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Cited by 135Gut microbiota and healthNeuroendocrine regulation and behaviorTryptophan and brain disorders

The role of the microbiome in the neurobiology of social behaviour

Open access
Sarkar, Amar, Harty, Siobhán, Johnson, Katerina V.‐A., Moeller, Andrew H., Carmody, Rachel N., Lehto, Soili M., Erdman, Susan E., Dunbar, Robin I. M. +1 more·2020·Biological Reviews
DOI 10.1111/brv.12603PMC PMC10040264
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Abstract

Microbes colonise all multicellular life, and the gut microbiome has been shown to influence a range of host physiological and behavioural phenotypes. One of the most intriguing and least understood of these influences lies in the domain of the microbiome's interactions with host social behaviour, with new evidence revealing that the gut microbiome makes important contributions to animal sociality. However, little is known about the biological processes through which the microbiome might influence host social behaviour. Here, we synthesise evidence of the gut microbiome's interactions with various aspects of host sociality, including sociability, social cognition, social stress, and autism. We discuss evidence of microbial associations with the most likely physiological mediators of animal social interaction. These include the structure and function of regions of the ‘social' brain (the amygdala, the prefrontal cortex, and the hippocampus) and the regulation of ‘social’ signalling molecules (glucocorticoids including corticosterone and cortisol, sex hormones including testosterone, oestrogens, and progestogens, neuropeptide hormones such as oxytocin and arginine vasopressin, and monoamine neurotransmitters such as serotonin and dopamine). We also discuss microbiome‐associated host genetic and epigenetic processes relevant to social behaviour. We then review research on microbial interactions with olfaction in insects and mammals, which contribute to social signalling and communication. Following these discussions, we examine evidence of microbial associations with emotion and social behaviour in humans, focussing on psychobiotic studies, microbe–depression correlations, early human development, autism, and issues of statistical power, replication, and causality. We analyse how the putative physiological mediators of the microbiome–sociality connection may be investigated, and discuss issues relating to the interpretation of results. We also suggest that other candidate molecules should be studied, insofar as they exert effects on social behaviour and are known to interact with the microbiome. Finally, we consider different models of the sequence of microbial effects on host physiological development, and how these may contribute to host social behaviour.

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Written from the paper’s full text.

TL;DR

This review synthesizes evidence that the gut microbiome influences animal social behaviour through social brain regions, social signalling molecules, gene/epigenetic processes, and olfactory signals. It concludes that direct causal microbiome → physiology → social behaviour pathways remain largely unidentified, especially in humans, where findings are mostly correlational and underpowered.

Key findings

  • The microbiome affects regions of the “social” brain: germ-free mice show altered amygdala volume and dendritic morphology, prefrontal myelination abnormalities, and hippocampal changes including reduced BDNF and altered neurogenesis; probiotics can alter GABA receptor mRNA in amygdala and prefrontal cortex.
  • The microbiome regulates social signalling molecules including glucocorticoids, sex steroids, oxytocin, vasopressin, serotonin, and dopamine. For example, germ-free rodents show elevated stress corticosterone; male germ-free mice have lower serum testosterone while female germ-free mice show the opposite; *Lactobacillus reuteri* restores oxytocin-expressing neurons and social deficits in autism models, with benefits abolished by vagotomy.
  • Rodent studies provide causal evidence that some aspects of normal sociality require a microbiome: germ-free mice show impaired sociability and social cognition in the three-chamber test, and microbial reconstitution attenuates sociability but not social cognition. In autism models, maternal immune activation can act via segmented filamentous bacteria and interleukin-17a, and *Lactobacillus reuteri* ameliorates social deficits across environmental, genetic, and idiopathic models.
  • Human evidence is promising but preliminary: psychobiotics lower cortisol and negative mood, depression and autism show microbial associations that are inconsistent across studies, and an open-label faecal transplant study in 18 autistic participants reported improved gastrointestinal and behavioural symptoms plus a 1.4-year gain in developmental age, with benefits persisting at 8 weeks and 2 years.

Methods

  • Narrative review and synthesis of laboratory and human evidence; no new primary data are reported.
  • Covers experimental approaches including antibiotics, probiotics, prebiotics, psychobiotics, germ-free models, co-housing, and faecal microbial transplants, drawing on rodent, insect, non-human mammal, and human studies.
  • Discusses putative mediators—social brain regions, social signalling molecules, gene expression/epigenetics, and olfaction—through interpretive synthesis rather than systematic meta-analysis.

Limitations

  • Stated: human microbiome–psychology research is typically underpowered and noisy due to variation in genetics, sex, age, diet, environmental exposures, and medicines; probiotic effects are inconsistent; many neuroimaging associations may be false positives; most human findings are correlational and do not provide direct evidence of causation.
  • Stated: rodent autism models have significant translational barriers, germ-free animals differ physiologically and socially from conventionally colonised animals, and antibiotics/prebiotics can have non-microbial off-target effects.
  • Evident: as a narrative review, no systematic search or quality appraisal is reported; many mechanistic links are adjacent-chain inferences rather than direct tests of microbiome → physiology → social behaviour, and key human trials are small or open-label, including the N = 18 faecal transplant study and the 11-donor autism transplant study with noted donor-clustering concerns.

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Registry

Crossref · 10.1111/brv.12603

Cites

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Claims the paper makes

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  • Premisecitation

    The microbiome affects the development and function of brain regions such as the amygdala, hippocampus, and prefrontal cortex.

    “First, the microbiome affects the development and function of brain regions such as the amygdala, hippocampus, and prefrontal cortex (Sudo et al., 2004; Hoban et al., 2016; Luczynski et al., 2016) that are known to contribute to social cognition and social behaviour.”
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    • Rests on an assumption: The amygdala, hippocampus, and prefrontal cortex contribute to social cognition and social behaviour.
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    The gut microbiome makes important contributions to animal sociality.

    “new evidence revealing that the gut microbiome makes important contributions to animal sociality”
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      “Several investigations in this area are beginning to reveal associations between the microbiome and animal sociality (Hsiao et al., 2013; Desbonnet et al., 2014; Arentsen et al., 2015; Tung et al., 2015; Buffington et al., 2016; Parashar & Udayabanu, 2016; Stilling et al., 2018)”
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    The microbiome is capable of generating or regulating the bioavailability of signalling molecules that influence animal social behaviour, including glucocorticoids, sex hormones, neuropeptides, and monoamines.

    “Second, the microbiome is capable of generating or regulating the bioavailability of a large number of signalling molecules that influence animal social behaviour, including glucocorticoids, sex hormones, neuropeptides, and monoamines (Sudo et al., 2004; Wikoff et al., 2009; Markle et al., 2013; Poutahidis et al., 2013).”
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    Gut microbes influence brain development and function.

    “More recently, gut microbes have been found to influence brain development and function (Diaz Heijtz et al., 2011; Braniste et al., 2014; Sampson & Mazmanian, 2015; Sharon et al., 2016; Vuong et al., 2017).”
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    The microbiome affects gene expression and epigenetic processes relevant to social behaviour.

    “Finally, the microbiome affects gene expression and epigenetic processes relevant to social behaviour.”
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    Premisecitation

    Gut microbes make important contributions to numerous aspects of animal health and physiology across the lifespan.

    “A surge of investigations on the gut microbiome during the past two decades has revealed that these microbes make important contributions to numerous aspects of animal health and physiology across the lifespan (McFall-Ngai et al., 2013; Kundu et al., 2017; Rook et al., 2017).”
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    Premisecitation

    Gut microbes contribute to the regulation of host metabolism, adiposity, and energy balance, as well as appetite and nutrient intake, and the maturation and activity of the immune system.

    “In particular, gut microbes contribute to the regulation of host metabolism, adiposity, and energy balance (Bäckhed et al., 2004; Turnbaugh et al., 2006; Nicholson et al., 2012), as well as appetite and nutrient intake (Perry et al., 2016), and the maturation and activity of the immune system (Fung, Olson, & Hsiao, 2017).”
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    Not all antibiotic effects necessarily occur via modulation of the microbiome; some antibiotic molecules may exert physiological and psychological effects by directly interacting with microglia, enteric neurons, or by modulating enzymatic action.

    “Furthermore, not all antibiotic effects necessarily occur via modulation of the microbiome (Forsythe, Kunze, & Bienenstock, 2016). For instance, some antibiotic molecules may exert physiological and psychological effects by directly interacting with microglia, enteric neurons, or by modulating enzymatic action (Forsythe et al., 2016).”
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    Interpretationcitation

    Germ-free animals differ from conventional animals in both physiology and social behaviour, and when colonised by bacteria, results cannot necessarily be extrapolated to animals with normal microbiomes.

    “However, it should be noted that germ-free animals differ from conventional animals in terms of both their physiology and social behaviour, and therefore when these animals are colonised by bacteria (e.g. via probiotics or microbiome transplants), the results cannot necessarily be extrapolated to animals with normal microbiomes (Hanage, 2014).”
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    The microbiome is extremely sensitive to the host's diet, with diet-induced changes becoming detectable in the microbiome even a day later in some instances.

    “In particular, the microbiome is extremely sensitive to the host’s diet (Wu et al., 2011; David et al., 2014a, 2014b; Carmody et al., 2015, 2019; Sonnenburg et al., 2016), with diet-induced changes becoming detectable in the microbiome even a day later in some instances (Wu et al., 2011; David et al., 2014a).”
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    Microbial homogenisation does not consistently occur in co-housed animals, and microbes may be transmitted unidirectionally.

    “However, microbial ‘homogenisation’ (or mixing of the microbiomes of co-housed animals) does not consistently occur, and in some cases, microbes may only be transmitted unidirectionally between animals.”
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    Interpretationreasoning

    Germ-free animals lack all microbiomes simultaneously, so differences observed in germ-free animals cannot necessarily be deduced to arise solely from the absence of the gut microbiome.

    “Germ-free animals lack all of these microbiomes simultaneously and thus it cannot necessarily be deduced that the differences observed in germ-free animals arise solely from the absence of the gut microbiome, given that conventionally colonised animals have numerous other microbiomes which may exert independent and interactive effects on host physiology.”
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    Mice carrying an 'obese' microbiome were sensitive to colonisation by microbes from co-housed mice carrying 'lean' microbiomes under specific dietary conditions, but the opposite was not the case.

    “Specifically, an important study found that mice carrying an ‘obese’ microbiome were sensitive to colonisation by microbes from co-housed mice carrying ‘lean’ microbiomes under specific dietary conditions, but the opposite was not the case (Ridaura et al., 2013).”
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    Faecal transplant experiments do not necessarily reveal the mechanisms underlying microbial contributions to the condition, or which microbes are involved.

    “It is important to keep in mind that these experiments do not necessarily reveal the mechanisms underlying microbial contributions to the condition, or which microbes are involved.”
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    Premisecitation

    Social disruption and social defeat can reduce gut bacterial diversity.

    “Social disruption and social defeat (in which mice are forced to interact with aggressive conspecifics) can reduce gut bacterial diversity (Galley et al., 2014; Bharwani et al., 2016; Szyszkowicz et al., 2017), and can also alter the abundance of specific bacterial taxa.”
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    Some changes in bacterial populations occur as early as within 2 hours of exposure to the social stressor and can last for at least 3 weeks.

    “Moreover, some of these changes in bacterial populations occur as early as within 2 hours of exposure to the social stressor (Galley et al., 2014), and can last for at least 3 weeks (Szyszkowicz et al., 2017), suggesting that microbial responses to the social environment may be both rapid and long-lasting.”
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    Microbial changes may occur in parallel with elevations in peripheral proinflammatory cytokines such as interleukin-6, although this is not always the case.

    “These microbial changes may occur in parallel with elevations in peripheral proinflammatory cytokines such as interleukin-6 (Bailey et al., 2011; Bharwani et al., 2016), although this is not always the case (Szyszkowicz et al., 2017).”
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    Postweaning separation of rats from conspecifics led to elevations in the Actinobacteria phylum, reductions in the Clostridia class, and an unexpected decrease in hippocampal interleukin-6.

    “Postweaning separation of rats from conspecifics led to elevations in the Actinobacteria phylum, reductions in the Clostridia class, and an unexpected decrease in hippocampal interleukin-6 (Dunphy-Doherty et al., 2018).”
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    Antibiotics attenuate stress-induced proinflammatory immunological activity, suggesting that gut microbes may mediate the relationship between social stress and inflammation.

    “Antibiotics have also been observed to attenuate stress-induced proinflammatory immunological activity, further suggesting that gut microbes may mediate the relationship between social stress and inflammation (Bailey et al., 2011).”
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    Mice more resilient to social stress had a higher prevalence of Bifidobacterium in the gut compared to susceptible individuals, suggesting that gut bacteria may buffer against stress.

    “For example, a recent study found that mice which were more resilient to social stress also had a higher prevalence of Bifidobacterium in the gut compared to susceptible individuals, suggesting that gut bacteria may buffer against stress (Yang et al., 2017).”
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    Interpretationcitation

    Different forms of social stress trigger different types of microbial changes, with inconsistencies across studies.

    “While social stress does appear to reliably alter microbial composition, it also seems that different forms of social stress – defeat and aggression (Bailey et al., 2011; Galley et al., 2014; Bharwani et al., 2016), and isolation and separation (Gareau et al., 2007; O’Mahony et al., 2009; Dunphy-Doherty et al., 2018) – trigger different types of changes, with inconsistencies across studies.”
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    Maternal separation of rat pups affects gut bacterial composition, reducing the relative abundance of the Lactobacillus genus, and elevating concentrations of proinflammatory cytokines.

    “In this regard, maternal separation of rat pups affects gut bacterial composition, reducing the relative abundance of the Lactobacillus genus, and elevating concentrations of proinflammatory cytokines (Gareau et al., 2007; O’Mahony et al., 2009).”
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    Study design and conductcitation

    The three-chamber test provides an index of rodent sociability and social cognition.

    “A widely used measure of rodent social behaviour is the three-chamber test (see Fig. 3), which provides an index of rodent sociability and social cognition (Nadler et al., 2004; Moy et al., 2007; Silverman et al., 2010; Yang, Silverman, & Crawley, 2011).”
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    Premisecitation

    Germ-free mice exhibit social impairments in the three-chamber test: they do not show normal preference for interacting with other rodents (impaired sociability), nor a preference for an unfamiliar mouse over a familiar one (impaired social cognition).

    “In particular, they do not show the normal preference for interacting with other rodents (impaired sociability), nor a preference for interacting with an unfamiliar mouse over a familiar one (impaired social cognition) (Desbonnet et al., 2014; Buffington et al., 2016; Stilling et al., 2018).”
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    Microbial reconstitution attenuated impairments in sociability but did not ameliorate social cognition in germ-free mice.

    “Microbial reconstitution attenuated the impairments in sociability, but did not ameliorate social cognition (Desbonnet et al., 2014; Stilling et al., 2018), suggesting that some – but not all – of the social deficits may be reversible.”
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    Interpretationreasoning

    The mice in that study were older than those in research finding decreased sociability, which may account for the divergent effects of germ-free status on sociability.

    “The mice used in this study were older than those used in some of the research that found that germ-free status decreased sociability (Desbonnet et al., 2014; Stilling et al., 2018), and this may account for the divergent effects of germ-free status on sociability.”
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    Premisecitation

    Faecal transplants from autistic-type mice to control mice caused recipients to develop social behavioural deficits, impaired long-term potentiation in the ventral tegmental area, and reductions in oxytocin-expressing neurons.

    “The causal role of the microbiome was revealed using faecal transplants to transfer microbes from the autistic-type mice to the control mice: the recipients developed social behavioural deficits and showed impaired long-term potentiation in the ventral tegmental area, as well as reductions in oxytocin-expressing neurons.”
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    Premisecitation

    Autistic-type mice showed lower levels of long-term potentiation in the ventral tegmental area after social interactions and had fewer oxytocin-expressing neurons.

    “In comparison, the autistic-type mice showed comparatively lower levels of long-term potentiation in the ventral tegmental area after social interactions, and also had fewer oxytocin-expressing neurons.”
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    Premisecitation

    In a comparison of maternal immune activation effects between C57BL/6J and NIH Swiss mice, NIH Swiss mice buried significantly more marbles, although sociability was similarly impaired in both strains.

    “For instance, in a comparison of the effects of maternal immune activation on autistic traits between C57BL/6J mice and NIH Swiss mice, the latter were found to bury significantly more marbles than the former, although sociability was similarly impaired in both strains following the intervention (Morais et al., 2018).”
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    Treatment with Lactobacillus reuteri attenuated behavioural deficits and increased expression of GABA receptors in affected brain regions in Shank3 knockout mice.

    “Crucially, treatment with the probiotic Lactobacillus reuteri attenuated the behavioural deficits and also increased expression of GABA receptors in the affected brain regions (Tabouy et al., 2018).”
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    Premisecitation

    Mice lacking Shank3 displayed autistic-like phenotypes alongside changes in gut bacterial composition and reductions in expression of GABA receptors in the hippocampus and prefrontal cortex.

    “A recent gene-knockout study found that mice lacking Shank3 displayed autistic-like phenotypes (e.g. impaired sociability and repetitive behaviours) alongside several changes in gut bacterial composition and reductions in the expression of γ-aminobutyric acid (GABA) receptors in the hippocampus and prefrontal cortex (Tabouy et al., 2018).”
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    Genetic research on autism in humans has implicated SHANK family genes in the aetiology of autism.

    “Genetic research on autism in humans has implicated SHANK family genes in the aetiology of autism (Jiang & Ehlers, 2013).”
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    Vagotomy abolished probiotic benefits, suggesting that the behavioural benefits of Lactobacillus reuteri are mediated by the vagus nerve.

    “Vagotomy (i.e. surgical removal of the vagus nerve) abolished probiotic benefits, suggesting that the behavioural benefits of Lactobacillus reuteri are mediated by the vagus nerve.”
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    Interpretationcitation

    Lactobacillus reuteri can exert its effects independent of other microbes and can rescue social impairments in diverse mouse models of autism.

    “These results suggest that this probiotic can exert its effects independent of other microbes and that it can rescue social impairments in diverse mouse models of autism.”
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    Premisenone given

    The microbiome affects the hippocampus, which plays a role in social cognition.

    “In addition, the microbiome has been found to affect the hippocampus, which also plays a role in social cognition.”
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    Premisecitation

    Experimental mice with autistic donor microbiomes showed reduced social engagement with conspecifics in a direct social interaction test and buried significantly more marbles compared to controls, with the marble effect only apparent when excluding donors diagnosed with mild autism.

    “However, the experimental mice did show reduced social engagement with conspecifics in a separate test investigating direct social interactions, and also buried significantly more marbles compared to the control group (although in this latter case, the effect was only apparent when excluding mice whose microbiomes were derived from donors diagnosed with mild autism).”
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    Premisecitation

    The amygdala mediates the experience of stress, fear, and anxiety.

    “and mediates the experience of stress, fear, and anxiety (Roozendaal, McEwen, & Chattarji, 2009).”
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    The amygdala plays an important role in processing social-affective information.

    “The amygdala is a subcortical brain structure that plays an important role in processing social-affective information (Phelps & LeDoux, 2005)”
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    Premisecitation

    The dendrites of pyramidal neurons in the basolateral amygdala of germ-free mice are longer, with increased density of thin, stubby, and mushroom spines.

    “The dendrites of pyramidal neurons in the basolateral amygdala of germ-free mice were also longer, with increased density of thin spines, stubby spines, and mushroom spines (Luczynski et al., 2016).”
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    The dendrites of aspiny interneurons in germ-free mice are longer and have more branch points than those of normally colonised controls.

    “the dendrites of aspiny interneurons of germ-free mice were both longer and had a greater number of branch points compared to normally colonised controls (Luczynski et al., 2016).”
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    The amygdala-nucleus accumbens circuit and the amygdala-anterior insula circuit are associated with microbially generated indole metabolites in humans.

    “Two reward-related networks, the amygdala–nucleus accumbens circuit and the amygdala–anterior insula circuit, have also recently been shown to be associated with microbially generated indole metabolites in humans (Osadchiy et al., 2018).”
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    The prefrontal cortex is involved in high-level cognition and executive functions.

    “The prefrontal cortex is involved in high-level cognition and executive functions (Miller & Cohen, 2001)”
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    Interpretationreasoning

    The strength of the association between the microbiome and the amygdala remains to be clarified.

    “As such, the strength of the association between the microbiome and the amygdala remains to be clarified.”
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    Germ-free status in mice triggers morphological abnormalities in the prefrontal cortex, particularly enhanced thickness of the myelin sheath and upregulation of genes associated with myelination and myelin plasticity.

    “Germ-free status in mice triggers morphological abnormalities in the prefrontal cortex, particularly enhanced thickness of the myelin sheath and an upregulation of genes associated with myelination and myelin plasticity (Hoban et al., 2016).”
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    The hippocampus plays an essential role in the generation and maintenance of cognitive spatial maps.

    “The hippocampus plays an essential role in the generation and maintenance of cognitive spatial maps (O’Keefe & Dostrovsky, 1971).”
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    Premisecitation

    The hippocampus contributes to social recognition and social memory.

    “the hippocampus contributes to social recognition and social memory (Kogan, Franklandand, & Silva, 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kogan, Franklandand, & Silva, 2000

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    Premisecitation

    The prefrontal cortex makes key contributions to social cognition, including impression formation, learning social value, and social and moral reasoning.

    “and also makes key contributions to social cognition, including impression formation (Mitchell, Macrae, & Banaji, 2005), learning social value (Behrens et al., 2008), and social and moral reasoning (Anderson et al., 1999).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Mitchell, Macrae, & Banaji, 2005

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    • cites Behrens et al., 2008

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    • cites Anderson et al., 1999

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    Premisecitation

    In humans, the prefrontal cortex is associated with social network size both volumetrically and functionally, and these relationships appear evident in other primates.

    “in humans, the prefrontal cortex is associated with social network size both volumetrically (Lewis et al., 2011) and functionally (Noonan et al., 2014, 2018), relationships that appear to be evident in other primates as well (Sallet et al., 2011).”
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    • cites Lewis et al., 2011

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    • cites Noonan et al., 2014, 2018

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    • cites Sallet et al., 2011

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    Premisecitation

    Both prebiotics and probiotics increase hippocampal BDNF levels.

    “both prebiotics and probiotics increase hippocampal BDNF levels (Desbonnet et al., 2008; Savignac et al., 2013; Burokas et al., 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Desbonnet et al., 2008

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    • cites Savignac et al., 2013

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    • cites Burokas et al., 2017

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    Premisecitation

    Overall hippocampal dendritic spine density is lower in germ-free mice, accounted for by reduced densities of stubby and mushroom spines.

    “Overall hippocampal dendritic spine density is also lower in germ-free mice, a reduction accounted for by reduced densities of stubby spines and mushroom spines (Luczynski et al., 2016).”
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    • cites Luczynski et al., 2016

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    Premisecitation

    These molecules may exert behavioural effects by entering the brain directly, via effects on the immune system, or by modulating activity of the vagus nerve.

    “these molecules may exert their behavioural effects by entering the brain directly (if the molecule or its precursor can cross the blood–brain barrier), via effects on the immune system, or by modulating activity of the vagus nerve (Johnson & Foster, 2018).”
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    • cites Johnson & Foster, 2018

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    Premisecitation

    Antibiotic exposure in adult mice suppresses hippocampal neurogenesis, but this can be reversed via treatment with probiotics.

    “antibiotic exposure in adult mice supresses hippocampal neurogenesis, but this can be reversed via treatment with probiotics (Möhle et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Möhle et al., 2016

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  • May combine two claims.

    Premisenone given

    Some signalling molecules readily cross the blood-brain barrier (e.g. glucocorticoids and sex steroids), while others are thought unable to do so (e.g. oxytocin).

    “some readily able to cross the blood–brain barrier (e.g. glucocorticoids and sex steroids), while others are thought to be unable to do so (e.g. oxytocin).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Subgroup analysis from one small study suggests that individuals with high levels of Prevotella spp. may have lower hippocampal volume and reduced hippocampal activity in response to negative emotional images.

    “subgroup analysis from one small study suggests that individuals with high levels of Prevotella spp. may have lower hippocampal volume, and also show reduced hippocampal activity in response to negative emotional images (Tillisch et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tillisch et al., 2017

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    Premisecitation

    Lactobacillus and Bifidobacterium secrete GABA, Lactobacillus secretes acetylcholine, Escherichia and Bacillus secrete norepinephrine, and Bacillus and Serratia secrete dopamine.

    “Lactobacillus and Bifidobacterium secrete GABA, Lactobacillus secretes acetylcholine, Escherichia and Bacillus secrete norepinephrine, and Bacillus and Serratia secrete dopamine (Lyte, 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lyte, 2011

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    Premisecitation

    Ingestion of probiotics and prebiotics reduces levels of circulating glucocorticoids in both humans and rodents, and is associated with decreased anxiety.

    “Ingestion of probiotics and prebiotics has been noted to reduce levels of circulating glucocorticoids in both humans and rodents, and is also associated with decreased anxiety (Bravo et al., 2011; Messaoudi et al., 2011; Schmidt et al., 2015; Allen et al., 2016; Burokas et al., 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bravo et al., 2011

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    • cites Messaoudi et al., 2011

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    • cites Schmidt et al., 2015

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    Premisecitation

    The microbiome regulates the bioavailability of endogenous steroids; germ-free rats produced very small quantities of steroids compared to normally colonised rats.

    “the microbiome regulates the bioavailability of endogenous steroids, as early studies found that germ-free rats produced very small quantities of steroids compared to normally colonised rats (Eriksson, Gustafsson, & Sjövall, 1969).”
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    • cites Eriksson, Gustafsson, & Sjövall, 1969

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    Premisecitation

    Pharmacologically elevating corticotropin-releasing factor in rodents enhances anxiety and suppresses normal social interaction.

    “pharmacologically elevating corticotropin-releasing factor in rodents enhances anxiety and supresses normal social interaction (Dunn & File, 1987).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Dunn & File, 1987

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    Premisecitation

    Glucocorticoids cross the blood-brain barrier and can interact directly with the central nervous system.

    “once glucocorticoids are released into systemic circulation, they are also able to cross the blood–brain barrier, and can therefore interact directly with the central nervous system (Pardridge & Mietus, 1979).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pardridge & Mietus, 1979

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  • May combine two claims.

    Premisecitation

    Sex steroids cross the blood-brain barrier and can bind directly to neurons in the brain.

    “Like glucocorticoids, sex steroids are capable of crossing the blood–brain barrier and can therefore bind directly to neurons in the brain (Pardridge & Mietus, 1979).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pardridge & Mietus, 1979

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    Premisecitation

    Impairment in blood-testis barrier integrity in germ-free mice is associated with reduced expression of cell adhesion proteins, while colonisation with Clostridium tyrobutyricum ameliorates expression and restores integrity.

    “The impairment in blood-testis barrier integrity in germ-free mice was associated with reduced expression of cell adhesion proteins, while colonisation with Clostridium tyrobutyricum ameliorated the expression of cell adhesion proteins and restored the integrity of the blood–testis barrier (Al-Asmakh et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Al-Asmakh et al., 2014

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    Premisecitation

    Male germ-free mice show markedly lower serum testosterone concentrations compared to normally colonised male conspecifics, while female germ-free mice show the opposite pattern.

    “Male germ-free mice show markedly lower serum testosterone concentrations compared to normally colonised male conspecifics, while female germ-free mice show the opposite pattern (Markle et al., 2013).”
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    • cites Markle et al., 2013

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    Premisecitation

    Ageing mice fed Lactobacillus reuteri show higher concentrations of serum testosterone and enhanced rates of spermatogenesis.

    “ageing mice fed Lactobacillus reuteri show higher concentrations of serum testosterone and enhanced rates of spermatogenesis (Poutahidis et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Poutahidis et al., 2014

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    Premisecitation

    Mice treated with Lactobacillus reuteri display greater testis size and proliferation of testosterone-producing Leydig cells relative to controls.

    “relative to controls, mice treated with Lactobacillus reuteri display both morpho-morphological changes (as measured by greater testis size) and cellular changes (as measured by a proliferation of testosterone-producing Leydig cells) (Poutahidis et al., 2014).”
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    • cites Poutahidis et al., 2014

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    Premisecitation

    Germ-free status interferes with normal reproduction in both males and females, and these effects are reversed by microbial colonisation.

    “Germ-free status was also found to interfere with normal reproduction in both males and females, and these effects were reversed by microbial colonisation (Shimizu et al., 1998).”
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    • cites Shimizu et al., 1998

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    Premisecitation

    The host microbiome changes continuously over the course of pregnancy, with particularly large differences between the first and third trimesters.

    “The host microbiome changes continuously over the course of pregnancy, with particularly large differences between the first and third trimesters (Koren et al., 2012).”
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    • cites Koren et al., 2012

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxytocin plays a prominent role in mammalian social attachment, beginning with the mother-infant bond, followed by bonds with other social partners as the mammal matures.

    “oxytocin plays a prominent role in mammalian social attachment, beginning with the mother–infant bond, followed by bonds with other social partners as the mammal matures (Feldman, 2017).”
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    • cites Feldman, 2017

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    Premisecitation

    Subsequent studies have failed to replicate the oxytocin-trust result, and the oxytocin → trust relationship is not as straightforward as originally anticipated.

    “subsequent studies have failed to replicate this result (Lane et al., 2015; Nave, Camerer, & McCullough, 2015), and at the very least, the oxytocin → trust relationship is not as straightforward as originally anticipated.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lane et al., 2015

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    • cites Nave, Camerer, & McCullough, 2015

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxytocin plays an evolutionarily conserved role in mating and reproductive behaviour.

    “It plays an evolutionarily conserved role in mating and reproductive behaviour (Garrison et al., 2012; Feldman, 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Garrison et al., 2012

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    • cites Feldman, 2017

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    Premisecitation

    The presence of progesterone sharply elevated the relative abundance of Bifidobacterium spp. both in vivo and in vitro, suggesting that progesterone is able to alter microbial composition.

    “the presence of progesterone sharply elevated the relative abundance of Bifidobacterium spp. both in vivo and in vitro, suggesting that progesterone is able to alter microbial composition (Nuriel-Ohayon et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nuriel-Ohayon et al., 2019

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exogenously administered oxytocin promotes interpersonal trust.

    “exogenously administered oxytocin promotes interpersonal trust (Kosfeld et al., 2005).”
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    • cites Kosfeld et al., 2005

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    Premisecitation

    Early ingestion of the probiotic Lactobacillus reuteri in the offspring restored the number of oxytocin-expressing neurons and attenuated social deficits.

    “early ingestion of the probiotic Lactobacillus reuteri in the offspring restored the number of oxytocin-expressing neurons in the mice and attenuated the social deficits.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Buffington et al., 2016

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    Premisecitation

    Offspring of mice fed high-fat diets during pregnancy display significant social impairments and have fewer hypothalamic oxytocin-expressing neurons, attributable to maternal diet-induced differences in their gut bacteria.

    “the offspring of mice fed high-fat diets during pregnancy display significant social impairments and have fewer hypothalamic oxytocin-expressing neurons, attributable to maternal diet-induced differences in their gut bacteria (Buffington et al., 2016).”
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    • cites Buffington et al., 2016

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    Premisecitation

    Antibiotic administration reduces hypothalamic oxytocin levels in mice, alongside depleting microbial populations.

    “Antibiotic administration reduces hypothalamic oxytocin levels in mice, alongside depleting microbial populations (Desbonnet et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Desbonnet et al., 2015

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  • May combine two claims.

    Premisereasoning

    Vagotomy abolished the beneficial effects of Lactobacillus reuteri, suggesting that the vagus nerve mediates this relationship.

    “vagotomy abolished the beneficial effects of Lactobacillus reuteri, suggesting that the vagus nerve mediates this relationship.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Shank3-knockout mice lacking oxytocin receptors in dopamine neurons did not show improvements in impaired social behaviour and did not show normal long-term potentiation in the ventral tegmental area following social interaction.

    “Shank3-knockout mice lacking oxytocin receptors in dopamine neurons did not show improvements in their impaired social behaviour, and also did not show normal levels of long-term potentiation in the ventral tegmental area following social interaction (Sgritta et al., 2019).”
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    • cites Sgritta et al., 2019

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Vasopressin is structurally similar to oxytocin and is produced mainly in the hypothalamus.

    “Arginine vasopressin (vasopressin) is a neuropeptide hormone that is structurally similar to oxytocin, and, like oxytocin, is produced mainly in the hypothalamus.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Systemic vasopressin is unable to cross the blood-brain barrier.

    “Like oxytocin, systemic vasopressin is unable to cross the blood–brain barrier.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lactobacillus reuteri appears to increase both oxytocin and testosterone signalling, and also suppresses glucocorticoid signalling.

    “Lactobacillus reuteri appears to increase both oxytocin and testosterone signalling, and also suppresses glucocorticoid signalling (Poutahidis et al., 2013; Buffington et al., 2016; Varian et al., 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Poutahidis et al., 2013

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    • cites Buffington et al., 2016

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    • cites Varian et al., 2017

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    Premisecitation

    Central vasopressin is positively associated with sociability in monkeys, with some evidence of a similar association in humans.

    “Central vasopressin has also been found to be positively associated with sociability in monkeys, with some evidence of a similar association in humans as well (Parker et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Parker et al., 2018

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Serotonin regulates a variety of physiological processes in the host, including normal gastrointestinal, cardiovascular, and excretory functions.

    “Serotonin regulates a variety of physiological processes in the host, including normal gastrointestinal, cardiovascular, and excretory functions (Berger, Gray, & Roth, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Berger, Gray, & Roth, 2009

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The serotonergic system is implicated in emotion regulation, social cognition, and social interaction.

    “the serotonergic system is implicated in emotion regulation, social cognition, and social interaction (Young & Leyton, 2002; Canli & Lesch, 2007).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Young & Leyton, 2002

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    • cites Canli & Lesch, 2007

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Serotonergic signalling is implicated in social dominance and aggression across the animal kingdom.

    “Serotonergic signalling is also implicated in social dominance and aggression across the animal kingdom (Nelson & Chiavegatto, 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nelson & Chiavegatto, 2001

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Clinical depression is a highly heterogeneous disorder with multiple intertwined aetiologies linked to alterations in brain plasticity and monoamine functions, as well as disturbances in the immune system and the HPA axis.

    “there is increasing evidence that clinical depression is a highly heterogeneous disorder with multiple, intertwined aetiologies linked to alterations in brain plasticity and monoamine functions in general, as well as disturbances in the immune system and the HPA axis (Miller & Raison, 2016; Pariante, 2017; Levy et al., 2018).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Miller & Raison, 2016

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    • cites Pariante, 2017

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    • cites Levy et al., 2018

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    Premisecitation

    Male germ-free mice have substantially higher plasma tryptophan but substantially lower plasma serotonin compared to normally colonised mice, suggesting that absence of gut microbes impairs peripheral conversion of tryptophan into serotonin.

    “Compared to normally colonised mice, male germ-free mice were found to have substantially higher levels of plasma tryptophan, but substantially lower levels of plasma serotonin, suggesting that the absence of gut microbes impairs the peripheral conversion of tryptophan into serotonin (Wikoff et al., 2009; Clarke et al., 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wikoff et al., 2009

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    • cites Clarke et al., 2013

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    Premisecitation

    Male (but not female) germ-free mice have significantly increased concentrations of serotonin in the hippocampus and increased serotonin turnover in the striatum.

    “male (but not female) germ-free mice also have significantly increased concentrations of serotonin in the hippocampus (Clarke et al., 2013) and increased serotonin turnover in the striatum (Diaz Heijtz et al., 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Clarke et al., 2013

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    • cites Diaz Heijtz et al., 2011

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One of the key roles of the microbiome is the regulation of host peripheral metabolism.

    “One of the key roles of the microbiome is the regulation of host peripheral metabolism (Turnbaugh et al., 2006; Nicholson et al., 2012; Perry et al., 2016)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Turnbaugh et al., 2006

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    • cites Nicholson et al., 2012

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    • cites Perry et al., 2016

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    Premisecitation

    The macaques with SHANK3 mutations showed social impairments and repetitive behaviour reminiscent of the hallmark features of autism.

    “the macaques showed social impairments and repetitive behaviour reminiscent of the hallmark features of autism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zhou et al., 2019

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    Premisecitation

    Enhancing serotonin levels using pharmacological and genetic manipulations substantially increases the abundance of Clostridia spp. and Turicibacter spp., suggesting that some gut bacteria are able to detect and respond to serotonin as a growth factor.

    “enhancing serotonin levels using pharmacological and genetic manipulations substantially increases the abundance of Clostridia spp. and Turicibacter spp., suggesting that some gut bacteria are able to detect and respond to serotonin as a growth factor (Fung et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fung et al., 2019

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    Premisecitation

    In mice colonised with an Escherichia coli mutant incapable of producing β-glucuronidase, luminal dopamine was conjugated and biologically inactive, whereas mice colonised with β-glucuronidase-capable E. coli had active dopamine.

    “comparisons between mice colonised with Escherichia coli (capable of secreting β-glucuronidase) and mice colonised with an Escherichia coli mutant (incapable of producing β-glucuronidase) revealed that luminal dopamine in mice colonised with the mutant strain (in which β-glucuronidase production was suppressed) was conjugated and biologically inactive”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Asano et al., 2012

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    Premisecitation

    Gut bacteria metabolise exogenously administered levodopa into dopamine and then convert dopamine into m-tyramine.

    “gut bacteria metabolise exogenously administered levodopa into dopamine, and then convert dopamine into m-tyramine (Maini Rekdal et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Maini Rekdal et al., 2019

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    Premisecitation

    In germ-free mice, a substantial proportion of luminal dopamine is conjugated with glucuronide or sulphate and biologically inactive, whereas the reverse pattern is observed in normally colonised mice.

    “Moreover, a substantial proportion of luminal dopamine in germ-free mice was conjugated with glucuronide or sulphate and biologically inactive, whereas the reverse pattern was observed in normally colonised mice (Asano et al., 2012).”
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    • cites Asano et al., 2012

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    Premisecitation

    Both conventionalisation with a normal microbiome and colonisation with Clostridium spp. increase levels of dopamine and β-glucuronidase.

    “Both conventionalisation with a normal microbiome and colonisation with Clostridium spp. increased levels of dopamine and β-glucuronidase.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Asano et al., 2012

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    Premisecitation

    Enhanced central dopamine turnover has not consistently been observed; one study found lower dopaminergic turnover in frontal cortex, hippocampus, and striatum in germ-free rats compared with normally colonised rats.

    “one study comparing germ-free and normally colonised rats found lower dopaminergic turnover in the frontal cortex, hippocampus, and striatum in germ-free specimens (Crumeyrolle-Arias et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Crumeyrolle-Arias et al., 2014

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    Premisecitation

    Germ-free mice show elevated hippocampal expression of mRNA encoding D1 dopamine receptor and elevated levels of striatal dopaminergic turnover compared with normally colonised conspecifics.

    “germ-free mice also showed elevated hippocampal expression of mRNA encoding D1, a key dopamine receptor (Diaz Heijtz et al., 2011), as well as elevated levels of striatal dopaminergic turnover (Diaz Heijtz et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Diaz Heijtz et al., 2011

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Changes in splicing and expression observed in germ-free animals likely represent aberrant alterations in host genetics as a result of the absence of microorganisms.

    “These changes in splicing and expression observed in germ-free animals likely represent aberrant alterations in host genetics as a result of the absence of microorganisms.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Ingestion of probiotic Lactobacillus casei normalised central BDNF levels and social recognition memory, although TrkB densities remained elevated.

    “ingestion of the probiotic Lactobacillus casei normalised both central BDNF levels and social recognition memory, although TrkB densities remained elevated (Guida et al., 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Guida et al., 2018

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    Premisecitation

    Germ-free mice have increased amygdalar BDNF levels accompanied by an exaggerated stress response.

    “germ-free mice have increased amygdalar BDNF levels, which is accompanied by an exaggerated stress response (Sudo et al., 2004).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sudo et al., 2004

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    Premisecitation

    Antibiotic-induced dysbiosis in mice reduced social recognition and hippocampal BDNF levels but elevated expression of BDNF receptor TrkB.

    “antibiotic-induced dysbiosis in mice reduced both social recognition and hippocampal BDNF levels, but elevated the expression of the BDNF receptor, tropomyosin receptor kinase B (TrkB) (Guida et al., 2018).”
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    • cites Guida et al., 2018

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  • May combine two claims.

    Interpretationreasoning

    A heightened stress response is likely to result in changes in activity of hippocampal and amygdalar neurocircuitry, with subsequent changes in social behaviour.

    “Therefore, a heightened stress response is likely to result in changes in activity of hippocampal and amygdalar neurocircuitry, with subsequent changes in social behaviour.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tan & Wahli, 2016

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  • May combine two claims.

    Interpretationreasoning

    The capacity of a single-strain probiotic to rescue deficits in social recognition from antibiotic-induced dysbiosis suggests the possibility that discrete changes in a complex microbial community may affect brain function, although effects may occur via other pathways such as immune modulation.

    “The capacity of this single-strain probiotic to rescue deficits in social recognition from antibiotic-induced dysbiosis suggests the possibility that discrete changes in a complex microbial community may be able to affect brain function, although of course these effects may occur via other pathways, such as modulation of the immune system.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Enrichment of RNA-splicing genes, but not MAPK cell signalling pathway genes, was observed in germ-free mice following social interaction.

    “an enrichment of RNA-splicing genes – but not those involved in mitogen-activated protein kinase (MAPK) cell signalling pathways – was observed in germ-free mice following social interaction (Stilling et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Stilling et al., 2018

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    Premisecitation

    SCFAs can enter systemic circulation and modulate sympathetic nervous system activity.

    “which can then enter systemic circulation and modulate sympathetic nervous system activity (Kimura et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kimura et al., 2011

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    Premisecitation

    Butyrate is readily absorbed by colon epithelial cells, used as an energy source, and promotes anti-inflammatory responses.

    “most of the butyrate is readily absorbed by epithelial cells of the colon where it is utilised as an energy source, and promotes anti-inflammatory responses (Koh et al., 2016).”
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    • cites Koh et al., 2016

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    Premisecitation

    Propionate and a proportion of acetate bind to specific receptors in the gut and initiate release of gut hormones; majority of acetate is taken up into vascular system and distributed throughout organs including brain.

    “While propionate and a proportion of the acetate bind to specific receptors in the gut and initiate the release of gut hormones (Koh et al., 2016), the majority of acetate is taken up into the vascular system and distributed throughout the organs, including the brain (Koh et al., 2016; Perry et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Koh et al., 2016

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    • cites Perry et al., 2016

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  • May combine two claims.

    Interpretationreasoning

    These findings collectively suggest effects of the microbiome on host RNA biology and post-transcriptional processes, and provide evidence of potential microbial contributions to the genetic basis of social behaviour.

    “These findings collectively suggest the effects of the microbiome on host RNA biology and post-transcriptional processes, and provide evidence of potential microbial contributions to the genetic basis of social behaviour.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Epigenetic gene silencing may be favourable for the maintenance of normal social interactions.

    “suggesting that epigenetic gene silencing may be favourable for the maintenance of normal social interactions”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In rats, oral administration of acetate and intake of bifidogenic oligosaccharides (prebiotics) can increase circulating acetate concentrations and expression of genes encoding central glutamate NMDA receptor subunits and BDNF.

    “In rats, both the oral administration of acetate and the intake of bifidogenic oligosaccharides (prebiotics) can increase the circulating concentrations of acetate, as well as the expression of genes encoding central glutamate N-methyl-D-aspartate (NMDA) receptor subunits and BDNF (Savignac et al., 2013; Gronier et al., 2018).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Savignac et al., 2013

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    • cites Gronier et al., 2018

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  • May combine two claims.

    Interpretationcitation

    Butyrate is a potent histone deacetylase inhibitor and may impact gene expression in the gut; since butyrate can cross the blood-brain barrier, its epigenetic effects may extend to the brain.

    “Like acetate, butyrate is also a potent histone deacetylase inhibitor, and accordingly may impact gene expression in the gut since this is where it is largely absorbed (Koh et al., 2016). However, since butyrate can cross the blood–brain barrier, its epigenetic effects may also extend to the brain.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Koh et al., 2016

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  • May combine two claims.

    Premisecitation

    Oral acetate supplementation rescued impairments in NMDA receptor function and was associated with inhibition of histone deacetylase activity.

    “oral acetate supplementation rescued impairments in NMDA receptor function and, importantly, was associated with the inhibition of histone deacetylase activity (Singh et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Singh et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The HDAC inhibitor in McCann et al. was sodium butyrate administered systemically or centrally at pharmacological doses, not representative of quantity and anatomical distribution of gut-derived SCFA.

    “the inhibitor in this instance was sodium butyrate that was systemically or centrally administered at pharmacological doses (McCann et al., 2017), and therefore was not representative of the quantity and anatomical distribution of this SCFA when it is derived from the gut microbiome.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites McCann et al., 2017

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  • May combine two claims.

    Premisecitation

    Prebiotic feeding enhances function of brain NMDA receptors and improves cognitive flexibility in rats.

    “Prebiotic feeding has also been shown to enhance the function of brain NMDA receptors, and improve cognitive flexibility in rats (Gronier et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gronier et al., 2018

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The fermentation hypothesis proposes that olfactory signals are products of bacterial metabolism which the host exploits for chemical communication.

    “The fermentation hypothesis proposes that olfactory signals are the products of bacterial metabolism which the host exploits for chemical communication (Albone et al., 1974; Albone & Perry, 1976).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Albone et al., 1974

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    • cites Albone & Perry, 1976

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The olfactory system plays an important role in conveying and detecting social information across the animal kingdom.

    “The olfactory system plays an important role in conveying and detecting social information across the animal kingdom (Steiger, Schmitt, & Schaefer, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Steiger, Schmitt, & Schaefer, 2011

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In spotted hyaenas, a subcaudal gland secretion known as hyaena 'paste' relays social information used for intra-specific signalling and communication, including as a marker of social rank.

    “in spotted hyaenas (Crocuta crocuta) a subcaudal gland secretion known as hyaena ‘paste’ relays a range of social information used for intra-specific signalling and communication (Drea et al., 2002a, 2002b; Burgener et al., 2009), including as a marker of social rank (Burgener et al., 2009).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Drea et al., 2002a

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    • cites Drea et al., 2002b

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    • cites Burgener et al., 2009

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  • May combine two claims.

    Premisecitation

    Compounds in scent gland secretions (paste) of spotted hyaenas contain bacterially derived odourants associated with signalling host sex, immigration status in males, and pregnancy and lactation status in females.

    “The compounds in the scent gland secretions (paste) of spotted hyaenas contain bacterially derived odourants that are associated with the signalling of important social information (Theis et al., 2013), including host sex, immigration status in males, and pregnancy and lactation status in females (Theis et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Theis et al., 2013

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  • May combine two claims.

    Premisecitation

    Experimental alteration or disruption of the external microbiome of harvester ants and the gut microbiome of lower termites interferes with nestmate recognition, leading to rejection of colony members.

    “experimental alteration or disruption of the external microbiome of harvester ants (Pogonomyrmex barbatus; Dosmann et al., 2016) and the gut microbiome of lower termites (Reticulitermes speratus; Matsuura, 2001) interferes with nestmate recognition, leading to rejection of colony members.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dosmann et al., 2016

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    • cites Matsuura, 2001

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  • May combine two claims.

    Premisecitation

    Swarming behaviour in the same locust species is also mediated by serotonin, which plays a role in behavioural gregarisation preceding swarming.

    “more recent research suggests that swarming behaviour in the same locust species is also mediated by serotonin, which plays a role in the behavioural gregarisation that precedes swarming (Anstey et al., 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Anstey et al., 2009

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  • May combine two claims.

    Premisecitation

    Infection with fungus Paranosema locustae inhibits locust swarming behaviour via acidification of the hindgut and suppresses serotonin-producing bacteria.

    “studies that investigate the effects of infection with the fungus Paranosema locustae, which both inhibits locust swarming behaviour via acidification of the hindgut and supresses seroton-inproducing bacteria (Shi et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shi et al., 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fruit flies show mating preferences for conspecifics with similar microbial compositions, a social cue attributed to Lactobacillus plantarum.

    “it has been suggested that fruit flies (Drosophila melanogaster) show mating preferences for conspecifics with similar microbial compositions, a social cue attributed to Lactobacillus plantarum (Najarro et al., 2015; Sharon et al., 2010; but see Leftwich et al., 2017; see also Rosenberg et al., 2018).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Najarro et al., 2015

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    • cites Sharon et al., 2010

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    • cites Leftwich et al., 2017

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  • May combine two claims.

    Premisecitation

    Mosquitoes rely on odour profiles to target potential hosts, and both composition of skin microbiome and compounds it produces can influence odour profiles and host attractiveness to mosquitoes.

    “These mosquitoes rely on odour profiles to target potential hosts, and both the composition of the skin microbiome and the compounds it produces can influence odour profiles and therefore the host’s attractiveness to mosquitoes (Verhulst et al., 2010a, 2010b, 2011).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Verhulst et al., 2010a

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    • cites Verhulst et al., 2010b

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    • cites Verhulst et al., 2011

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  • May combine two claims.

    Premisecitation

    There is some evidence that the skin microbiome may contribute to human odour profiles, but the association is weak at best and sensitive to behaviours and external factors.

    “There is some evidence that the skin microbiome may contribute to human odour profiles, but overall, the association is weak at best and appears to be very sensitive to behaviours (e.g. bathing, deodorant use) and external factors (Xu et al., 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Xu et al., 2007

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  • May combine two claims.

    Premisecitation

    The murine microbiome generates trimethylamine, which acts as an attractive olfactory cue; antibiotic treatment reduces trimethylamine production, causing mice to become less sexually attractive to conspecifics.

    “the murine microbiome generates trimethylamine, which acts as an attractive olfactory cue. Antibiotic treatment reduces trimethylamine production, causing mice to become less sexually attractive to conspecifics (Li et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Li et al., 2013

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  • May combine two claims.

    Premisecitation

    Relative to placebo, participants treated with Bifidobacterium longum 1714 displayed increased resting-state θ power in frontal and cingulate cortices and reduced β2 power in hippocampus, fusiform gyrus, temporal cortex, and cerebellum.

    “Relative to participants treated with a placebo, those treated with the psychobiotic displayed increased resting-state θ power in the frontal and cingulate cortices, and reduced β2 power in the hippocampus, the fusiform gyrus, the temporal cortex, and the cerebellum (Wang et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wang et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Consumption of psychobiotics lowers cortisol levels and is accompanied by self-reported reductions in negative mood.

    “consumption of psychobiotics lowers cortisol levels (Messaoudi et al., 2011; Schmidt et al., 2015; Allen et al., 2016) and is accompanied by self-reported reductions in negative mood (Messaoudi et al., 2011; Steenbergen et al., 2015).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Messaoudi et al., 2011

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    • cites Schmidt et al., 2015

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    • cites Allen et al., 2016

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  • May combine two claims.

    Premisecitation

    Depressed individuals show order-level increases in Bacteroidales and family-level increases in Lachnospiraceae.

    “or order-level increases in Bacteriodales and family-level increases in Lachnospiraceae (Naseribafrouei et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Naseribafrouei et al., 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These results suggest that psychobiotics may be capable of modulating brain activity both at rest and in response to social experiences.

    “they do suggest that psychobiotics may be capable of modulating brain activity both at rest and in response to social experiences.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Depressed individuals show increases in Enterobacteriaceae family and Alistipes genus and decreases in Faecalibacterium genus relative to healthy controls.

    “Others have found increases in the Enterobacteriaceae family and the Alistipes genus and decreases in the Faecalibacterium genus in depressed individuals relative to healthy controls (Jiang et al., 2015)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jiang et al., 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prebiotics can reduce waking cortisol levels and emotional attention to negative stimuli.

    “There is also evidence that prebiotics can reduce waking cortisol levels and emotional attention to negative stimuli (Schmidt et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schmidt et al., 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    As with most other human studies, the sample sizes were relatively small.

    “However, as with most other human studies, the sample sizes were relatively small.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Depression is associated with changes in relative abundance of numerous bacterial taxa, including increases in Firmicutes, decreases in Bacteroides, and increases in Prevotella, Klebsiella, Streptococcus, and Clostridium.

    “depression has recently been associated with changes in the relative abundance of numerous bacterial taxa. These include increases in the Firmicutes phylum, decreases in the Bacteroides phylum, and increases in the genera Prevotella, Klebsiella, Streptococcus and Clostridium (Lin et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lin et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alistipes spp. may be linked to increased inflammation, which is often a prominent physiological marker of depression.

    “Alistipes spp. may be linked to increased inflammation (Naseribafrouei et al., 2014), which is often a prominent physiological marker of depression (Miller, Maletic, & Raison, 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Naseribafrouei et al., 2014

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    • cites Miller, Maletic, & Raison, 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Growth of bacterial isolate KLE1738 depends on GABA as a nutrient, which is produced by members of Bacteroides genus under pH conditions similar to human gut.

    “growth of the bacterial isolate KLE1738 appears to depend on GABA as a nutrient, which is produced by members of the Bacteroides genus under pH conditions similar to the human gut (Strandwitz et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Strandwitz et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced Bacteroides abundance is linked to stronger functional connectivity between left dorsolateral prefrontal cortex and default mode network, and such increased functional connectivity has previously been associated with depression.

    “reduced Bacteroides abundance was linked to stronger functional connectivity between the left dorsolateral prefrontal cortex and the default mode network (Strandwitz et al., 2019), and such increased functional connectivity has previously been associated with depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Strandwitz et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In infants and young children, microbial composition correlates with temperament and emotional regulation, as well as cognitive development and linguistic skill.

    “In infants and young children, microbial composition has been shown to correlate with temperament and emotional regulation (Christian et al., 2015; Aatsinki et al., 2019), as well as cognitive development and linguistic skill (Carlson et al., 2018), which are beneficial for social interaction.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Christian et al., 2015

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    • cites Aatsinki et al., 2019

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    • cites Carlson et al., 2018

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  • May combine two claims.

    Premisecitation

    Inflammation and depression are often robustly associated, and childhood inflammation can predict future depression in young adults even several years later.

    “inflammation and depression are often robustly associated (Dowlati et al., 2010), and that childhood inflammation can predict future depression in young adults, even several years later (Khandaker et al., 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Dowlati et al., 2010

      Not checked in the free run.

    • cites Khandaker et al., 2014

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  • May combine two claims.

    Interpretationreasoning

    Variations in subsequent psychological outcomes are consistent with the possibility of antibiotic-induced microbial disturbances, but may also arise from modulation of non-microbial targets.

    “while variations in subsequent psychological outcomes are certainly consistent with the possibility of antibiotic-induced microbial disturbances, they may also arise from modulation of non-microbial targets.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the first 110 postnatal days, higher levels of maternal prenatal stress are associated with shifts in infant microbial composition that, in turn, are associated with greater levels of inflammation and poorer health outcomes.

    “in the first 110 postnatal days, higher levels of maternal prenatal stress were found to be associated with shifts in infant microbial composition that, in turn, were associated with greater levels of inflammation and poorer health outcomes (Zijlmans et al., 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zijlmans et al., 2015

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Because antibiotics are administered in response to infection, the observed increase in childhood depression may be attributable to elevated inflammation caused by the infection for which antibiotics were used.

    “because antibiotics are administered in response to infection, the observed increase in childhood depression may be attributable to elevated inflammation caused by the infection for which antibiotics were used in the first instance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    These studies add inductive support to the hypothesis that a healthy microbiome in early life is important for typical social-emotional development in humans, and that antibiotics may disrupt this development.

    “These studies add inductive support to the hypothesis that a healthy microbiome in early life is important for typical social–emotional development in humans, and that antibiotics may disrupt this development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    It is plausible that vertical transmission of stress-associated microbes to the infant during vaginal births may occur in humans as well, with neurodevelopmental implications for the infant.

    “Thus, it is plausible that vertical transmission of stress-associated microbes to the infant during vaginal births may occur in humans as well, with neurodevelopmental implications for the infant.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The vaginal microbiome is the first microbial exposure for mammalian infants, with vaginal microbes colonising the infant gut microbiome during parturition.

  • May combine two claims.

    Premisecitation

    A stress-associated vaginal microbiome in female mice can be transmitted to the infant during birth, which can impact the developing infant's health, metabolism, and stress response.

    “A stress-associated vaginal microbiome in female mice can be transmitted to the infant during birth, which in turn can impact the developing infant’s health, metabolism, and stress response (Jašarević et al., 2015, 2018).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Jašarević et al., 2015

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    • cites Jašarević et al., 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    At present, the existence of placental, amniotic, or foetal microbiomes remains controversial and requires rigorous confirmatory evidence.

    “At present, the existence of placental, amniotic, or foetal microbiomes, although intriguing, remains controversial and requires rigorous confirmatory evidence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A recent systematic review of 16 studies found cross-study evidence of some consistent microbial differences in autistic individuals compared to neurotypical controls, including increased Bacteroides, Clostridium, Desulfovibrio, Lactobacillus, and Proteobacter, and decreased Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter.

    “A recent systematic review of 16 studies did find cross-study evidence of some consistent microbial differences in autistic individuals compared to neurotypical controls, including increased Bacteroides, Clostridium, Desulfovibrio, Lactobacillus, and Proteobacter, and decreased Bifidobacterium, Blautia, Dialister, Prevotella, Veillonella, and Turicibacter (Liu et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Liu et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One probiotic administration study that implemented a double-blind, crossover design failed to detect changes in behaviour in autistic participants, but did observe some differences in microbial composition.

    “For instance, one probiotic administration study that implemented a double-blind, crossover design failed to detect changes in behaviour in autistic participants, but did observe some differences in microbial composition (Parracho et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Parracho et al., 2010

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  • May combine two claims.

    Premisecitation

    At the end of the faecal transplant treatment, participants showed substantial improvement in both gastrointestinal symptoms and social deficits and other behavioural features.

    “At the end of the treatment, participants showed substantial improvement in both gastrointestinal symptoms (e.g. diarrhoea and indigestion), and social deficits and other behavioural features (e.g. repetitive behaviours).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kang et al., 2017

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    It is likely unfeasible to engage in chronic antibiotic treatment for autism, as there is presently no way of controlling the detrimental effects on the microbiome, as well as the inevitable development of antibiotic resistance that prolonged exposure would induce.

    “Furthermore, though some antibiotics may provide short-term benefits (e.g. Sandler et al., 2000), it is likely unfeasible to engage in chronic antibiotic treatment for autism, as there is presently no way of controlling the detrimental effects on the microbiome, as well as the inevitable development of antibiotic resistance that prolonged exposure would induce.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The benefits of vancomycin were transient, mostly absent within just 2 weeks following treatment, and absent at long-term follow-ups.

    “However, these benefits were transient, and were mostly absent within just 2 weeks following vancomycin treatment, and were also absent at long-term follow-ups (Sandler et al., 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sandler et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At 2 years following completion of the microbial transplant, most of the gastrointestinal and behavioural improvements had persisted, and several autism-related symptoms had improved even further.

    “Even more striking were the results of follow-up assessments conducted on these participants 2 years following the completion of the microbial transplant: most of the gastrointestinal and behavioural improvements had persisted through the intervening period, and several of the autism-related symptoms had improved even further (Kang et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kang et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    The small initial sample size (N = 18), the open-label nature of the design, and the lack of a control group all pose substantial challenges to the generalisability and applicability of the faecal transplant results.

    “Of course, while these results (Kang et al., 2017, 2019) are promising, the small initial sample size (N = 18), the open-label nature of the design, and the lack of a control group all pose substantial challenges to the generalisability and applicability of these results.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Human research on the link between the microbiome and psychological processes is fraught with noise arising from variations in genetics, sex, age, diet, past and present environmental exposures, and use of medicines, all of which can be strictly controlled in laboratory-based rodent studies.

    “As noted elsewhere (Forsythe et al., 2016; Sarkar et al., 2018), human research on the link between the microbiome and psychological processes is fraught with noise arising from variations in genetics, sex, age, diet, past and present environmental exposures, and use of medicines, all of which can be strictly controlled in laboratory-based rodent studies.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Forsythe et al., 2016

      Not checked in the free run.

    • cites Sarkar et al., 2018

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  • Classified as probably not a substantial claim.

    Interpretationnone given

    There is limited research that conclusively identifies a biological mediator of the relationship between the microbiome and host sociality.

    “There is limited research that conclusively identifies a biological mediator of the relationship between the microbiome and host sociality, although of course such mediators must exist.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Biological mediators of the microbiome–sociality relationship must exist.

  • Classified as probably not a substantial claim.

    Premisecitation

    Variations in amygdala structure and function may be involved in autism.

    “The second link, from cognitive neuroscience and biological psychiatry, is the finding that variations in amygdala structure and function may be involved in autism (Baron-Cohen et al., 1999, 2000).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baron-Cohen et al., 1999

      Not checked in the free run.

    • cites Baron-Cohen et al., 2000

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    While some stress- and emotion-related findings in humans resemble rodent findings in several respects, they have much lower statistical power.

    “While some of the stress- and emotion-related findings in humans resemble rodent findings in several respects, they have much lower statistical power.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Even when the microbiome does influence testosterone bioavailability, the hormone may not necessarily affect behaviour, since there are many different physiological actions of testosterone, some of which may have no significant behavioural correlates.

    “Even when the microbiome does influence testosterone bioavailability, the hormone may not necessarily affect behaviour, since there are many different physiological actions of testosterone, some of which may have no significant behavioural correlates.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: All of these molecules (neurotransmitters, steroids, and neuropeptides) perform numerous physiological functions for the host, and variations in their bioavailability cannot be assumed to exert psychological effects on the host.

  • May combine two claims.

    Interpretationreasoning

    The microbiome regulates a wide range of other molecules and some of these may also influence animal social behaviour.

    “However, the microbiome regulates a wide range of other molecules and some of these may also influence animal social behaviour.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    At best, the current set of findings permits the possibility that a microbiome → amygdala → autism connection may exist and could be subject to future investigation.

    “Therefore, at best, the current set of findings permits the possibility that a microbiome → amygdala → autism connection may exist and could be subject to future investigation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    There is as yet no report of a microbiome → testosterone → aggression connection in rodents.

    “But there is as yet no report of a microbiome → testosterone → aggression connection in rodents.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Lactobacillus reuteri only ameliorates social deficits in mice with functioning oxytocin systems, as conditional deletion of oxytocin receptors in neurons in the ventral tegmental area prevented Lactobacillus reuteri treatment from rescuing social impairments.

    “Another example is the finding that Lactobacillus reuteri only ameliorates social deficits in mice with functioning oxytocin systems, as conditional deletion of oxytocin receptors in neurons in the ventral tegmental area prevented Lactobacillus reuteri treatment from rescuing social impairments (Sgritta et al., 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Sgritta et al., 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Researchers have recently found evidence suggesting that the proinflammatory cytokine interferon-γ may play a role in social behaviour across the animal kingdom.

    “For instance, researchers have recently found evidence suggesting that the proinflammatory cytokine interferon-γ may play a role in social behaviour across the animal kingdom (Filiano et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Filiano et al., 2016

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The proposition that microbial effects on neurotransmitters, brain circuitry, the endocrine system, and the olfactory system arise independently of microbial regulation of host metabolism and immunity is unlikely.

    “Or is it that microbial effects on neurotransmitters, brain circuitry, the endocrine system, and the olfactory system, all of which play key roles in sociality, arise independently of microbial regulation of host metabolism and immunity? This latter proposition is unlikely, but may have some utility as a point of comparison for more probable models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Microbiome-sociality associations include relationships between the microbiome and social stress, social interaction, and autistic phenotypes.

    “Microbiome–sociality associations include relationships between the microbiome and social stress, social interaction, and autistic phenotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Germ-free status has been linked to many physiological impairments, supporting the claim that microbes are essential for normal development.

    “Germ-free status has been linked to many physiological impairments, supporting the claim that microbes are essential for normal development.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    It is not known how the numerous microbial effects on host physiological, psychological, and social development are connected to one another.

    “Despite the many deficits of germ-free animals, it is not known how the numerous microbial effects on host physiological, psychological, and social development are connected to one another.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    The microbiome affects animal social behaviour, but the specific biological pathways that mediate these associations are yet to be fully elucidated.

    “The microbiome affects animal social behaviour, but the specific biological pathways that mediate these associations are yet to be fully elucidated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The microbiome in early infancy may play a role in the development of social and emotional traits, and may even influence individual susceptibility to developing autism.

    “The microbiome in early infancy may also play a role in the development of social and emotional traits, and may even influence individual susceptibility to developing autism.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The microbiome affects multiple aspects of physiology, including the nervous system, metabolism, and immunity.

    “It will be important to understand the order of microbial effects on host sociality, since the microbiome affects multiple aspects of physiology, including the nervous system, metabolism, and immunity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Researchers have detected correlations between microbial composition and depression, although the functional role of bacteria in depression remains largely unknown.

    “Researchers have also detected correlations between microbial composition and depression, although the functional role of bacteria in depression remains largely unknown.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    There is limited direct evidence connecting the microbiome to a specific social behaviour via a physiological mediator.

    “There is limited direct evidence connecting the microbiome to a specific social behaviour via a physiological mediator.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Human microbiome research is typically underpowered and the data are characterised by a great deal of variation.

    “At the same time, human microbiome research is typically underpowered and the data are characterised by a great deal of variation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    The microbiome generates a range of olfactory signalling molecules (odourants) that can bind to olfactory receptors distributed throughout the host's body.

    “The microbiome generates a range of olfactory signalling molecules (odourants) that can bind to olfactory receptors distributed throughout the host’s body.”
    Quote in the paperNot a substantial claim
166 of 166

  • The paper relies on this without support.

    Little is known about the biological processes through which the microbiome might influence host social behaviour.

    “However, little is known about the biological processes through which the microbiome might influence host social behaviour.”

  • The paper relies on this without support.

    To date there is little evidence that elucidates which causal physiological pathways mediate microbial contributions to host social behaviour.

    “However, to date there is little evidence that elucidates which causal physiological pathways (at the systems, cellular, and molecular levels) mediate microbial contributions to host social behaviour.”

  • The authors state this as an assumption.

    The faecal microbiome accurately captures the total gut microbiome.

    “assuming that the faecal microbiome accurately captures the total gut microbiome”

  • The paper relies on this without support.

    The amygdala, hippocampus, and prefrontal cortex contribute to social cognition and social behaviour.

    “that are known to contribute to social cognition and social behaviour”

  • The paper relies on this without support.

    There is as yet no universally accepted rodent model that is considered equivalent to the behavioural impairments associated with autism in humans.

    “there is as yet no universally accepted rodent model that is considered equivalent to the behavioural impairments associated with autism in humans.”

  • The paper relies on this without support.

    Levodopa can cross the blood–brain barrier and is converted into dopamine there, whereas peripheral dopamine cannot cross the blood–brain barrier.

    “It is able to cross the blood–brain barrier, where it is converted into dopamine. Peripheral dopamine, however, cannot cross the blood–brain barrier.”

  • The authors state this as an assumption.

    The vaginal microbiome is the first microbial exposure for mammalian infants, with vaginal microbes colonising the infant gut microbiome during parturition.

    “The vaginal microbiome is important in this context because it is assumed to be the first microbial exposure for mammalian infants, with vaginal microbes colonising the infant gut microbiome during parturition (Dominguez-Bello et al., 2010; Mueller et al., 2015; Sprockett et al., 2018).”

  • The paper relies on this without support.

    Any effect of the microbiome on human sociality is expected to occur through the mechanisms inferred from studies using mammalian models.

    “Any effect of the microbiome on human sociality is expected to occur through the mechanisms inferred from studies using mammalian models.”

  • The paper relies on this without support.

    Biological mediators of the microbiome–sociality relationship must exist.

    “There is limited research that conclusively identifies a biological mediator of the relationship between the microbiome and host sociality, although of course such mediators must exist.”

  • The paper relies on this without support.

    The microbiome–sociality relationship is mediated, at least in part, by changes in the anatomy and function of regions in the social brain, or in the biosynthesis and bioavailability of social signalling molecules.

    “While it is likely that the microbiome–sociality relationship is mediated, at least in part, by changes in the anatomy and function of regions in the social brain, or in the biosynthesis and bioavailability of social signalling molecules, there are few studies that have identified such underlying pathways from changes in the microbiome to changes at the behavioural level.”

  • The paper relies on this without support.

    All of these molecules (neurotransmitters, steroids, and neuropeptides) perform numerous physiological functions for the host, and variations in their bioavailability cannot be assumed to exert psychological effects on the host.

    “Furthermore, it is important to keep in mind that all of these molecules (neurotransmitters, steroids, and neuropeptides) perform numerous physiological functions for the host, and variations in their bioavailability cannot be assumed to exert psychological effects on the host.”
11 of 11

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Authors
Sarkar, A., Harty, S., Johnson, K. V. ‐., Moeller, A. H., Carmody, R. N., Lehto, S. M., Erdman, S. E., Dunbar, R. I. M., & Burnet, P. W. J.
Affiliations
  • University of Cambridge (GB)
  • Trinity College Dublin (IE)
  • Warneford Hospital (GB)
  • Cornell University (US)
  • Harvard University (US)
  • University of Helsinki (FI)
  • Massachusetts Institute of Technology (US)
  • University of Oxford (GB)
Corresponding author
Sarkar, Amar
ORCID
Venue
Biological Reviews
Publisher
Wiley
Published
2020-05-07
Volume
95
Issue
5
Pages
1131-1166
ISSN
  • 0006-3231 (ISSN-L)
  • 1464-7931
  • 1469-185X
DOI
10.1111/brv.12603
PMC
PMC10040264
OpenAlex
W3014849405
Semantic Scholar
2130d5f55352fb302d9a763d5d5d80a436b52831
Cited by
135
References
365
Citations by year
2026: 14 · 2025: 27 · 2024: 23 · 2023: 23 · 2022: 19 · 2021: 21 · 2020: 8
FWCI
1.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological reviews/Biological reviews of the Cambridge Philosophical Society (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by)
  • Työväentutkimus Vuosikirja (submittedVersion)
Funders
  • John Templeton Foundation
  • Suomen Lääketieteen Säätiö
  • National Institutes of Health (RO1CA108854, U01 CA164337, P30 ES02109, R01AG049395)
  • National Science Foundation (BCS‐1919892)
  • University of California Berkeley
  • Adolph C. and Mary Sprague Miller Institute for Basic Research in Science, University of California Berkeley
  • Cornell University
  • Biotechnology and Biological Sciences Research Council (BB/J014427/1, BB/I006311/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
gut microbiota, social behavior, sociability, social cognition, social stress, autism spectrum disorder, social brain, amygdala, prefrontal cortex, hippocampus, glucocorticoids, sex hormones, oxytocin, vasopressin, serotonin, dopamine, epigenetics, olfaction, social signaling, psychobiotics, depression, early human development, host-microbe interactions
MeSH terms
Gastrointestinal Microbiome, Animals, Brain, Humans, Mammals, Social Behavior, Microbiota

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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