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Cited by 446Gut microbiota and healthStress Responses and CortisolGastrointestinal motility and disorders

Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis

Open access
Rusch, Jody A., Layden, Brian T., Dugas, Lara R.·2023·Frontiers in Endocrinology
DOI 10.3389/fendo.2023.1130689PMC PMC10316519
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Abstract

Cognitive function in humans depends on the complex and interplay between multiple body systems, including the hypothalamic-pituitary-adrenal (HPA) axis. The gut microbiota, which vastly outnumbers human cells and has a genetic potential that exceeds that of the human genome, plays a crucial role in this interplay. The microbiota-gut-brain (MGB) axis is a bidirectional signalling pathway that operates through neural, endocrine, immune, and metabolic pathways. One of the major neuroendocrine systems responding to stress is the HPA axis which produces glucocorticoids such as cortisol in humans and corticosterone in rodents. Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life. Stress can significantly impact the MGB axis via the HPA axis and other pathways. Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease. Preclinical and human trials are currently underway to determine how these animal models translate to humans. In this review article, we summarize the current knowledge of the relationship between the gut microbiota, HPA axis, and cognition, and provide an overview of the main findings and conclusions in this broad field.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review summarizes bidirectional signaling between the gut microbiota, the hypothalamic-pituitary-adrenal (HPA) axis, and cognition via the microbiota-gut-brain axis. It concludes that microbial metabolites, neural pathways, immune signaling, and HPA-axis glucocorticoids are interlinked, but human causal evidence remains limited.

Key findings

  • The gut microbiota and HPA axis are bidirectionally linked: germ-free mice show enhanced HPA-axis activity after acute stress, including increased ACTH and corticosterone responses, and altered cognition; microbial colonization can rescue some effects if given early in life.
  • Human observational data link microbiota diversity to cognition: in 597 middle-aged adults, β-diversity was positively associated with all higher cognitive functions tested; in >4,000 healthy people aged 18–90, metagenomic profiles predicted chronological age within approximately six years.
  • Antibiotic exposure is associated with cognitive risk: in a prospective cohort of 14,542 participants, chronic midlife antibiotic use was associated with later cognitive impairment, corresponding to an additional three years of aging compared with no antibiotic exposure.
  • Mechanistic pathways include SCFAs, bile acids, tryptophan/kynurenine metabolites, serotonin, GABA, catecholamines, endocannabinoids, immune modulation, the vagus nerve, and the enteric nervous system; SCFA supplementation attenuated the cortisol response to psychosocial stress in healthy men.

Methods

  • Design: narrative review article summarizing current knowledge of the gut microbiota, HPA axis, and cognition.
  • Data/sample: no primary data; synthesizes preclinical animal studies, germ-free models, human observational studies, randomized controlled trials, and mechanistic literature.
  • Main analysis: thematic synthesis of proposed microbiota-gut-brain mechanisms and evidence relating microbiota, HPA-axis function, and cognitive outcomes.

Limitations

  • The paper states that mechanisms by which the gut microbiota impacts the human brain are not fully understood, human evidence remains sparse, and whether microbiota changes are causal, consequential, or coincidental is unresolved.
  • The paper states that animal models, especially germ-free models, may not directly transfer to human function and calls for rigorous causal human studies and adequately powered, standardized clinical trials.
  • Evident from the text: as a narrative review, it does not describe a systematic search strategy, formal quality appraisal, or meta-analytic synthesis, and it cites many small, short-term, or heterogeneous studies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fendo.2023.1130689

Cites

530 of 530 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 562 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In the gut, the GM and its metabolites modulate gastrointestinal functions via effects on intestinal permeability, mucosal immune function, intestinal motility and sensitivity, and the ENS.

    “In the gut, the GM and its metabolites have been shown to modulate gastrointestinal functions via their effects on intestinal permeability (32–35), mucosal immune function (36–38), intestinal motility and sensitivity (39, 40), and the enteric nervous system (ENS) (21, 24, 25, 41).”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [32] Cani, 2012, Involvement of gut microbiota in the development of low-grade inflammation and type 2 diabetes associated with obesity, Gut Microbes source

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    • cites [33] Rutsch, 2020, The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology, Front Immunol source

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    • cites [34] Frazier, 2011, Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury, JPEN J Parenter Enteral Nutr source

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    • cites [35] Fasano, 2017, Gut permeability, obesity, and metabolic disorders: who is the chicken and who is the egg, Am J Clin Nutr source

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    • cites [36] Round, 2009, The gut microbiota shapes intestinal immune responses during health and disease, Nat Rev Immunol source

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    • cites [39] Cani, 2013, Gut microbiota, enteroendocrine functions and metabolism, Curr Opin Pharmacol source

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    • cites [40] Valdez-Morales, 2013, Sensitization of peripheral sensory nerves by mediators from colonic biopsies of diarrhea-predominant irritable bowel syndrome patients: a role for PAR2, Am J Gastroenterol source

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  • Interpretationnone given

    The GM, HPA axis, and cognitive processes are linked bidirectionally via multiple pathways, including the vagus nerve, neurotransmitter and metabolite production, immune system and blood-brain barrier regulation, and hormone metabolism.

    “Emerging evidence suggests that the GM, the hypothalamic-pituitary-adrenal (HPA) axis, and cognitive processes are linked bidirectionally via multiple pathways, including the vagus nerve, neurotransmitter and metabolite production, immune system and blood-brain barrier regulation, and hormone metabolism.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Animal model findings about the GM-HPA-cognition relationship are informative about human biology.
  • Interpretationnone given

    Stress can significantly impact the MGB axis via the HPA axis and other pathways.

    “Stress can significantly impact the MGB axis via the HPA axis and other pathways.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Animal model findings about the GM-HPA-cognition relationship are informative about human biology.
  • Premisecitation

    The GM can modulate host physiological processes through microbial constituents, microbial products, hormone release, and substrate metabolism.

    “As a key regulator, the GM can modulate host physiological processes through several proposed mechanisms (25, 26).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Cryan, 2019, The microbiota-gut-brain axis, Physiol Rev source

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    • cites [26] Dinan, 2017, The microbiome-Gut-Brain axis in health and disease, Gastroenterol Clin North Am source

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  • Premisecitation

    Meyer et al. found a significant positive association between β-diversity and all higher cognitive functions tested in 597 middle-aged adults.

    “Confirming the role of the GM in cognitive function in midlife, Meyer et al. explored the relationship between gut microbial community composition and cognitive function in 597 middle-aged adults, and found a significant positive association between β-diversity and all higher cognitive functions tested (89).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Meyer, 2022, Association of the gut microbiota with cognitive function in midlife, JAMA Netw Open source

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  • May combine two claims. 144
  • Classified as probably not a substantial claim. 11
  • The quote only partly states this claim. 2

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    Premisecitation

    The GM influences the stress system, behavior, and cognition in animals.

    “Studies in animals have demonstrated the effect that the GM has on neural development and neurochemistry in the host, influencing the stress system, behavior, and cognition (42–47).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [42] Dinan, 2017, Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration, J Physiol source

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    • cites [43] Moloney, 2014, The microbiome: stress, health and disease, Mamm Genome source

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    • cites [44] Salami, 2021, Interplay of good bacteria and central nervous system: cognitive aspects and mechanistic considerations, Front Neurosci source

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    • cites [45] Sampson, 2015, Control of brain development, function, and behavior by the microbiome, Cell Host Microbe source

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    • cites [46] Vuong, 2017, The microbiome and host behavior, Annu Rev Neurosci source

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    • cites [47] Connell, 2022, Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia, Mol Neurodegener source

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

    Interpretationnone given

    Alterations in the GM, whether due to diet, antibiotics, or other factors, can impact the stress response, HPA axis activity, and overall cognitive health.

    “Alterations in the GM, whether due to diet, antibiotics, or other factors, can impact the stress response, HPA axis activity, and overall cognitive health.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Animal model findings about the GM-HPA-cognition relationship are informative about human biology.

  • May combine two claims.

    Premisecitation

    Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory.

    “Appropriate concentrations of cortisol are essential for normal neurodevelopment and function, as well as cognitive processes such as learning and memory, and studies have shown that microbes modulate the HPA axis throughout life.”
    • Also stated in: § The HPA axis, glucocorticoids, and the stress response · plain
      “Glucocorticoids also play a vital role in central nervous system (CNS) development and are required for normal maturation (139).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Strehl, 2019, Glucocorticoids–All-Rounders tackling the versatile players of the immune system, Front Immunol source

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    Premisecitation

    Acquisition of microbes occurs primarily at birth, with delivery through the birth canal exposing the infant to its mother's microbiota, resulting in vertical transmission of an initial maternal signature.

    “However, the acquisition of microbes occurs primarily at birth, with delivery through the birth canal exposing the infant to its mother’s microbiota, resulting in vertical transmission of an initial maternal signature (81).”
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    • cites [81] Frese, 2015, Birth of the infant gut microbiome: moms deliver twice, Cell Host Microbe source

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    Premisecitation

    Elevated cortisol levels have been associated with alterations in GM composition and increased gut permeability, which can lead to inflammation and contribute to brain dysfunction and various CNS disorders.

    “Elevated cortisol levels have been associated with alterations in GM composition and increased gut permeability, which can lead to inflammation and contribute to brain dysfunction and various CNS disorders (56).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Mangiola, 2016, Gut microbiota in autism and mood disorders, World J Gastroenterol source

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    Premisecitation

    Chronic or prolonged stress can lead to dysregulation of the HPA axis, which can have negative effects on various bodily systems, including the MGB axis.

    “Chronic or prolonged stress can lead to dysregulation of the HPA axis, which can have negative effects on various bodily systems, including the MGB axis (55).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Kelly, 2016, Transferring the blues: depression-associated gut microbiota induces neurobehavioural changes in the rat, J Psychiatr Res source

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    Premisecitation

    Cortisol receptors are expressed on various cells of the gut, including epithelial cells, immune cells, and enteroendocrine cells, indicating a direct effect of cortisol on gut function.

    “Cortisol receptors are expressed on various cells of the gut, including epithelial cells, immune cells, and enteroendocrine cells, indicating a direct effect of cortisol on gut function (21, 29, 48).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [21] Carabotti, 2015, The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems, Ann Gastroenterol

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    • cites [29] Tetel, 2018, Steroids, stress and the gut microbiome-brain axis, J Neuroendocrinol source

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    • cites [48] Mayer, 2000, The neurobiology of stress and gastrointestinal disease, Gut source

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    Premisecitation

    Cortisol can affect the gut microbiota by altering gut transit time, intestinal permeability, and nutrient availability, which can in turn impact the composition and diversity of the GM.

    “Cortisol can also affect the gut microbiota by altering gut transit time, intestinal permeability, and nutrient availability, which can in turn impact the composition and diversity of the GM (48).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Mayer, 2000, The neurobiology of stress and gastrointestinal disease, Gut source

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    Premisecitation

    A more stable and complex, adult-like microbiota starts to emerge as early as one to three years of age, although this development may continue as late as pre-adolescence.

    “A more stable and complex, adult-like microbiota starts to emerge as early as one to three years of age, although this development may continue as late as pre-adolescence (85, 86).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Yatsunenko, 2012, Human gut microbiome viewed across age and geography, Nature source

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    • cites [86] Hollister, 2015, Structure and function of the healthy pre-adolescent pediatric gut microbiome, Microbiome source

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    Premisecitation

    The HPA axis plays a central role in mediating the stress response and regulating the interaction between the GM, gut, and brain.

    “The HPA axis plays a central role in mediating the stress response and regulating the interaction between the GM, gut, and brain (42).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Dinan, 2017, Gut instincts: microbiota as a key regulator of brain development, ageing and neurodegeneration, J Physiol source

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

    Premisecitation

    In adulthood, the core GM is relatively stable, and the main factors influencing its composition are diet, exercise, stress, disease, and medications.

    “In adulthood, the core GM is relatively stable, and the main factors influencing its composition are diet, exercise, stress, disease, and medications (88).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Martino, 2022, Microbiota succession throughout life from the cradle to the grave, Nat Rev Microbiol source

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    Premisecitation

    Germ-free animal studies demonstrate that the GM is necessary for normal stress responsivity, anxiety-like behaviors, sociability, and cognition.

    “Finally, germ-free animal studies demonstrate that the GM is necessary for normal stress responsivity, anxiety-like behaviors, sociability, and cognition (123).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Luczynski, 2016, Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior, Int J Neuropsychopharmacol source

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    Premisecitation

    Diversity levels of the GM differ with aging, with a reduction in the number of different bacterial species present and changes in the relative abundance of different bacterial phyla, with a decrease in beneficial bacteria such as Bifidobacteria and an increase in potentially harmful bacteria such as Proteobacteria.

    “There is also evidence that the diversity levels of the GM differ with aging, with a reduction in the number of different bacterial species present and changes in the relative abundance of different bacterial phyla, with a decrease in beneficial bacteria such as Bifidobacteria and an increase in potentially harmful bacteria such as Proteobacteria (93–96).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [93] Claesson, 2011, Composition, variability, and temporal stability of the intestinal microbiota of the elderly, Proc Natl Acad Sci U.S.A. source

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    • cites [94] O’Toole, 2015, Gut microbiota and aging, Science source

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    • cites [95] Odamaki, 2016, Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study, BMC Microbiol source

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    • cites [96] Biagi, 2010, Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians, PloS One source

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    Premisecitation

    Human studies comparing the composition of the GM of elderly participants suffering from cognitive impairment with healthy individuals indicate significant changes in GM composition, specifically an increase in pro-inflammatory taxa and a reduction in anti-inflammatory taxa.

    “Human studies comparing the composition of the GM of elderly participants suffering from cognitive impairment with healthy individuals indicate significant changes in GM composition. Specifically, there is an increase in pro-inflammatory taxa and a reduction in anti-inflammatory taxa (104–109).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [104] Cattaneo, 2017, Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly, Neurobiol Aging source

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    • cites [105] Vogt, 2017, Gut microbiome alterations in alzheimer’s disease, Sci Rep source

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    • cites [106] Manderino, 2017, Preliminary evidence for an association between the composition of the gut microbiome and cognitive function in neurologically healthy older adults, J Int Neuropsychol Soc source

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    • cites [107] Zhuang, 2018, Gut microbiota is altered in patients with alzheimer’s disease, J Alzheimers Dis source

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    • cites [108] Saji, 2019, Analysis of the relationship between the gut microbiome and dementia: a cross-sectional study conducted in Japan, Sci Rep source

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    • cites [109] Sheng, 2021, Altered gut microbiota in adults with subjective cognitive decline: the SILCODE study, J Alzheimers Dis source

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    Premisecitation

    Dysbiosis has been associated with increased cortisol secretion, decreased negative feedback at the level of the hypothalamus, and changes in the circadian rhythm of cortisol release.

    “Similar to aging, dysbiosis has been associated with increased cortisol secretion, decreased negative feedback at the level of the hypothalamus, and changes in the circadian rhythm of cortisol release (113).”
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    • cites [113] Farzi, 2018, Gut microbiota and the neuroendocrine system, Neurotherapeutics source

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    Interpretationcitation

    The HPA axis appears to become less responsive with aging, contributing to the dysregulation of stress responses and the resultant development of cognitive decline.

    “Essentially, the HPA axis appears to become less responsive with aging, contributing to the dysregulation of stress responses and the resultant development of cognitive decline (111, 112).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Lupien, 1998, Cortisol levels during human aging predict hippocampal atrophy and memory deficits, Nat Neurosci source

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    • cites [112] Hinkelmann, 2012, Changes in cortisol secretion during antidepressive treatment and cognitive improvement in patients with major depression: a longitudinal study, Psychoneuroendocrinology source

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    • Rests on an assumption: Animal model findings about the GM-HPA-cognition relationship are informative about human biology.

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    Premisecitation

    These peptides stimulate the release of ACTH from corticotropic cells of the anterior pituitary gland, which in turn targets the zona fasciculata of the adrenal cortex to produce glucocorticoids, such as cortisol in humans and corticosterone in rodents.

    “These peptides stimulate the release of adrenocorticotropic hormone (ACTH) from corticotropic cells of the anterior pituitary gland, which in turn targets the zona fasciculata of the adrenal cortex to produce glucocorticoids, such as cortisol in humans and corticosterone in rodents (133–135).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [133] Rifai, 2018

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    • cites [134] Buckingham, 1996, The physiology of immunity, Progress in Brain Research

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    • cites [135] Buckingham, 2006, Glucocorticoids: exemplars of multi-tasking, Br J Pharmacol source

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

    Premisecitation

    The HPA axis is a major stress response system in the body, with neurons in the hypothalamic paraventricular nucleus synthesizing and secreting CRH and ADH in response to stress.

    “The HPA axis is a major stress response system in the body, with neurons in the hypothalamic paraventricular nucleus (PVN) synthesizing and secreting corticotropin-releasing hormone (CRH) and antidiuretic hormone (ADH) in response to stress (133).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Rifai, 2018

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

    Premisecitation

    Cortisol acts on the hypothalamus and pituitary in a negative feedback loop to regulate the response.

    “Cortisol acts on the hypothalamus and pituitary in a negative feedback loop to regulate the response (133).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [133] Rifai, 2018

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    Premisecitation

    HPA axis dysfunction is linked to a decline in cognitive function, aging, immune system dysfunction, and systemic inflammation.

    “HPA axis dysfunction is linked to a decline in cognitive function, aging, immune system dysfunction, and systemic inflammation (135).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Buckingham, 2006, Glucocorticoids: exemplars of multi-tasking, Br J Pharmacol source

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  • May combine two claims.

    Premisecitation

    Microbes influence CNS processes via modulation of the nervous system, endocrine system, and immune system, together with their ability to synthesize neurotransmitters and produce metabolites.

    “Microbes influence CNS processes via modulation of the nervous system (52), endocrine system (51, 126), and immune system (120), together with their ability to synthesize neurotransmitters (127–129) and produce metabolites (127, 130–132) ( Figure 1 ).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [52] Forsythe, 2014

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    • cites [51] Sudo, 2004, Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice, J Physiol source

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    • cites [126] Mudd, 2017, Serum cortisol mediates the relationship between fecal ruminococcus and brain n-acetylaspartate in the young pig, Gut Microbes source

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    • cites [120] Erny, 2015, Host microbiota constantly control maturation and function of microglia in the CNS, Nat Neurosci source

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  • May combine two claims.

    Premisecitation

    Male germ-free mice have increased hippocampal serotonin levels, which colonization immediately post-weaning does not reverse.

    “male germ-free mice have increased hippocampal serotonin levels, which colonization immediately post-weaning does not reverse (124).”
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    • cites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci source

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  • May combine two claims.

    Interpretationnone given

    GABA does not cross the BBB, so microbial-derived GABA would need to act locally on the ENS or vagus nerve to influence the CNS.

    “GABA does not cross the BBB and so microbial-derived GABA would need to act locally on the ENS or vagus nerve to influence the CNS.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: GABA does not cross the blood-brain barrier.

  • May combine two claims.

    Interpretationreasoning

    The development of the serotonergic system within the MGB axis depends on a low-stress environment and early life events may be critical.

    “the development of the serotonergic system within the MGB axis depends on a low-stress environment and early life events may be critical.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In rats, B. infantis reduces frontal cortex 5-HIAA and increases blood tryptophan and kynurenic acid.

    “When administered to rats, B. infantis results in reduced 5-HIAA (serotonin metabolite) concentrations in the frontal cortex, and a marked increase in blood concentrations of tryptophan and kynurenic acid (224).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [224] Desbonnet, 2008, The probiotic bifidobacteria infantis: an assessment of potential antidepressant properties in the rat, J Psychiatr Res source

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    Premisecitation

    Brainstem catecholaminergic centers regulate the HPA axis, and noradrenergic neurons are required for normal activation in response to a variety of stressors.

    “brainstem catecholaminergic centers play an important role in the regulation of the HPA axis (227) and noradrenergic neurons are required for normal activation in response to a variety of stressors.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [227] Herman, 2016, Regulation of the hypothalamic-Pituitary-Adrenocortical stress response, Compr Physiol source

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  • May combine two claims.

    Premisecitation

    In healthy women, Bacteroides levels are associated with increased grey matter in the cerebellum, hippocampus, and frontal regions, and reduced anxiety, distress, and irritability.

    “in a study of healthy women, levels of Bacteroides, identified as the major microbial producers of GABA, were associated with increased grey matter in the cerebellum, hippocampus, and frontal regions of the brain, as well as reduced levels of anxiety, distress, and irritability (236).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [236] Tillisch, 2017, Brain structure and response to emotional stimuli as related to gut microbial profiles in healthy women, Psychosom Med source

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  • May combine two claims.

    Premisecitation

    The GM regulates serotonin availability by signaling enterochromaffin cells to produce serotonin via TPH expression, and by altering SCFAs and BAs.

    “The GM can further regulate serotonin availability by signaling enterochromaffin cells to produce serotonin via expression of tryptophan hydroxylase, and by altering levels of SCFAs and BAs which can influence serotonin production (46, 164, 221–223).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [46] Vuong, 2017, The microbiome and host behavior, Annu Rev Neurosci source

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    • cites [164] Yano, 2015, Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis, Cell source

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    • cites [221] Gershon, 2007, The serotonin signaling system: from basic understanding to drug development for functional GI disorders, Gastroenterology source

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    • cites [222] Reigstad, 2015, Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells, FASEB J Off Publ Fed Am Soc Exp Biol source

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    • cites [223] Wikoff, 2009, Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites, Proc Natl Acad Sci source

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    Premisecitation

    The GM can metabolize GABA, and certain microbes produce GABA required for their growth.

    “The GM can metabolize GABA and recent research has shown that certain microbes can produce GABA, required for their growth (235).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [235] Strandwitz, 2019, GABA-modulating bacteria of the human gut microbiota, Nat Microbiol source

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  • May combine two claims.

    Interpretationreasoning

    The GM can indirectly influence the activity of the serotonergic system, which in turn can affect the HPA axis and stress response.

    “the GM can indirectly influence the activity of the serotonergic system, which in turn can affect the HPA axis and stress response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SCFAs such as acetate can cross the BBB and be incorporated into the GABA metabolic cycle.

    “SCFAs such as acetate can cross the BBB and be incorporated into the GABA metabolic cycle (237).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [237] Frost, 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nat Commun source

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    Premisecitation

    Bacteria produce noradrenaline as a quorum sensing molecule, and noradrenaline and adrenaline can promote pathogenesis and growth.

    “bacteria produce noradrenaline as a quorum sensing molecule, and noradrenaline and adrenaline can promote pathogenesis and growth (229, 230)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [229] Sperandio, 2003, Bacteria–host communication: the language of hormones, Proc Natl Acad Sci source

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    • cites [230] Lyte, 1992, Catecholamine induced growth of gram negative bacteria, Life Sci source

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  • May combine two claims.

    Premisecitation

    Activation of stress-responsive TDO or immune-responsive IDO limits tryptophan availability for serotonin synthesis and increases production of neurotoxic or neuroprotective metabolites.

    “Activation of stress-responsive TDO or immune-responsive IDO can limit the availability of tryptophan for serotonin synthesis and increase the downstream production of neurotoxic or neuroprotective metabolites (31).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] O’Mahony, 2015, Serotonin, tryptophan metabolism and the brain-gut-microbiome axis, Behav Brain Res source

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  • May combine two claims.

    Premisecitation

    Glucocorticoids and tryptophan induce TDO, while cytokines induce IDO.

    “Glucocorticoids and tryptophan induce TDO, while cytokines induce IDO (200).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Ruddick, 2006, Tryptophan metabolism in the central nervous system: medical implications, Expert Rev Mol Med source

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  • May combine two claims.

    Premisecitation

    The ECS modulates the HPA axis, cognition, learning and memory, intestinal-barrier function, inflammation, and energy metabolism.

    “The ECS modulates a multitude of physiological processes, including the HPA axis (241), cognition, learning and memory (242), intestinal-barrier function (243), inflammation (244), energy metabolism (245), among others (reviewed recently (239)).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [241] Micale, 2018, Endocannabinoid system, stress and HPA axis, Eur J Pharmacol source

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    • cites [242] Zanettini, 2011, Effects of endocannabinoid system modulation on cognitive and emotional behavior, Front Behav Neurosci source

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    • cites [243] Muccioli, 2010, The endocannabinoid system links gut microbiota to adipogenesis, Mol Syst Biol source

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    • cites [244] Donvito, 2018, The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain, Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol source

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    • cites [245] Wang, 2008, Role of the endocannabinoid system in metabolic control, Curr Opin Nephrol Hypertens source

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    • cites [239] Cristino, 2020, Cannabinoids and the expanded endocannabinoid system in neurological disorders, Nat Rev Neurol source

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  • May combine two claims.

    Premisecitation

    The HPA axis is regulated by GABAergic signaling at the level of CRH, and nearly 50% of synapses in the PVN are GABAergic.

    “The HPA axis is also regulated by GABAergic signaling at the level of CRH, and nearly 50% of all synapses in the PVN are GABAergic (233).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Miklós, 2002, GABAergic innervation of corticotropin-releasing hormone (CRH)-secreting parvocellular neurons and its plasticity as demonstrated by quantitative immunoelectron microscopy, Neuroscience source

      Not checked in the free run.

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    Premisecitation

    Serotonergic neurons have significant influence on neuroendocrine function, and there is crosstalk between the serotonergic system and HPA axis.

    “Serotonergic neurons have a significant influence on neuroendocrine function, and there is a dynamic interplay and extensive crosstalk between the serotonergic system and HPA axis (215).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [215] Berger, 2009, The expanded biology of serotonin, Annu Rev Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The GM modulates the tryptophan and kynurenine pathways and is a humoral route through which the GM may influence cognition at the level of the CNS.

    “Mounting evidence suggests that the GM modulates the tryptophan and kynurenine pathways and is a humoral route through which the GM may influence cognition at the level of the CNS (206–210).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [206] Bosi, 2020, Tryptophan metabolites along the microbiota-Gut-Brain axis: an interkingdom communication system influencing the gut in health and disease, Int J Tryptophan Res source

      Not checked in the free run.

    • cites [207] Kiser, 2012, The reciprocal interaction between serotonin and social behaviour, Neurosci Biobehav Rev source

      Not checked in the free run.

    • cites [208] Homberg, 2012, Serotonin and decision making processes, Neurosci Biobehav Rev source

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    • cites [209] Schwarcz, 2012, Kynurenines in the mammalian brain: when physiology meets pathology, Nat Rev Neurosci source

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    • cites [210] Szalardy, 2012, Manipulating kynurenic acid levels in the brain - on the edge between neuroprotection and cognitive dysfunction, Curr Top Med Chem source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The GM can ultimately influence levels of neurotransmitters in the brain and alter brain function and cognition.

    “there is a growing body of evidence suggesting that the GM can ultimately influence the levels of neurotransmitters in the brain and alter brain function and cognition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Germ-free mice exhibit reduced colonic serotonin production and decreased blood serotonin, which normalize with microbial colonization.

    “Germ-free mice exhibit reduced colonic serotonin production and decreased levels in the blood, which normalize with microbial colonization (164, 223).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [164] Yano, 2015, Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis, Cell source

      Not checked in the free run.

    • cites [223] Wikoff, 2009, Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites, Proc Natl Acad Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice colonized with Candida albicans show anxiety-like behavior and increased corticosterone inversely correlated with forebrain AEA, demonstrating HPA axis disruption via ECS dysregulation.

    “Healthy mice colonized with Candida albicans showed marked anxiety-like behavior and increased corticosterone concentrations that were inversely correlated with forebrain AEA, demonstrating disruption of the HPA axis through dysregulation of the ECS (253).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [253] Markey, 2020, Colonization with the commensal fungus candida albicans perturbs the gut-brain axis through dysregulation of endocannabinoid signaling, Psychoneuroendocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microbes and microbial products gain access to the circulation and may gain easier access to the CNS.

    “Microbes and microbial products then gain access to the circulation and may gain easier access to the CNS (262).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [262] Logsdon, 2018, Gut reactions: how the blood-brain barrier connects the microbiome and the brain, Exp Biol Med (Maywood) source

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  • May combine two claims.

    Premisecitation

    Dysbiosis affects eCB signaling, and vice versa.

    “Dysbiosis affects eCB signaling, and vice versa (243).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [243] Muccioli, 2010, The endocannabinoid system links gut microbiota to adipogenesis, Mol Syst Biol source

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  • May combine two claims.

    Premisecitation

    SCFAs are necessary for the maintenance of CNS homeostasis, learning and cognition, and reward-associated behaviors.

    “SCFAs are necessary for the maintenance of CNS homeostasis, learning and cognition, and reward-associated behaviors (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Cryan, 2019, The microbiota-gut-brain axis, Physiol Rev source

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  • May combine two claims.

    Premisecitation

    SCFAs modulate neurotransmitter and neurotrophic factor levels and regulate expression of tryptophan 5-hydroxylase and tyrosine hydroxylase.

    “SCFAs can modulate the levels of neurotransmitters and neurotrophic factors and regulate the expression of tryptophan 5-hydroxylase, the enzyme involved in the synthesis of serotonin, and tyrosine hydroxylase, the enzyme involved in the rate-limiting step in dopamine, noradrenaline, and adrenaline synthesis (18, 132, 164, 222).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [18] Clarke, 2014, Minireview: gut microbiota: the neglected endocrine organ, Mol Endocrinol source

      Not checked in the free run.

    • cites [132] Dalile, 2019, The role of short-chain fatty acids in microbiota–gut–brain communication, Nat Rev Gastroenterol Hepatol source

      Not checked in the free run.

    • cites [164] Yano, 2015, Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis, Cell source

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    • cites [222] Reigstad, 2015, Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells, FASEB J Off Publ Fed Am Soc Exp Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microbial products, cytokines, and other immune molecules released under the influence of the GM may influence BBB integrity, alter BBB transport rates, and promote release of neuroimmune molecules from BBB cells.

    “microbial products, cytokines, and other immune molecules released under the influence of the GM may further influence the BBB’s integrity, alter BBB transport rates, and promote the release of neuroimmune molecules from the cells of the BBB (262).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [262] Logsdon, 2018, Gut reactions: how the blood-brain barrier connects the microbiome and the brain, Exp Biol Med (Maywood) source

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  • May combine two claims.

    Interpretationreasoning

    These factors may lead to neuroinflammation, which is an important process shaping brain function.

    “These factors may lead to neuroinflammation, which is an important process shaping brain function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Perturbations in microbial diversity due to antimicrobials influence pro-inflammatory cytokine secretion in the CNS and alter microglial morphology.

    “Perturbations in microbial diversity, secondary to antimicrobials, have been shown to influence pro-inflammatory cytokine secretion in the CNS and alter microglial morphology (268–270).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [268] Minter, 2016, Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of alzheimer’s disease, Sci Rep source

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    • cites [269] Minter, 2017, Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APP SWE /PS1 ΔE9 murine model of alzheimer’s disease OPEN, Sci Rep source

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    • cites [270] Jang, 2018, Evidence for interplay among antibacterial-induced gut microbiota disturbance, neuro-inflammation, and anxiety in mice, Mucosal Immunol source

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  • May combine two claims.

    Premisecitation

    The GM is closely linked to the immune system, and they interact in several ways.

    “The GM is therefore closely linked to the immune system, and they interact in several ways [reviewed recently (256, 257)].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [256] Zheng, 2020, Interaction between microbiota and immunity in health and disease, Cell Res source

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    • cites [257] Zhang, 2022, The complex link and disease between the gut microbiome and the immune system in infants, Front Cell Infect Microbiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In response to stress, eCB signaling modulates glucocorticoid and CRH signaling in the brain and is crucial for recovering homeostasis.

    “In response to stress, eCB signaling modulates glucocorticoid and CRH signaling in the brain and is crucial in recovering homeostasis (241, 246, 247).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [241] Micale, 2018, Endocannabinoid system, stress and HPA axis, Eur J Pharmacol source

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    • cites [246] Srivastava, 2022, The microbiome and gut endocannabinoid system in the regulation of stress responses and metabolism, Front Cell Neurosci source

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    • cites [247] Hillard, 2016, Endocannabinoid signaling and the hypothalamic-Pituitary-Adrenal axis, Compr Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some BAs serve as substrates for gut microbes, while others exhibit antimicrobial properties, shaping the GM at the highest taxonomic levels.

    “Some BAs serve as substrates for gut microbes, while others exhibit antimicrobial properties, actively shaping the GM at the highest taxonomic levels (318).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [318] Peter, 2006, Mechanism of growth inhibition by free bile acids in lactobacilli and bifidobacteria, J Bacteriol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The GM influences BA metabolism, and BAs affect the GM's composition.

    “The GM influences BA metabolism, and BAs affect the GM’s composition (296).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [296] Ramírez-Pérez, 2017, The role of the gut microbiota in bile acid metabolism, Ann Hepatol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    SCFAs regulate CNS processes through both direct and indirect mechanisms and may ultimately affect host cognition and response to stress.

    “These findings suggest that SCFAs regulate CNS processes through both direct and indirect mechanisms and may ultimately affect host cognition and response to stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TGR5 is expressed in brain and peripheral neurons, glial and microglial cells, and can be activated by several neurosteroids.

    “TGR5, expressed in brain and peripheral neurons, as well as glial and microglial cells, can be activated by several neurosteroids (305).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [305] Keitel, 2010, The bile acid receptor TGR5 (Gpbar-1) acts as a neurosteroid receptor in brain, Glia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Changes in the GM's composition correspond to changes in blood and brain BA profiles, and specific BA ligands' physicochemical properties determine the potency of BA receptor activation.

    “Changes in the GM’s composition correspond to changes in blood and brain BA profiles, which are essential because specific BA ligands’ distinct physicochemical properties determine the potency of BA receptor activation (320–323).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [320] Grant, 2020, Bile acid signaling in neurodegenerative and neurological disorders, Int J Mol Sci source

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    • cites [321] Jia, 2020, Expert insights: the potential role of the gut microbiome-bile acid-brain axis in the development and progression of alzheimer’s disease and hepatic encephalopathy, Med Res Rev source

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    • cites [322] Makishima, 1999, Identification of a nuclear receptor for bile acids, Science source

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    • cites [323] Sayin, 2013, Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist, Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In stressed mice, SCFA administration reduces HPA axis hyperactivity and intestinal permeability.

    “In stressed mice, SCFA administration reduced HPA axis hyperactivity and intestinal permeability (291).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [291] van de Wouw, 2018, Short-chain fatty acids: microbial metabolites that alleviate stress-induced brain–gut axis alterations, J Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FXR knockout mice exhibit abnormal BA and neurotransmitter concentrations, resulting in impaired cognition and motor coordination.

    “FXR knockout mice exhibit abnormal BA and neurotransmitter concentrations, resulting in impaired cognition and motor coordination (304).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [304] Huang, 2015, Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior, Front Behav Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BAs are important modulators of the MGB axis, functioning directly via BA receptors in the ENS and brain or indirectly via GLP-1 or the FXR-FGF15/19 axis.

    “these metabolites have emerged as important modulators of the MGB axis, functioning directly via BA receptors in the ENS and brain or indirectly via GLP-1 or the FXR-FGF15/19 axis (297, 319).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [297] Mertens, 2017, Bile acid signaling pathways from the enterohepatic circulation to the central nervous system, Front Neurosci source

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    • cites [319] Katafuchi, 2022, Molecular basis of bile acid-FXR-FGF15/19 signaling axis, Int J Mol Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BA receptors are present in the brain, and BAs can be synthesized locally or actively transported across the BBB by BA transporters from circulation.

    “BA receptors are present in the brain, and BAs can either be synthesized locally or actively transported across the BBB by BA transporters from circulation (297, 301, 302).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [297] Mertens, 2017, Bile acid signaling pathways from the enterohepatic circulation to the central nervous system, Front Neurosci source

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    • cites [301] Trauner, 2003, Bile salt transporters: molecular characterization, function, and regulation, Physiol Rev source

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    • cites [302] Baloni, 2020, Metabolic network analysis reveals altered bile acid synthesis and metabolism in alzheimer’s disease, Cell Rep Med source

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  • May combine two claims.

    Premisecitation

    Cholestasis is associated with suppression of the HPA axis, likely due to BA interactions with glucocorticoid receptors in the brain.

    “Cholestasis, associated with suppression of the HPA axis, likely due to BA interactions with glucocorticoid receptors in the brain (299, 312).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [299] McMillin, 2015, Suppression of the HPA axis during cholestasis can be attributed to hypothalamic bile acid signaling, Mol Endocrinol source

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    • cites [312] Perry, 2015, FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic–pituitary–adrenal axis, Nat Commun source

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  • May combine two claims.

    Premisecitation

    FXR activation regulates lipoprotein receptors and transporters and steroidogenic enzymes, and increases corticosterone levels in mice.

    “FXR activation is known to regulate lipoprotein receptors and transporters, as well as enzymes in the steroidogenic pathway, and has been shown to increase corticosterone levels in mice (311).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [311] Theiler-Schwetz, 2019, Bile acids and glucocorticoid metabolism in health and disease, Biochim Biophys Acta - Mol Basis Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice supplemented with a branched-chain amino acid-enriched cocktail exhibited improved physical endurance and an extended lifespan.

    “Mice supplemented with a BCAA-enriched cocktail exhibited improved physical endurance and an extended lifespan (335).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [335] D’Antona, 2010, Branched-chain amino acid supplementation promotes survival and supports cardiac and skeletal muscle mitochondrial biogenesis in middle-aged mice, Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stress during pregnancy disrupts the vertical transmission of microbes from mother to offspring, leading to alterations in the maternal microbiota that are then transferred to the offspring.

    “Stress during pregnancy disrupts the vertical transmission of microbes from mother to offspring, leading to alterations in the maternal microbiota, which are then transferred to the offspring (342).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [342] Dinan, 2012, Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology, Psychoneuroendocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The microbiota and HPA axis develop rapidly and profoundly in the first years of life.

    “The microbiota and HPA axis develop rapidly and profoundly in the first years of life, and environmental stressors can affect both (146–148).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [146] Gur, 2019, Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring, Behav Brain Res source

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    • cites [147] Zijlmans, 2015, Maternal prenatal stress is associated with the infant intestinal microbiota, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [148] Jang, 2018, Immobilization stress-induced escherichia coli causes anxiety by inducing NF-κB activation through gut microbiota disturbance, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In response to early life stress, younger rats had increased neurogenesis, decreased BDNF IV promoter histone methylation, increased hippocampal BDNF concentration, and improved spatial and non-spatial learning.

    “In response to early life stress, younger rats had increased neurogenesis, decreased BDNF IV promoter histone methylation, with a complementary increase in hippocampal BDNF concentration, and associated improvements in spatial and non-spatial learning (348).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [348] Suri, 2013, Early stress evokes age-dependent biphasic changes in hippocampal neurogenesis, BDNF expression, and cognition, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Middle-aged rats demonstrated opposing changes to younger rats after early life stress, with impairments in hippocampal-dependent cognitive tasks.

    “In contrast, middle-aged rats demonstrated opposing changes, concomitant with impairments in hippocampal-dependent cognitive tasks.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [348] Suri, 2013, Early stress evokes age-dependent biphasic changes in hippocampal neurogenesis, BDNF expression, and cognition, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Glutamate and GABA modulate the hypothalamic-pituitary-adrenal axis.

    “In the CNS, BCAAs play roles in protein synthesis, food intake regulation, and serve as nitrogen donors involved in intercellular shuttling and the synthesis of the neurotransmitters glutamate and GABA (both modulate the HPA axis) (336).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336] Sperringer, 2017, Branched-chain amino acids and brain metabolism, Neurochem Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early life stressors and in utero stressors can impact the development and function of the HPA axis.

    “Early life stressors, and in utero stressors, can impact the development and function of the HPA axis (149).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [149] Maniam, 2014, Early-life stress, HPA axis adaptation, and mechanisms contributing to later health outcomes, Front Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early life stress, such as maternal separation, activates the HPA axis with associated changes to the developing microbiota, ultimately leading to an imbalance in the gut microbiota and an inappropriate stress response.

    “Early life stress, such as maternal separation, activates the HPA axis with associated changes to the developing microbiota, ultimately leading to an imbalance in the GM and an inappropriate stress response (18).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Clarke, 2014, Minireview: gut microbiota: the neglected endocrine organ, Mol Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Environmental stressors can affect both the microbiota and the HPA axis.

    “The microbiota and HPA axis develop rapidly and profoundly in the first years of life, and environmental stressors can affect both (146–148).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [146] Gur, 2019, Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring, Behav Brain Res source

      Not checked in the free run.

    • cites [147] Zijlmans, 2015, Maternal prenatal stress is associated with the infant intestinal microbiota, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [148] Jang, 2018, Immobilization stress-induced escherichia coli causes anxiety by inducing NF-κB activation through gut microbiota disturbance, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Early life stress has biphasic consequences and indicates a role for epigenetic modification of BDNF expression.

    “These discordant results illustrate the biphasic consequences of early life stress and indicate a role for epigenetic modification of BDNF expression.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Jašarević et al. demonstrated changes in the microbiome of offspring and alterations in the metabolome of the gut and brain.

    “Jašarević et al. demonstrated changes in the microbiome of these offspring, as well as alterations in the metabolome of the gut and brain (343).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [343] Jašarević, 2015, Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain, Endocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the central nervous system, branched-chain amino acids play roles in protein synthesis, food intake regulation, and serve as nitrogen donors involved in intercellular shuttling and synthesis of the neurotransmitters glutamate and GABA.

    “In the CNS, BCAAs play roles in protein synthesis, food intake regulation, and serve as nitrogen donors involved in intercellular shuttling and the synthesis of the neurotransmitters glutamate and GABA (both modulate the HPA axis) (336).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336] Sperringer, 2017, Branched-chain amino acids and brain metabolism, Neurochem Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following chronic restraint stress, germ-free mice showed significantly greater HPA axis activity, whereas SPF mice exhibited more anxiety-like behaviors under the same stress.

    “Following chronic restraint stress, germ-free mice showed significantly greater HPA axis activity, whereas the SPF mice exhibited more anxiety-like behaviors under the same stress (349).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [349] Huo, 2017, Microbiota modulate anxiety-like behavior and endocrine abnormalities in hypothalamic-pituitary-adrenal axis, Front Cell Infect Microbiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiota is necessary for stress-induced immunomodulation, with enhancement of splenic macrophage reactivity occurring in colonized controls but not in germ-free mice in response to social disruption stress.

    “A study by Allen et al. demonstrated that the GM is necessary for stress-induced immunomodulation, with enhancement of splenic macrophage reactivity occurring in colonized controls but not in germ-free mice, in response to social disruption stress (360).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [360] Allen, 2012, The intestinal microbiota are necessary for stressor-induced enhancement of splenic macrophage microbicidal activity, Brain Behav Immun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the four-week study, participants reported reductions in perceived stress, but these were not significantly different from controls, and markers of stress were unaffected.

    “Participants reported reductions in perceived stress, but these were not significantly different to controls, and markers of stress were unaffected.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [374] Berding, 2022, Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population, Mol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In another randomized control trial, a combination probiotic (L. helveticus R0052 and B. longum R0175) administered to healthy volunteers was associated with beneficial psychological effects and a decrease in 24-hour urinary cortisol, suggesting attenuation of the HPA axis in response to stressors.

    “In another RCT, a combination probiotic (L. helveticus (R0052) and B. longum (R0175)) administered to healthy volunteers was associated with beneficial psychological effects in participants and a decrease in 24-hour urinary cortisol, suggesting attenuation of the HPA axis in response to stressors (372).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [372] Messaoudi, 2011, Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and bifidobacterium longum R0175) in rats and human subjects, Br J Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The introduction of pathogenic bacteria reduced cognitive abilities and heightened anxiety-like behaviors.

    “The introduction of pathogenic bacteria reduced cognitive abilities and heightened anxiety-like behaviors (362, 363).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [362] Gareau, 2011, Bacterial infection causes stress-induced memory dysfunction in mice, Gut source

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    • cites [363] Jiang, 2013, The effect of maternal infection on cognitive development and hippocampus neuronal apoptosis, proliferation and differentiation in the neonatal rats, Neuroscience source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pre-treatment with L. farciminis reduced HPA hyper-reactivity, intestinal permeability, and neuroinflammation resulting from restraint stress.

    “Similarly, pre-treatment with L. farciminis reduced HPA hyper-reactivity, intestinal permeability, and neuroinflammation resulting from restraint stress (367).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [367] Ait-Belgnaoui, 2012, Prevention of gut leakiness by a probiotic treatment leads to attenuated HPA response to an acute psychological stress in rats, Psychoneuroendocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Animal models of chronic stress demonstrate altered intestinal physiology and gut microbiota composition, with an increased secretory state and permeability.

    “Animal models of chronic stress demonstrate altered intestinal physiology and GM composition, with an increased secretory state and permeability (352–355).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [352] Söderholm, 2002, Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine, Gastroenterology source

      Not checked in the free run.

    • cites [353] Cameron, 2005, Stress impairs murine intestinal barrier function: improvement by glucagon-like peptide-2, J Pharmacol Exp Ther source

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    • cites [354] Sun, 2013, Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice, Gastroenterology source

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    • cites [355] Lutgendorff, 2008, The role of microbiota and probiotics in stress-induced gastro-intestinal damage, Curr Mol Med source

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    Alterations in cognition occurred both in the short- and long-term after LPS-induced inflammatory stress, confirming mechanisms for both the promotion and inhibition of cognitive performance.

    “Alterations in cognition occurred both in the short- and long-term, confirming mechanisms for both the promotion and inhibition of cognitive performance during acute inflammatory stress.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [371] Grigoleit, 2011, Dose-dependent effects of endotoxin on neurobehavioral functions in humans, PloS One source

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    Premisecitation

    Chronically stressed mice challenged orally with C. rodentium had an increased pathogen load and increased colonic TNF-α expression.

    “When challenged orally with the enteric murine pathogen C. rodentium, chronically stressed mice had an increased pathogen load and increased colonic TNF-α expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [359] Bailey, 2010, Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by citrobacter rodentium, Infect Immun source

      Not checked in the free run.

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    Premisecitation

    The neurochemical effects of L. rhamnosus were not found in vagotomised mice, implicating the vagal pathway.

    “Notably, the neurochemical effects were not found in vagotomised mice, implicating the vagal pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Bravo, 2011, Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve, Proc Natl Acad Sci source

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    Premisecitation

    Germ-free mice showed decreased expression of NMDA receptor subunits NR-1 in the cortex and NR-2a in the cortex and hippocampus, and lower BDNF levels in the cortex and hippocampus.

    “Moreover, these animals showed decreased expression of NMDA receptor subunits (NR-1) in the cortex, and of NR-2a in the cortex and hippocampus, while BDNF levels were lower in the cortex and hippocampus.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Sudo, 2004, Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice, J Physiol source

      Not checked in the free run.

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    Premisecitation

    A recent meta-analysis of randomized control trials showed that probiotic use generally reduced subjective stress levels and appeared to alleviate stress-related sub-threshold anxiety and depression in healthy individuals.

    “A recent meta-analysis of RCTs focusing on the efficacy of probiotics on stress in healthy individuals showed that probiotic use generally reduced subjective stress levels and appeared to alleviate stress-related sub-threshold anxiety and depression (373).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [373] Zhang, 2020, Efficacy of probiotics on stress in healthy volunteers: a systematic review and meta-analysis based on randomized controlled trials, Brain Behav source

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    Premisecitation

    Without a complex microbiota, both antibiotic-treated and germ-free mice exhibited altered fear-associated behavior, changes in gene expression in brain cells, and alterations in the firing patterns and rewiring ability of neurons.

    “Without a complex microbiota, both types of mice exhibited altered fear-associated behavior, changes in gene expression in brain cells, and alterations in the firing patterns and rewiring ability of neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [385] Chu, 2019, The microbiota regulate neuronal function and fear extinction learning, Nature source

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    Premisecitation

    Supplementation with various Lactobacillus species resulted in improvements in cognitive abilities and social deficits, and these changes occurred alongside altered GABA expression in the brain, as well as significant changes in the oxytocin and vagus nerve pathways.

    “Supplementation with various Lactobacillus species resulted in improvements in cognitive abilities and social deficits and these changes were shown to occur alongside altered GABA expression in the brain, as well as significant changes in the oxytocin and vagus nerve pathways (191, 391).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [191] Bravo, 2011, Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve, Proc Natl Acad Sci source

      Not checked in the free run.

    • cites [391] Buffington, 2016, Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring, Cell source

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    Premisecitation

    The probiotic B. longum (NCC3001) demonstrated vagal pathway-mediated anxiolytic effects in mice, and B. longum (1714) showed improved learning and memory after 11 weeks of supplementation.

    “The probiotic B. longum (NCC3001) demonstrated vagal pathway-mediated anxiolytic effects in mice and B. longum (1714) showed improved learning and memory after 11 weeks of supplementation (192, 390).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [192] Bercik, 2011, The anxiolytic effect of bifidobacterium longum NCC3001 involves vagal pathways for gut–brain communication, Neurogastroenterol Motil source

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    • cites [390] Savignac, 2015, Bifidobacteria modulate cognitive processes in an anxious mouse strain, Behav Brain Res source

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    Premisecitation

    Behavioral differences in germ-free mice include an anxiolytic-like manner when compared to SPF controls, although some studies report increased anxiety-like behavior in different species.

    “Behavioral differences in germ-free mice include their anxiolytic-like manner when compared to SPF controls, although some studies report increased anxiety-like behavior in different species (124, 189, 351, 376).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci source

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    • cites [189] Neufeld, 2011, Reduced anxiety-like behavior and central neurochemical change in germ-free mice, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source

      Not checked in the free run.

    • cites [351] Crumeyrolle-Arias, 2014, Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats, Psychoneuroendocrinology source

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    • cites [376] Bercik, 2011, The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice, Gastroenterology source

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  • May combine two claims.

    Premisecitation

    Germ-free mice present with social cognitive deficits, which may be associated with biochemical changes such as decreased hippocampal BDNF and c-FOS expression.

    “Germ-free mice present with social cognitive deficits, which may be associated with biochemical changes, such as decreased hippocampal BDNF and c-FOS expression, important in memory (124, 362, 376, 377).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci source

      Not checked in the free run.

    • cites [362] Gareau, 2011, Bacterial infection causes stress-induced memory dysfunction in mice, Gut source

      Not checked in the free run.

    • cites [376] Bercik, 2011, The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice, Gastroenterology source

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    • cites [377] Desbonnet, 2014, Microbiota is essential for social development in the mouse, Mol Psychiatry source

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  • May combine two claims.

    Premisecitation

    Six weeks of administration with the probiotic Clostridium butyricum restored cognitive function in a mouse model for vascular dementia, which was associated with increased butyrate levels in fecal and brain samples and activation of the hippocampal BDNF-PI3K/Akt pathway.

    “Six weeks of administration with the probiotic Clostridium butyricum restored cognitive function in a mouse model for vascular dementia, which was associated with increased butyrate levels in fecal and brain samples, and activation of the hippocampal BDNF-PI3K/Akt pathway (392).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [392] Liu, 2015, Neuroprotective effects of clostridium butyricum against vascular dementia in mice via metabolic butyrate, BioMed Res Int source

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  • May combine two claims.

    Premisecitation

    Female offspring displayed increased cognitive deficits and anxiety-like behavior following prenatal stress, which were associated with gut microbiota alterations in pregnant females and increased IL-1β and decreased BDNF levels in utero.

    “Female offspring displayed increased cognitive deficits and anxiety-like behavior following prenatal stress, which were associated with GM alterations in the pregnant females and increased IL-1β and decreased BDNF levels in utero (381).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [381] Gur, 2017, Prenatal stress affects placental cytokines and neurotrophins, commensal microbes, and anxiety-like behavior in adult female offspring, Brain Behav Immun source

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  • May combine two claims.

    Premisecitation

    Selective colonization revealed a critical developmental period, indicating that microbiota-derived signals were required during early post-natal and adult life for normal learning.

    “Selective colonization revealed a critical developmental period, indicating that microbiota-derived signals were required during early post-natal and adult life for normal learning.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [385] Chu, 2019, The microbiota regulate neuronal function and fear extinction learning, Nature source

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  • May combine two claims.

    Premisecitation

    These changes include increased hippocampal dopamine D1 receptor mRNA levels, decreased dopamine D1 receptor in the striatum and nucleus accumbens, increased serotonin in the blood and hippocampus, and decreased serotonin receptor expression.

    “These changes include increased hippocampal dopamine D1 receptor mRNA levels and decreased dopamine D1 receptor in the striatum and nucleus accumbens, as well as increased serotonin in the blood and hippocampus, with decreased serotonin receptor expression, respectively.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci source

      Not checked in the free run.

    • cites [189] Neufeld, 2011, Reduced anxiety-like behavior and central neurochemical change in germ-free mice, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source

      Not checked in the free run.

    • cites [350] Clarke, 2013, The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner, Mol Psychiatry source

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    • cites [378] Lukić, 2019, Role of tryptophan in microbiota-induced depressive-like behavior: evidence from tryptophan depletion study, Front Behav Neurosci source

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    • cites [379] Lyte, 2020, Gut-brain axis serotonergic responses to acute stress exposure are microbiome-dependent, Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc source

      Not checked in the free run.

    • cites [380] Matsumoto, 2013, Cerebral low-molecular metabolites influenced by intestinal microbiota: a pilot study, Front Syst Neurosci source

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  • May combine two claims.

    Premisecitation

    Administering Mycobacterium vaccae as a probiotic or vaccine to young adult mice improved behavior, learning, and memory during cognitive testing, confirming the role of the immune and serotonergic systems in microbiota-gut-brain pathways.

    “Administering Mycobacterium vaccae, a transient commensal microbe, as a probiotic or vaccine to young adult mice improved behavior, learning, and memory during cognitive testing, confirming the role of the immune and serotonergic systems in MGB pathways (388, 389).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [388] Matthews, 2013, Ingestion of mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice, Behav Processes source

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    • cites [389] Lowry, 2007, Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior, Neuroscience source

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    Premisecitation

    Microbial peptidoglycans can traverse the mouse placenta, such that maternal administration of peptidoglycans could be detected in the fetal brain.

    “Humann et al. showed that microbial PGs can traverse the mouse placenta, such that maternal administration of PGs could be detected in the fetal brain (64).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Humann, 2016, Bacterial peptidoglycan traverses the placenta to induce fetal neuroproliferation and aberrant postnatal behavior, Cell Host Microbe source

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    Premisecitation

    In the absence of microbes, germ-free mice exhibit deficits in learning, memory formation and recognition, and social and emotional behaviors.

    “Studies in germ-free mice have shown that, in the absence of microbes, the brain is markedly affected, exhibiting deficits in learning, memory formation and recognition, and social and emotional behaviors (58, 123, 124, 362).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [58] Foster, 2017, Stress & the gut-brain axis: regulation by the microbiome, Neurobiol Stress source

      Not checked in the free run.

    • cites [123] Luczynski, 2016, Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior, Int J Neuropsychopharmacol source

      Not checked in the free run.

    • cites [124] Heijtz, 2011, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci source

      Not checked in the free run.

    • cites [362] Gareau, 2011, Bacterial infection causes stress-induced memory dysfunction in mice, Gut source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Offspring exposed to maternal peptidoglycans exhibited decreased cognitive function related to TLR-2-mediated neuroproliferation via FoxG1 induction in the cortex.

    “The offspring exhibited decreased cognitive function related to TLR-2-mediated neuroproliferation via FoxG1 induction in the cortex.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Humann, 2016, Bacterial peptidoglycan traverses the placenta to induce fetal neuroproliferation and aberrant postnatal behavior, Cell Host Microbe source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The use of exogenous corticosteroids is not always associated with deleterious effects on cognition; some studies in animals and humans have failed to demonstrate an association, while some provide evidence of corticosteroid-induced cognitive enhancement.

    “Furthermore, the use of exogenous corticosteroids is not always associated with deleterious effects on cognition, and some studies in animals and humans have failed to demonstrate an association, while some provide evidence of corticosteroid-induced cognitive enhancement (438–443).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [438] Lupien, 1997, The acute effects of corticosteroids on cognition: integration of animal and human model studies, Brain Res Rev source

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    • cites [439] Cottrell, 1977, Effect of corticosteroids in the hippocampus on passive avoidance behavior in the rat, Pharmacol Biochem Behav source

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    • cites [440] Sandi, 1997, Experience-dependent facilitating effect of corticosterone on spatial memory formation in the water maze, Eur J Neurosci source

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    • cites [441] Sandi, 1994, Corticosterone enhances long-term retention in one-day-old chicks trained in a weak passive avoidance learning paradigm, Brain Res source

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    • cites [442] Buchanan, 2001, Enhanced memory for emotional material following stress-level cortisol treatment in humans, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [443] Lupien, 2002, The modulatory effects of corticosteroids on cognition: studies in young human populations, Psychoneuroendocrinology source

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  • May combine two claims.

    Premisecitation

    In a longitudinal study of 136 infants, those delivered by C-section had lower cortisol concentrations at baseline and in response to a painful stress test at six-month follow-up, signifying an altered HPA axis.

    “In a longitudinal study of 136 infants, those delivered by C-section had lower cortisol concentrations at baseline and in response to a painful stress test at six-month follow-up, signifying an altered HPA axis (402).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [402] Martinez, 2020, Cesarean delivery and infant cortisol regulation, Psychoneuroendocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Delivery mode is linked with neurocognitive development and long-term poor immune and metabolic health outcomes.

    “Other studies have also linked delivery mode with neurocognitive development and long-term poor immune and metabolic health outcomes, highlighting the importance of microbial colonization at birth (400, 401).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [400] Polidano, 2017, The relation between cesarean birth and child cognitive development, Sci Rep source

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    • cites [401] Blustein, 2015, Time to consider the risks of caesarean delivery for long term child health, BMJ Br Med J source

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

    Premisecitation

    It has been postulated that the development of higher cognition in humans may not have evolved in the absence of microbes.

    “Indeed, it has been postulated that the development of higher cognition in humans may not have evolved in the absence of microbes (398).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [398] Montiel-Castro, 2013, The microbiota-gut-brain axis: neurobehavioral correlates, health and sociality, Front Integr Neurosci source

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    Premisecitation

    In a large prospective cohort of 14,542 participants, chronic antibiotic use in midlife was associated with cognitive impairment later in life, such that antibiotic use was associated with an additional three years of aging compared to those with no antibiotic exposure.

    “In a large prospective cohort of 14,542 participants, chronic antibiotic use in midlife was associated with cognitive impairment later in life, such that antibiotic use was associated with an additional three years of aging, compared to those with no antibiotic exposure (407).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [407] Mehta, 2022, Association of midlife antibiotic use with subsequent cognitive function in women, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The differences in inflammatory and stress markers between C-section and vaginal delivery were not significant if C-section was performed during labor, suggesting that the labor process itself initiates important endocrine, physiological, and biochemical processes relevant to the neonatal immune system and stress response.

    “Interestingly, these differences were not significant if C-section was performed during labor, suggesting that the labor process itself initiates important endocrine, physiological, and biochemical processes relevant to the neonatal immune system and stress response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [403] Kiilerich, 2021, Delivery modality affect neonatal levels of inflammation, stress, and growth factors, Front Pediatr source

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    Premisecitation

    Cognitive impairment arising due to hepatic encephalopathy is mediated by microbial disturbances and can be reversed with oral antibiotic treatment.

    “For example, it is well established that the cognitive impairment arising due to hepatic encephalopathy is mediated by microbial disturbances and can be reversed with oral antibiotic treatment (414–417).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [414] Bajaj, 2015, Decompensated cirrhosis and microbiome interpretation, Nature source

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    • cites [415] Patidar, 2013, Antibiotics for the treatment of hepatic encephalopathy, Metab Brain Dis source

      Not checked in the free run.

    • cites [416] Sung, 2019, Predicting clinical outcomes of cirrhosis patients with hepatic encephalopathy from the fecal microbiome, Cell Mol Gastroenterol Hepatol source

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    • cites [417] Festi, 1992, Treatment of hepatic encephalopathy with non-absorbable antibiotics, Ital J Gastroenterol

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    Premisecitation

    Administration of non-absorbable antibiotics in patients with hepatic encephalopathy and mild cognitive impairment improves cognitive performance, subcortical brain activity, fronto-parietal connectivity, and serum metabolomic profile.

    “Administration of non-absorbable antibiotics in patients with hepatic encephalopathy and mild cognitive impairment improves cognitive performance, subcortical brain activity, fronto-parietal connectivity, and serum metabolomic profile (418, 419).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [418] Ahluwalia, 2014, Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with rifaximin in cirrhosis: implications for the gut-liver-brain axis, Metab Brain Dis source

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    • cites [419] Bajaj, 2013, Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy, PloS One source

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  • May combine two claims.

    Premisecitation

    The memory deficit from neonatal E. coli was only observed if an LPS challenge was administered at the time of learning and could be prevented by daily handling of the neonatal rats, which significantly altered their basal HPA axis activity.

    “Intriguingly, the deficit was only observed if an LPS challenge was administered at the time of learning and could be prevented by daily handling of the neonatal rats, which significantly altered their basal HPA axis activity (395).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [395] Bilbo, 2007, Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood, Brain Behav Immun source

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    Premisecitation

    Studies have identified compositional and functional changes in the intestine and brain, along with distinct changes in brain morphology, resting-state brain function, brain activity, and functional connectivity in regions known to regulate stress.

    “These studies have identified compositional and functional changes in the intestine and brain, along with distinct changes in brain morphology, resting-state brain function, brain activity and functional connectivity in regions known to regulate stress (472, 473).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [472] Rode, 2022, Multi-strain probiotic mixture affects brain morphology and resting state brain function in healthy subjects: an RCT, Cells source

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    • cites [473] Edebol Carlman, 2022, Probiotic mixture containing lactobacillus helveticus, bifidobacterium longum and lactiplantibacillus plantarum affects brain responses to an arithmetic stress task in healthy subjects: a randomised clinical trial and proof-of-Concept study, Nutrients source

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  • May combine two claims.

    Premisecitation

    Several studies in healthy participants have demonstrated reduced stress-induced cortisol levels and pro-inflammatory cytokines, along with improved cognitive test performance, perceptions of stress, anxiety, and mood.

    “Several studies in healthy participants have demonstrated reduced stress-induced cortisol levels and pro-inflammatory cytokines, along with improved cognitive test performance, perceptions of stress, anxiety, and mood (465–469).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [465] Allen, 2016, Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers, Transl Psychiatry source

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    • cites [466] Chung, 2014, Fermented milk of lactobacillus helveticus IDCC3801 improves cognitive functioning during cognitive fatigue tests in healthy older adults, J Funct Foods source

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    • cites [467] Lew, 2019, Probiotic lactobacillus plantarum P8 alleviated stress and anxiety while enhancing memory and cognition in stressed adults: a randomised, double-blind, placebo-controlled study, Clin Nutr source

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    • cites [468] Steenbergen, 2015, A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood, Brain Behav Immun source

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    • cites [469] Dahiya, 2022, Clinical potential of microbial strains, used in fermentation for probiotic food, beverages and in synbiotic supplements, as psychobiotics for cognitive treatment through gut-brain signaling, Microorganisms source

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    Premisecitation

    C. difficile has been shown to alter the metabolism of dopamine and interfere with cognitive functions that involve the neuromodulatory action of dopamine, such as motivation and memory consolidation.

    “C. difficile has been shown to alter the metabolism of dopamine and interfere with cognitive functions that involve the neuromodulatory action of dopamine, such as motivation and memory consolidation (456).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [456] Vinithakumari, 2022, Clostridioides difficile infection dysregulates brain dopamine metabolism, Microbiol Spectr source

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  • May combine two claims.

    Premisecitation

    Mechanistic studies have linked the stress response, cognition, and microbiota-gut-brain axis, demonstrating a relative abundance of fibre-degrading bacteria that produce short-chain fatty acids, as well as changes in the serotonin and dopamine-norepinephrine pathways.

    “Mechanistic studies have further linked the stress response, cognition, and MGB axis, demonstrating a relative abundance of fibre-degrading bacteria that produce SCFAs, as well as changes in the serotonin and dopamine-norepinephrine pathways (474, 475).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [474] Bloemendaal, 2021, Probiotics-induced changes in gut microbial composition and its effects on cognitive performance after stress: exploratory analyses, Transl Psychiatry source

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    • cites [475] Liu, 2020, Lactobacillus plantarum DR7 modulated bowel movement and gut microbiota associated with dopamine and serotonin pathways in stressed adults, Int J Mol Sci source

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

    Premisecitation

    The gut is often an unwarranted target of chemotherapeutic agents, with mucositis being a common complication.

    “The gut is often an unwarranted target of chemotherapeutic agents, with mucositis being a common complication (449).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [449] Bajic, 2018, From the bottom-up: chemotherapy and gut-brain axis dysregulation, Front Behav Neurosci source

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    Premisecitation

    Proton pump inhibitors have been shown to cause dysbiosis and are associated with cognitive decline.

    “Another group of drugs that has been shown to cause dysbiosis and is associated with cognitive decline is the proton pump inhibitors (PPI) (446, 447).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [446] Bruno, 2019, Proton pump inhibitors and dysbiosis: current knowledge and aspects to be clarified, World J Gastroenterol source

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    • cites [447] Lochhead, 2017, Association between proton pump inhibitor use and cognitive function in women, Gastroenterology source

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  • May combine two claims.

    Premisecitation

    In a study of non-obese and obese individuals, gut microbiota composition was found to be associated with scores of cognitive speed, attention, and flexibility, along with significant changes in neural activity in specific brain regions (thalamus, hypothalamus, and amygdala).

    “In a study of non-obese and obese individuals, GM composition was found to be associated with scores of cognitive speed, attention, and flexibility, along with significant changes in neural activity in specific brain regions (thalamus, hypothalamus, and amygdala) (481).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [481] Fernandez-Real, 2015, Gut microbiota interacts with brain microstructure and function, J Clin Endocrinol Metab source

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    Premisecitation

    Co-administration of a probiotic containing L. rhamnosus, B. animalis, and magnesium chloride for nine weeks to obese male and female participants with depression did not rescue their altered cognition, mood, and intestinal integrity, but did decrease CRP levels.

    “Co-administration of a probiotic containing L. rhamnosus, B. animalis, and magnesium chloride for nine weeks to obese male and female participants with depression did not rescue their altered cognition, mood, and intestinal integrity, but did decrease CRP levels (482).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [482] Mahboobi, 2022, Effects of probiotic and magnesium co-supplementation on mood, cognition, intestinal barrier function and inflammation in individuals with obesity and depressed mood: a randomized, double-blind placebo-controlled clinical trial, Front Nutr source

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  • May combine two claims.

    Premisecitation

    Women diagnosed with breast cancer undergoing chemotherapy experience disruption in gut microbiota diversity and composition, cognitive impairment, and symptoms of stress such as anxiety and depression.

    “Women diagnosed with breast cancer undergoing chemotherapy experience disruption in GM diversity and composition, cognitive impairment, and symptoms of stress, such as anxiety and depression (450).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [450] Bilenduke, 2022, Impacts of breast cancer and chemotherapy on gut microbiome, cognitive functioning, and mood relative to healthy controls, Sci Rep source

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  • May combine two claims.

    Premisecitation

    The cumulative effect of exposure to multiple infectious pathogens, both bacterial and viral, over several years is associated with changes in cognition, as well as multi-system biological dysfunction before clinical disease is apparent.

    “Evidence suggests that the cumulative effect of exposure to multiple infectious pathogens, both bacterial and viral, over several years is associated with changes in cognition, as well as multi-system biological dysfunction before clinical disease is apparent (459, 460).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [459] Tarter, 2014, Persistent viral pathogens and cognitive impairment across the life course in the third national health and nutrition examination survey, J Infect Dis source

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    • cites [460] Noppert, 2018, Investigating pathogen burden in relation to a cumulative deficits index in a representative sample of US adults, Epidemiol Infect source

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    Premisecitation

    Outcomes for proton pump inhibitors vary, with some studies showing no association.

    “Outcomes vary, with some studies showing no association.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [446] Bruno, 2019, Proton pump inhibitors and dysbiosis: current knowledge and aspects to be clarified, World J Gastroenterol source

      Not checked in the free run.

    • cites [447] Lochhead, 2017, Association between proton pump inhibitor use and cognitive function in women, Gastroenterology source

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  • May combine two claims.

    Premisecitation

    In two case reports in humans, fecal microbiota transplantation improved gastrointestinal symptoms, cognition, and mood, along with eradication of C. difficile in patients with Alzheimer's disease.

    “In two case reports in humans, FMT improved gastrointestinal symptoms, cognition, and mood, along with the eradication of C. difficile in patients with Alzheimer’s disease (457, 458).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [457] Hazan, 2020, Rapid improvement in alzheimer’s disease symptoms following fecal microbiota transplantation: a case report, J Int Med Res source

      Not checked in the free run.

    • cites [458] Park, 2021, Cognitive function improvement after fecal microbiota transplantation in alzheimer’s dementia patient: a case report, Curr Med Res Opin source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic stress is associated with cognitive deficits, systemic inflammation, premature aging, immune system dysfunction, and a higher likelihood of metabolic disorders such as diabetes, cardiovascular disease, and IBD.

    “Chronic stress is associated with various cognitive deficits, systemic inflammation, premature aging, immune system dysfunction, and a higher likelihood of suffering from metabolic disorders such as diabetes, cardiovascular disease, and IBD (490–492).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [490] Sweis, 2013, Individual differences in the effects of chronic stress on memory: behavioral and neurochemical correlates of resiliency, Neuroscience source

      Not checked in the free run.

    • cites [491] Roos, 2019, Higher trait reappraisal predicts stronger HPA axis habituation to repeated stress, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [492] Frankiensztajn, 2020, The microbiota and the hypothalamus-pituitary-adrenocortical (HPA) axis, implications for anxiety and stress disorders, Curr Opin Neurobiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that trial, the participants were healthy adult males and not patients with stress-related disorders.

    “Notably, the participants were healthy adult males and not patients with stress-related disorders.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [487] Kelly, 2017, Lost in translation? the potential psychobiotic lactobacillus rhamnosus (JB-1) fails to modulate stress or cognitive performance in healthy male subjects, Brain Behav Immun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a D-galactose/aluminum chloride-induced Alzheimer's disease model, selenium nanoparticles-enriched L. casei (ATCC 393) administered for thirteen weeks significantly improves cognitive dysfunction and minimizes β-amyloid aggregation, Tau hyperphosphorylation, and neuronal death by modulating the Akt/CREB/BDNF signaling pathway.

    “In a D-galactose/aluminum chloride-induced model of Alzheimer’s disease, selenium nanoparticles-enriched L. casei (ATCC 393) administered for thirteen weeks significantly improved cognitive dysfunction and minimized β-amyloid aggregation, hyperphosphorylation of Tau protein, and prevented neuronal death by modulating the Akt/cAMP-response element binding protein/BDNF signaling pathway (502).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [502] Li, 2009, Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria, Physiol Behav source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent systematic review of interventions in children and adolescents to enhance cognitive functioning and emotional behavior found limited consistent effects in these developing populations, although study heterogeneity was seen as a major factor.

    “A recent systematic review of interventions in children and adolescents to enhance cognitive functioning and emotional behavior found limited consistent effects in these developing populations, although study heterogeneity was seen as a major factor (488).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [488] Basso, 2022, A systematic review of psychobiotic interventions in children and adolescents to enhance cognitive functioning and emotional behavior, Nutrients source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stress is considered a trigger in patients with functional gastrointestinal disorders such as IBS and functional dyspepsia, and in IBDs such as ulcerative colitis and Crohn's disease.

    “Stress is considered a trigger in patients with functional gastrointestinal disorders, such as IBS and functional dyspepsia, as well as IBDs like ulcerative colitis and Crohn’s disease (493).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [493] Ge, 2022, Psychological stress in inflammatory bowel disease: psychoneuroimmunological insights into bidirectional gut–brain communications, Front Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GM signaling pathways involving the vagus nerve, immune system, microbial metabolites, hormones, and neurotransmitters may impact cognition directly or indirectly through the HPA axis, but their involvement might not always require the HPA axis.

    “Additionally, while GM signaling pathways and mechanisms involving the vagus nerve, immune system, microbial metabolites, hormones, and neurotransmitters may impact cognition either directly or indirectly through the HPA axis, their involvement might not always require the HPA axis (223).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [223] Wikoff, 2009, Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites, Proc Natl Acad Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dysbiosis can predict the development of neurocognitive impairment disorders and influence their pathogenesis.

    “Barrio et al. reviewed the association between the GM and conditions with neurocognitive impairment, finding that dysbiosis can predict the development of these disorders and influence their pathogenesis (486).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [486] Barrio, 2022, The gut microbiota-brain axis, psychobiotics and its influence on brain and behaviour: a systematic review, Psychoneuroendocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a study where healthy individuals were given the prebiotic inulin, subjective improvements in mood were noted, along with improved scores on a set of memory tasks.

    “In a study where healthy individuals were given the prebiotic inulin, subjective improvements in mood were noted, along with improved scores on a set of memory tasks (484).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [484] Smith, 2015, An investigation of the acute effects of oligofructose-enriched inulin on subjective wellbeing, mood and cognitive performance, Nutrients source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The L. casei intervention mitigates intestinal barrier dysfunction, inhibits microglia activation, and protects brain neurons from oxidative stress and neuroinflammation.

    “The intervention was shown to mitigate intestinal barrier dysfunction, inhibit the activation of microglia, and protect brain neurons from oxidative stress and neuroinflammation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [502] Li, 2009, Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria, Physiol Behav source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of heat-killed M. vaccae to terminal lung cancer patients was shown to improve emotional health and cognitive function, thought to be as a result of enhanced release of neurotransmitters such as serotonin, as part of the immune response to the microbial products.

    “Administration of heat-killed M. vaccae to terminal lung cancer patients was shown to improve emotional health and cognitive function, thought to be as a result of the enhanced release of neurotransmitters such as serotonin, as part of the immune response to the microbial products (483).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [483] O’Brien, 2004, SRL172 (killed mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer: phase III results, Ann Oncol Off J Eur Soc Med Oncol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Prebiotics may modulate the HPA axis and benefit cognition.

    “Therefore, prebiotics may modulate the HPA axis and benefit cognition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In an α-synuclein-overexpressing mouse model of Parkinsonism, MGB axis signaling is required for motor deficits, microglia activation, and synucleinopathies.

    “In a mouse model that overexpresses the protein α-synuclein, resulting in Parkinsonism, Sampson et al. were able to show that MGB axis signaling is required for motor deficits, microglia activation, and synucleinopathies (75).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Sampson, 2016, Gut microbiota regulate motor deficits and neuroinflammation in a model of parkinson’s disease, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interventions such as dietary fiber supplementation or probiotics (Lactobacillus sp.) have been shown to improve cognitive function and modulate HPA axis activity, reducing cortisol response.

    “Additionally, interventions such as dietary fiber supplementation or probiotics (Lactobacillus sp.) have been shown to improve cognitive function and modulate HPA axis activity (reducing cortisol response).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [486] Barrio, 2022, The gut microbiota-brain axis, psychobiotics and its influence on brain and behaviour: a systematic review, Psychoneuroendocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic antibiotic treatment subdues C/EBPβ/AEP signaling, diminishes amyloidogenic processes, and rescues cognitive functions in an Alzheimer's disease model.

    “Chronic antibiotic treatment subdued C/EBPβ/AEP signaling and diminished amyloidogenic processes, rescuing cognitive functions.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [501] Chen, 2022, Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in alzheimer’s disease mouse model, Sci Adv source

      Not checked in the free run.

    • Rests on an assumption: In Alzheimer’s disease, C/EBPβ/AEP signaling mediates disease progression by cleaving both β-amyloid precursor protein and Tau.

  • May combine two claims.

    Premisecitation

    Vagus nerve stimulation improves cognitive processes and has been attributed to modulation of central noradrenergic and GABA systems and neuronal adaptations in the amygdala, hippocampus, and prefrontal cortex.

    “Vagus nerve stimulation has been shown to improve cognitive processes and has been attributed to modulation of central noradrenergic and GABA systems, as well as neuronal adaptations within the amygdala, hippocampus, and prefrontal cortex (500).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [500] Klarer, 2017, Cognitive effects of subdiaphragmatic vagal deafferentation in rats, Neurobiol Learn Mem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another systematic review evaluating the utility of prebiotics, probiotics, and fermented food interventions on cognitive performance had negative findings, possibly due to the limited number of small and short-term studies, as well as clinical heterogeneity relating to the population, cognitive tests, and interventions.

    “Another systematic review evaluating the utility of prebiotics, probiotics, and fermented food interventions on cognitive performance had negative findings, possibly due to the limited number of small and short-term studies, as well as clinical heterogeneity relating to the population, cognitive tests, and interventions (489).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [489] Marx, 2020, Prebiotics, probiotics, fermented foods and cognitive outcomes: a meta-analysis of randomized controlled trials, Neurosci Biobehav Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IBS patients show impairments in tests of cognitive flexibility and have abnormal brain activity in frontal regions of the brain.

    “IBS patients also show impairments in tests of cognitive flexibility and have abnormal brain activity in frontal regions of the brain (499).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [499] Aizawa, 2012, Altered cognitive function of prefrontal cortex during error feedback in patients with irritable bowel syndrome, based on FMRI and dynamic causal modeling, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In another study, B-GOS supplementation was compared to placebo in healthy participants and found to decrease waking salivary cortisol concentrations and increase the positive processing of information in a dot-probe task.

    “In another study, B-GOS supplementation was compared to placebo in healthy participants and found to decrease waking salivary cortisol concentrations and increase the positive processing of information in a dot-probe task (485).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [485] Schmidt, 2015, Prebiotic intake reduces the waking cortisol response and alters emotional bias in healthy volunteers, Psychopharmacology source

      Not checked in the free run.

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

    Premisenone given

    The role of the GM with regard to the distinct structures of the HPA axis remains understudied.

    “While the GM plays an important role in shaping brain function, including the activity of the HPA axis, its role with regards to the distinct structures of the HPA axis remains understudied.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Proposed mechanisms linking poor diet and obesity to cognitive dysfunction include changes in GM composition and function, alterations in microbial metabolites, compromised barrier integrity, peripheral and central inflammatory processes, and hormonal, glucoregulatory, and cardiovascular changes.

    “Proposed mechanisms include changes in GM composition and function, alterations in microbial metabolites, compromised barrier integrity, and peripheral and central inflammatory processes, as well as hormonal, glucoregulatory, and cardiovascular changes (502, 511, 512).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [502] Li, 2009, Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria, Physiol Behav source

      Not checked in the free run.

    • cites [511] Leigh, 2020, Diet, inflammation and the gut microbiome: mechanisms for obesity-associated cognitive impairment, Biochim Biophys Acta - Mol Basis Dis source

      Not checked in the free run.

    • cites [512] Ohland, 2013, Effects of lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome, Psychoneuroendocrinology source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Whether GM changes in human diseases are causal, consequential, or co-incidental remains unresolved.

    “However, whether these changes are causal, consequential, or co-incidental remain unresolved.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Animal models, including germ-free models, may not be directly transferable to models of human function.

    “While animal models have been critical to our understanding of how microbes influence host development and function, and germ-free models are a cornerstone for studying alterations that arise from microbial perturbations, they may not be directly transferable to models of human function.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In chronic adrenal insufficiency patients, 30% suffered frequent and incapacitating gut symptoms consistent with Rome IV criteria for IBS, and they had decreased quality of life.

    “A study of chronic adrenal insufficiency patients highlighted that 30% of the participants suffered frequent and incapacitating gut symptoms, consistent with the Rome IV criteria for IBS, and that they had a decreased quality of life (530).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [530] Quénéhervé, 2021, Digestive symptoms in daily life of chronic adrenal insufficiency patients are similar to irritable bowel syndrome symptoms, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extra-adrenal glucocorticoid production occurs in the gut and other tissues, and these glucocorticoids regulate local homeostasis, cell development, and immune activation.

    “Extra-adrenal glucocorticoid production is known to occur in the gut and other tissues, and these glucocorticoids play a highly specific role in regulating local homeostasis, cell development, and immune activation (522–526).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [522] Kostadinova, 2014, Why does the gut synthesize glucocorticoids, Ann Med source

      Not checked in the free run.

    • cites [523] Noti, 2009, Extra-adrenal glucocorticoid synthesis in the intestinal epithelium: more than a drop in the ocean, Semin Immunopathol source

      Not checked in the free run.

    • cites [524] Huang, 2018, Local synthesis of immunosuppressive glucocorticoids in the intestinal epithelium regulates anti-viral immune responses, Cell Immunol source

      Not checked in the free run.

    • cites [525] Merk, 2021, Regulation of tissue immune responses by local glucocorticoids at epithelial barriers and their impact on interorgan crosstalk, Front Immunol source

      Not checked in the free run.

    • cites [526] Talabér, 2013, Extra-adrenal glucocorticoid synthesis: immune regulation and aspects on local organ homeostasis, Mol Cell Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice colonized with GM from donors fed a high-fat diet show compositionally distinct microbiota, altered biochemical markers, and impairments in exploratory, cognitive, and stereotypical behaviors without significant body weight differences.

    “Mice colonized with GM from donors fed a high-fat diet demonstrated compositionally distinct microbiota, altered biochemical markers, and developed impairments in exploratory, cognitive, and stereotypical behaviors, in the absence of significant differences in body weight (516).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [516] Bruce-Keller, 2015, Obese-type gut microbiota induce neurobehavioral changes in the absence of obesity, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight gain and obesity do not appear to be necessary for diet-induced cognitive impairment and age-related cognitive decline.

    “Notably, weight gain and obesity do not appear to be necessary for diet-induced cognitive impairment and age-related cognitive decline (514, 515).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [514] Proctor, 2017, Diet, gut microbiota and cognition, Metab Brain Dis source

      Not checked in the free run.

    • cites [515] Otaegui-Arrazola, 2014, Diet, cognition, and alzheimer’s disease: food for thought, Eur J Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A poor diet and obesity are associated with GM alterations, cognitive dysfunction, and an increased risk for dementia.

    “Conversely, a poor diet and obesity are associated with GM alterations, cognitive dysfunction, and an increased risk for dementia [reviewed in (511)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [511] Leigh, 2020, Diet, inflammation and the gut microbiome: mechanisms for obesity-associated cognitive impairment, Biochim Biophys Acta - Mol Basis Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nod1 ligands derived from the GM modulate catecholamine storage and secretion, so intestinal bacteria modulate the adreno-medullary response through Nod1 sensing in chromaffin cells.

    “Xiang et al. showed that nucleotide-binding oligomerization domain 1 (Nod1) ligands, derived from the GM, modulate catecholamine storage and secretion, and therefore intestinal bacteria modulate the adreno-medullary response through Nod1 sensing in chromaffin cells (521).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [521] Xiang, 2021, Intestinal microbiota modulates adrenomedullary response through Nod1 sensing in chromaffin cells, iScience source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    GM-based studies of adrenal insufficiency and Cushing's syndrome are severely lacking.

    “Furthermore, GM-based studies of adrenal insufficiency and Cushing’s syndrome are also severely lacking, although, as has been demonstrated throughout this review, there are mechanistic reasons to believe that important associations may be uncovered.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The development and maintenance of higher cognitive function in humans are influenced and modulated by bidirectional HPA axis and GM mechanisms in the complex interplay of the MGB axis.

    “It is clear that the development and maintenance of higher cognitive function in humans are influenced and modulated by bidirectional HPA axis and GM mechanisms in the complex interplay of the MGB axis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In mice with diet-induced obesity, antibacterial treatment improves metabolic parameters, brain insulin signaling, and neurobehavioral changes indicative of anxiety and depression.

    “In mice with diet-induced obesity, antibacterial treatment improved metabolic parameters, insulin signaling in the brain, and neurobehavioral changes indicative of anxiety and depression (517).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [517] Soto, 2018, Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism, Mol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These changes are associated with altered levels of tryptophan, GABA, BDNF, amino acids, and acylcarnitines, and are transferable to germ-free mice by FMT.

    “These changes were associated with altered levels of tryptophan, GABA, BDNF, amino acids, and acylcarnitines, while these effects were transferable to germ-free mice by FMT.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [517] Soto, 2018, Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism, Mol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A significant body of evidence demonstrates that consuming a GM-favorable diet can positively influence the GM, improve health status, and enhance cognitive function.

    “A comprehensive review of this topic is beyond the scope of this review, however, a significant body of evidence demonstrates that consuming a GM-favorable diet can positively influence the GM, improve health status, and enhance cognitive function (506–510).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [506] Tilg, 2015, Food, immunity, and the microbiome, Gastroenterology source

      Not checked in the free run.

    • cites [507] Luciano, 2017, Mediterranean-Type diet and brain structural change from 73 to 76 years in a Scottish cohort, Neurology source

      Not checked in the free run.

    • cites [508] Ghosh, 2020, Mediterranean Diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries, Gut source

      Not checked in the free run.

    • cites [509] Horn, 2022, Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders, Transl Psychiatry source

      Not checked in the free run.

    • cites [510] Romanenko, 2021, Nutrition, gut microbiota, and alzheimer’s disease, Front Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice exposed to environmental low-dose radiation show long-term impairments in cognitive function, hippocampal synaptic ultrastructure, and signaling through the Akt/mTOR pathway.

    “Guo et al. showed that mice exposed to environmental low-dose radiation demonstrated long-term impairments in cognitive function, hippocampal synaptic ultrastructure, and signaling through the Akt/mTOR pathway (519).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [519] Guo, 2023, Long-term LDR exposure may induce cognitive impairments: a possible association through targeting gut microbiota-gut-brain axis, Ecotoxicol Environ Saf source

      Not checked in the free run.

153 of 153

  • The paper relies on this without support.

    Animal model findings about the GM-HPA-cognition relationship are informative about human biology.

    “Animal research has advanced our understanding of these mechanisms and pathways, leading to a paradigm shift in conceptual thinking about the influence of the microbiota on human health and disease.”
    “Preclinical and human trials are currently underway to determine how these animal models translate to humans.”

  • The paper relies on this without support.

    GABA does not cross the blood-brain barrier.

    “GABA does not cross the BBB”

  • The paper relies on this without support.

    The GM synthesizes and responds to catecholamines.

    “The GM also synthesize and respond to catecholamines.”

  • The paper relies on this without support.

    Findings from animal models of the microbiota-HPA axis-cognition relationship can be extrapolated to humans.

    “Although there remains a dearth of evidence from human studies, a recent pilot study of 34 healthy infants found that GM composition at one month (measured as alpha diversity) was positively associated with HPA axis reactivity following a painful stressor (369).”
    “Animal and human studies indicate an association between prenatal bacterial or viral exposure and the subsequent development of various disorders.”

  • The paper relies on this without support.

    Functional gastrointestinal disorders and IBDs exhibit cognitive and behavioral alterations along with dysbiotic GM profiles.

    “These conditions exhibit cognitive and behavioral alterations, along with dysbiotic GM profiles.”

  • The paper relies on this without support.

    In Alzheimer’s disease, C/EBPβ/AEP signaling mediates disease progression by cleaving both β-amyloid precursor protein and Tau.

    “In Alzheimer’s disease, CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling mediates disease progression by cleaving both β-amyloid precursor protein and Tau.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Gut maturation, energy metabolism, nutrition uptake, and the immune system are processes influenced by the gut microbiota and also by our microbiome.

    “Gut maturation, energy metabolism, nutrition uptake, and the immune system are processes influenced by the gut microbiota and also by our microbiome (billions of microorganisms that form a complex ecology in our gastrointestinal tract) [2].”

    From The Potential Impact of Probiotics on Human Health: An Update on Their Health-Promoting Properties (2024) · cites this paper as [2]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 4 names 2-AE instead of the stated endocannabinoid 2-AG

    Minor

    The text identifies 2-AG and AEA as the two primary endocannabinoids, while the Figure 4 caption names the products of its depicted pathway as 2-AE and AEA. The caption also defines 2-AG later, leaving its use of 2-AE inconsistent with the text.

  • SCFA discussion points to the endocannabinoid figure

    Minor

    The SCFA receptor discussion refers readers to Figure 4, but Figure 4 is titled "Endocannabinoid system"; the figure caption that describes SCFA signaling is Figure 2.

  • HPA axis components are listed in the wrong order in Figure 1

    Minor

    Figure 1 expands HPA as hypothalamic-adrenal-pituitary, whereas the paper defines it as hypothalamic-pituitary-adrenal.

  • Microbial cell ratio conflicts with "vastly outnumbers"

    Minor

    The abstract says the gut microbiota vastly outnumbers human cells, but the introduction gives the current estimate as approximately 1.3 microbial cells per human cell-a 30% excess, not a vast one.

4 of 4

Cites

2 retracted

Flagged first, then by citations

1 of the 531 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Buckingham, 1996, The physiology of immunity, Progress in Brain Research

Cited by

Sorted by citations

Related

Authors
Rusch, J. A., Layden, B. T., & Dugas, L. R.
Affiliations
  • National Health Laboratory Service (ZA)
  • University of Illinois Chicago (US)
  • University of Cape Town (ZA)
Corresponding author
Rusch, Jody A.
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2023-06-19
Volume
14
Pages
1130689-1130689
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2023.1130689
PMC
PMC10316519
OpenAlex
W4381251484
Semantic Scholar
eacd78fdce11880adae9b837c05f11fef2ddd662
Cited by
415
References
531
Citations by year
2026: 155 · 2025: 182 · 2024: 73 · 2023: 5
FWCI
10.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • AXA Research Fund
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL148271)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK104927, R01DK111848, P30DK020595)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords
gut microbiota, hypothalamic-pituitary-adrenal axis, microbiota-gut-brain axis, cognition, stress, cortisol, glucocorticoids, learning and memory, neuroendocrine signalling, animal models
MeSH terms
Gastrointestinal Microbiome, Animals, Brain, Cognition, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Pituitary-Adrenal System

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.

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