra finch is a social species
that typically forms monogamous
pair bonds during mating season.
These birds tend to forage in
groups for food rather than
individually.1. Firmicutes
2. ProteobacteriaZebra finches have been shown
to transmit bacteria through
allogrooming that results
in colonization of the
gastrointestinal tract.(142, 143) Mouse (Mus
musculus)Rodents such as mice are social
animals that prefer to exist
within groups. Mice react
aversely to social isolation,
which is considered a stressor on
the animal. Mice participate
in cooperative behaviors such
as grooming and play.1. Firmicutes
2. Bacteroidetes
3. Proteobacteria
4. Actinobacteria1. The microbial metabolite
trimethylamine is excreted
in the urine of mice and acts
as a chemoattractant toward
mouse conspecifics and a
repellent of predators
such as rats.
2. Mouse models of autism
display microbiota alterations
in addition to deficits in
social behavior.
3. Germ-free and antibiotic
-treated mice display
deficits in social behavior
that can be partly restored
after reconstitution
with microbiota.(15, 17, 109, 130, 134) Hyena (Hyaena
hyaena)Hyenas live in large social
communities called clans.
Females are typically the
dominant sex in these
communities and can dominate
males and subordinate females.
Social cognition is quite
developed in hyenas, with
animals capable of recognizing
individual conspecifics and
even distant relatives.1. Firmicutes
2. Actinobacteria
3. Bacteroidetes
4. FusobacteriaFermentative bacteria in the
scent glands produce volatile
fatty acids that facilitate
specific odors for social
recognition among hyena
conspecifics.(14) Meerkats
(Suricata
suricatta)Meerkats are social animals
existing within groups of up to
30 conspecifics. They engage in
cooperative behaviors such as
grooming and teaching of young
to forage for food; females
protect offspring of the
dominant members of the group.1. Firmicutes
2. Bacteroidetes
3. Proteobacteria
4. Actinobacteria
5. FusobacteriaThe anal gland of the meerkat
contains volatile chemicals
that correlate with the
presence of various bacterial
species. Genes related to
lipid metabolism are expressed
at higher amounts in the anal
pouch of dominant males
compared to subordinates,
which may enhance
communication.(71) Koala
(Phascolarctos
cinereus)Koalas are typically asocial, with
females and males existing in
separate territories until
breeding season. Although koalas
tend to avoid aggressive
interactions, antagonistic
behaviors can occur, especially
when one male occupies the
territory of another male.1. Bacteroidetes
2. FirmicutesAt weaning, the mother produces
a liquid form of feces, called
pap, which the offspring (joey)
ingests. This pap contains a
microbiota that aids in the
digestion of eucalyptus, the
primary food of the koala.(144) Gorilla (Gorilla
gorilla)This great ape species exists within
communities typically comprising
an alpha male, several females,
and offspring. Multiple-male
troops also exist. Gorillas engage
in social behaviors such as
grooming and playing.1. Firmicutes
2. Proteobacteria
3. BacteroidetesLess social gorillas have a
reduced risk of contracting
the Ebola-Zaire virus. The
composition of the gorilla gut
microbiota can be influenced
by interactions with gorilla
conspecifics and sympatry
with other ape species.(61, 145) Chimpanzee (Pan
troglodytes)Primates exhibit highly social
behavior within large communities.
Chimpanzees participate in
cooperative behaviors such as
grooming and play.1. Proteobacteria
2. Firmicutes
3. BacteroidetesSocial interaction among
conspecifics results in the
horizontal transmission
of microbiota, resulting in
the preservation of microbial
diversity across generations.(61, 146) Humans (Homo
sapiens)Humans are highly social animals
existing within large and
complex social communities.
Social interaction in humans
consists of a wide variety of
intricate languages, values,
rituals, and cultures. Humans
interact on a daily basis
to facilitate work, education,
and rearing of offspring.1. Firmicutes
2. Bacteroidetes
3. Actinobacteria
4. Proteobacteria1. Humans occupying the same
environment share similar
gut microbiota characteristics
relative to those who do not.
2. Kissing can facilitate the
horizontal transmission of
microbiota from one
individual to another.
3. Alterations to the composition
of the gut microbiota have
been documented in
individuals with deficits in
sociability such as autism
spectrum disorder.(53, 100, 147) - Table 2 Clinical and preclinical studies of microbiota-based interventions for the treatment of social behavior deficits.
ASD, autism spectrum disorder; ATEC, Autism Treatment Evaluation Checklist; CFU, colony-forming units; PBS, phosphate-buffered saline; FOS, fructo-oligosaccharide; GABA, γ-aminobutyric acid; GOS, galacto-oligosaccharide; poly(I:C), polyinosinic:polycytidylic acid; Shank3, SH3 and multiple ankyrin repeat domains 3.
Subjects Intervention Behavioral outcomes Biological outcomes Reference Clinical studies 17 ASD subjects (4 to 16 years of age) Daily oral Lactobacillus
plantarum WCFS1 (4 ×
1010 CFU per capsule)
administration for
12 weeksAnxiety and antisocial measures
improved after probiotic
supplementation, as assessed by
the standardized developmental
behavioral checklistIncreased relative abundance of
Lactobacillus species and a
decrease in Clostridium cluster
XIVa in fecal samples(113) 30 ASD subjects (19 boys and 11 girls;
5 to 9 years of age); 30 age- and
gender-matched controls from
ASD participants’ familiesDaily oral L. rhamnosus,
L. acidophilus, and
Bifidobacterium longum
(500 × 106 CFU
per sachet) for 3 monthsSociability, speech and
language communication,
and sensory awareness
improved after treatment,
as assessed by the
ATEC checklistProbiotic treatment improved
gastrointestinal symptoms
(abdominal pain, flatulence,
constipation, etc.)(114) 18 ASD subjects (7 to 17 years of age);
20 age- and gender-matched
neurotypical controlsOral dose of standard
human microbiota
cocktail (2.5 × 1012 CFU
for 2 days followed by
2.5 × 109 CFU
maintenance dose
for 8 weeks)Sociability, communication,
and hyperactivity scores
improved after treatment, as
assessed by the Childhood
Autism Rating Scale and
Parent Global Impressions
III scaleGastrointestinal symptoms (i.e.,
constipation, abdominal pain,
etc.) improved by 80%
according to the Gastrointestinal
Symptom Rating Scale(115) 26 ASD subjects (4 to 11 years of age) Oral dose of 1.8 g of
Bimuno-GOS (B-GOS) or
maltodextrin for
6 weeks combined with a
gluten and casein
exclusion dietAntisocial behavior
improved after treatment, as
assessed by the ATEC
checklist and the Autism
Spectrum QuotientExclusionary diet improved
gastrointestinal symptoms (i.e.,
abdominal pain); B-GOS
consumption increased the
relative abundance of B. longum
in fecal samples and reduced
urinary arachidonic acid(128) 13 male ASD subjects (10 to
12 years of age)Oral dose of 1.5 g of
omega-3 fatty acids
(eicosapentanoic acid and
docosahexanoic acid) per
day for 6 weeksHyperactive behavior
improved after treatment, as
assessed by the Aberrant
Behavior ChecklistNo measurements included in study (124) 24 ASD subjects (3 to 8 years of age) Oral dose of 1.3 g of
omega-3 fatty acids
(eicosapentanoic acid and
docosahexanoic acid) for
12 weeksNonsignificant improvement
in hyperactive behavior,
as assessed by the
Aberrant Behavior
ChecklistDecreases in percentages of
monosaturated and omega-9
fatty acids in blood plasma
after treatment(125) Preclinical studies Male C57BL/6N mice from mothers
administered either saline vehicle or
poly(I:C) 20 mg/kg (induces in utero
inflammation; environmental model of
ASD) via the intraperitoneal cavity on
gestational day 12.5; aged 6 weeks
at the beginning of behavioral testing1 × 1010 CFU of
Bacteroides fragilis
NCTC 9343 or vehicle
was administered in
sugar-free applesauce
over standard rodent
chowImprovement in anxiety-
like and stereotyped
behaviors after probiotic
treatment; treatment also
improved ultrasonic
vocalizations; sociability
was unaffected by treatmentTreatment with B. fragilis
ameliorated heightened
intestinal permeability,
intestinal inflammation,
and alterations to the
intestinal microbiota(109) Male C57BL6/J mice from mothers fed a
high-fat diet (60% fat consistency;
environmental model of ASD) before
and during pregnancy until weaning of
offspring were used for experimentation;
mice were aged 7 to 12 weeks at the
beginning of behavioral testing1 × 108 CFU of L. reuteri
MM4-1A or a PBS
vehicle was administered
in drinking water and
changed dailyTreatment with L. reuteri
improved deficits in social behavior; anxiety or stereotyped behaviors were unaffected by treatmentTreatment with L. reuteri
increased hypothalamic
oxytocin expression(17) Male C57BL/6J mice aged 7 weeks at the
beginning of behavioral testingFOS and GOS were
administered separately
or in combination in
drinking water at a dose
of 0.3 to 0.4 g per mouse
per dayA combination of GOS and
FOS reversed chronic social
stress–induced deficits in
social interaction, anxiety,
and cognitionA combination of GOS
and FOS protected gut
microbiota composition
against exposure to
chronic stress; the
combination of both
prebiotics reduced
circulating corticosterone
and attenuated stress-
induced pro-inflammatory
cytokine production(88) Male and female Shank3 (ASD risk gene;
genetic model of ASD) knockout and
wild-type mice aged 8 to 11 weeks at
the beginning of behavioral testing1 × 109 CFU of L. reuteri
MM4-1A or a PBS
vehicle was administered
via oral gavage twice a
week for 3 weeksTreatment with L. reuteri
improved deficits in social
behavior in male but not female Shank3 knockout
mice; L. reuteri also
reduced stereotyped
behaviorsTreatment with L. reuteri
increased the expression
of GABAA receptor subunits
in the prefrontal cortex and
hippocampus in both male
and female Shank3 mice;
oxytocin expression in the
hypothalamus was also
increased after treatment(107) Male Shank3 knockout (genetic model
of ASD), oxytocin receptor knockout,
germ-free, BTBR, and C57BL/6J mice
exposed to in utero valproic acid
(teratogenic drug; environmental
model of ASD) on gestational day 12.51 × 108 CFU of L. reuteri
MM4-1A or a PBS
vehicle was administered
in drinking water and
changed dailyTreatment with L. reuteri
improved deficits in social
behavior in all animal
models of ASD testedTreatment with L. reuteri
increased hypothalamic
expression of oxytocin
in all animal models tested(108)
