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Microbiota and the social brain

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Science  01 Nov 2019:
Vol. 366, Issue 6465, eaar2016
DOI: 10.1126/science.aar2016

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.

    SpeciesBehaviorRanking of dominant
    phyla in the microbiota
    Relationship between
    social behavior and microbiota
    Reference
    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. Proteobacteria
    Social 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.
    ProteobacteriaVolatile 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. Firmicutes
    The 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. Firmicutes
    Social 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. Firmicutes
    Modulation 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. Proteobacteria
    Zebra 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. Actinobacteria
    1. 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. Fusobacteria
    Fermentative 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. Fusobacteria
    The 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. Firmicutes
    At 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. Bacteroidetes
    Less 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. Bacteroidetes
    Social 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. Proteobacteria
    1. 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.

    SubjectsInterventionBehavioral outcomesBiological outcomesReference
    Clinical studies
    17 ASD subjects (4 to 16 years of age)Daily oral Lactobacillus
    plantarum WCFS1 (4 ×
    1010 CFU per capsule)
    administration for
    12 weeks
    Anxiety and antisocial measures
    improved after probiotic
    supplementation, as assessed by
    the standardized developmental
    behavioral checklist
    Increased 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’ families
    Daily oral L. rhamnosus,
    L. acidophilus, and
    Bifidobacterium longum
    (500 × 106 CFU
    per sachet) for 3 months
    Sociability, speech and
    language communication,
    and sensory awareness
    improved after treatment,
    as assessed by the
    ATEC checklist
    Probiotic 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 controls
    Oral 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 scale
    Gastrointestinal 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 diet
    Antisocial behavior
    improved after treatment, as
    assessed by the ATEC
    checklist and the Autism
    Spectrum Quotient
    Exclusionary 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 weeks
    Hyperactive behavior
    improved after treatment, as
    assessed by the Aberrant
    Behavior Checklist
    No 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 weeks
    Nonsignificant improvement
    in hyperactive behavior,
    as assessed by the
    Aberrant Behavior
    Checklist
    Decreases 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 testing
    1 × 1010 CFU of
    Bacteroides fragilis
    NCTC 9343 or vehicle
    was administered in
    sugar-free applesauce
    over standard rodent
    chow
    Improvement in anxiety-
    like and stereotyped
    behaviors after probiotic
    treatment; treatment also
    improved ultrasonic
    vocalizations; sociability
    was unaffected by treatment
    Treatment 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 testing
    1 × 108 CFU of L. reuteri
    MM4-1A or a PBS
    vehicle was administered
    in drinking water and
    changed daily
    Treatment with L. reuteri
    improved deficits in social behavior; anxiety or stereotyped behaviors were unaffected by treatment
    Treatment with L. reuteri
    increased hypothalamic
    oxytocin expression
    (17)
    Male C57BL/6J mice aged 7 weeks at the
    beginning of behavioral testing
    FOS and GOS were
    administered separately
    or in combination in
    drinking water at a dose
    of 0.3 to 0.4 g per mouse
    per day
    A combination of GOS and
    FOS reversed chronic social
    stress–induced deficits in
    social interaction, anxiety,
    and cognition
    A 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 testing
    1 × 109 CFU of L. reuteri
    MM4-1A or a PBS
    vehicle was administered
    via oral gavage twice a
    week for 3 weeks
    Treatment with L. reuteri
    improved deficits in social
    behavior in male but not female Shank3 knockout
    mice; L. reuteri also
    reduced stereotyped
    behaviors
    Treatment 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 12.5
    1 × 108 CFU of L. reuteri
    MM4-1A or a PBS
    vehicle was administered
    in drinking water and
    changed daily
    Treatment with L. reuteri
    improved deficits in social
    behavior in all animal
    models of ASD tested
    Treatment with L. reuteri
    increased hypothalamic
    expression of oxytocin
    in all animal models tested
    (108)

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