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Cited by 573Gut microbiota and healthGastrointestinal motility and disordersNeuropeptides and Animal Physiology

Anxiety, depression, and the microbiome: A role for gut peptides

Open access
Lach, Gilliard, Schellekens, Harriet, Dinan, Timothy G., Cryan, John F.·2018·Neurotherapeutics
DOI 10.1007/s13311-017-0585-0PMC PMC5794698
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Abstract

The complex bidirectional communication between the gut and the brain is finely orchestrated by different systems, including the endocrine, immune, autonomic, and enteric nervous systems. Moreover, increasing evidence supports the role of the microbiome and microbiota-derived molecules in regulating such interactions; however, the mechanisms underpinning such effects are only beginning to be resolved. Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling. Given the emerging role of the gut-brain axis in a variety of brain disorders, such as anxiety and depression, it is important to understand the contribution of bidirectional interactions between peptide hormones released from the gut and intestinal bacteria in the context of this axis. Indeed, the gastrointestinal tract is the largest endocrine organ in mammals, secreting dozens of different signaling molecules, including peptides. Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication. Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota. In this review, we will discuss the gut microbiota as a regulator of anxiety and depression, and explore the role of gut-derived peptides as signaling molecules in microbiome-gut-brain communication. Here, we summarize the potential interactions of the microbiota with gut hormones and endocrine peptides, including neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, and ghrelin in microbiome-to-brain signaling. Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review proposes that gut-derived peptides are key mediators of microbiota–gut–brain signaling in anxiety and depression. It synthesizes evidence that microbiota composition and microbial metabolites alter peptides such as NPY, PYY, PP, GLP-1, CCK, ghrelin, CRF, and oxytocin, with psychobiotics suggested as a future therapeutic route.

Key findings

  • The gastrointestinal tract is described as the largest endocrine organ in mammals, with enteroendocrine cells representing no more than 1% of the total gut epithelium cell population and releasing more than 20 signaling molecules. The review argues these gut peptides can signal to the brain via immune cells, vagus nerve terminals, and the bloodstream.
  • Microbiota manipulations are reported to alter gut peptides: germ-free mice, antibiotic-treated mice, and animals given probiotics or prebiotics show increases in NPY and PYY and increases in GLP-1; germ-free mice show decreased CCK and ghrelin; fasted germ-free mice show increased ghrelin; antibiotic treatment from adolescence decreases oxytocin without changing CRF; and *Lactobacillus reuteri* increases oxytocin.
  • GLP-1 is reported to be rapidly degraded, with <10% of secreted GLP-1 reaching systemic circulation. The review notes that GLP-1 receptor agonists blunt anxiety-like behavior in diabetic mice, promote antidepressant-like effects in rodents, and a 4-week GLP-1 agonist treatment reverted cognitive deficits in patients with mood disorders without affecting metabolic parameters.
  • PP is about 100 times more potent than NPY in activating Y4 receptors, and the review suggests PP/Y4 signaling may be an important gut–brain route in anxiety and depression. CCK levels are positively correlated with increased anxiety-like behavior in human and rodent studies, while ghrelin and CRF are discussed as modulators of stress, fear, and depressive-like phenotypes.

Methods

  • Design: narrative review of the microbiota–gut–brain axis, focusing on gut peptides as signaling molecules in anxiety and depression.
  • Data/sample: synthesis of preclinical animal studies, germ-free and antibiotic-treated rodent models, probiotic/prebiotic interventions, human cohort data, and human clinical trials cited in the reference list.
  • Main analysis: thematic discussion of peptide families and systems—NPY/PYY/PP, GLP-1, CCK, ghrelin, CRF, and oxytocin—and their interactions with gut microbiota, immune signaling, vagal pathways, and psychobiotic strategies.

Limitations

  • The paper states that mechanisms underlying enteroendocrine cell–microbiota interactions have yet to be fully resolved, that a direct link between the gut microbiota and ghrelin modulation remains absent, that more studies linking PYY changes and the gut microbiota are needed, and that additional studies are needed to demonstrate a functional role of the gut microbiota in the host oxytocin system.
  • The paper states we are at very early stages of understanding microbiota–gut–brain communication.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis; many findings are from animal models or correlative human data, and the review notes interspecies variability and contrasting results between humans and animals, so causal direction is often not established.

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

Integrity signals

Registry

Crossref · 10.1007/s13311-017-0585-0

Cites

414 of 414 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 237 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The activity of enteroendocrine cells is modulated by the gut microbiota.

    “It is now also becoming clear that the activity of EECs, which represent no more than 1% of the total gut epithelium cell population, is modulated by the gut microbiota [2][3][4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2][3][4]

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  • Premisecitation

    Enteric bacterial diversity and composition uniquely influence the release of gut peptides, including GLP-1, PYY, CCK, CRF, oxytocin, and ghrelin.

    “Enteric bacterial diversity and composition uniquely influence the release of gut peptides, including glucagon-like peptide (GLP-1), peptide YY (PYY), cholecystokinin (CCK), corticotropin-releasing factor (CRF), oxytocin, and ghrelin [1,[5][6][7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1,[5][6][7]

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  • Premisecitation

    Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals, thereby enabling indirect gut-brain communication.

    “Gut peptides in the systemic circulation can bind cognate receptors on immune cells and vagus nerve terminals thereby enabling indirect gut-brain communication.”
    • Also stated in: § Gut peptide receptor · hedged
      “Following secretion, gut peptides diffuse throughout the lamina propria, which is occupied by a variety of immune cells, ultimately to reach the bloodstream, to stimulate sensory neurons and potentially to act on the vagus nerve, thereby creating an intersection for gut peptidergic signaling to the brain [111].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Okano-Matsumoto, 2011, Electrophysiological evidence for distinct vagal pathways mediating CCK-evoked motor effects in the proximal versus distal stomach, J Physiol source

      Not checked in the free run.

  • Interpretationreasoning

    Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.

    “Together, gut peptides are important regulators of microbiota-gut-brain signaling in health and stress-related psychiatric illnesses.”
    Quote in the paperSubstantial claim
  • Premisecitation

    For the peptides discussed in this review, beyond the role in satiety, they can be stimulated by bacterial products that come into contact with the gut epithelium.

    “For the peptides discussed in this review, beyond the role in satiety, they can be stimulated by bacterial products that come into contact with the gut epithelium [83,105,106].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [83] Tolhurst, 2012, Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2, Diabetes source

      Not checked in the free run.

    • cites [105] Lin, 2012, Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms, PLOS ONE

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    • cites [106] Gao, 2009, Butyrate improves insulin sensitivity and increases energy expenditure in mice, Diabetes source

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  • Classified as probably not a substantial claim. 22
  • May combine two claims. 73

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

    Findingnone given

    A direct link between gut microbiota and modulation of ghrelin remains absent.

    “Nevertheless, a direct link between the gut microbiota and the modulation of ghrelin remains absent.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Alterations in the gut microbiota may influence conditions such as obesity, allergies, autoimmune disorders, IBS, IBD, and psychiatric disorders.

    “Alterations in the gut microbiota may influence conditions such as obesity, allergies, autoimmune disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and psychiatric disorders [8][9][10][11][12][13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8][9][10][11][12][13]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gut peptide concentrations are modulated by enteric microbiota signals and vary according to the composition of the intestinal microbiota.

    “Gut peptide concentrations are not only modulated by enteric microbiota signals, but also vary according to the composition of the intestinal microbiota.”
    • Also stated in: § Introduction · plain
      “Enteric bacterial diversity and composition uniquely influence the release of gut peptides, including glucagon-like peptide (GLP-1), peptide YY (PYY), cholecystokinin (CCK), corticotropin-releasing factor (CRF), oxytocin, and ghrelin [1,[5][6][7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1,[5][6][7]

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    Premisecitation

    More than 20 signaling molecules released from enteroendocrine cells in the GI tract have significant endocrine and metabolic functions and are able to communicate with the brain.

    “The more than 20 signaling molecules released from specialized enteroendocrine cells (EECs) in the GI tract have significant endocrine and metabolic functions and are able to communicate with the brain [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Dockray, 2014, Gastrointestinal hormones and the dialogue between gut and brain, J Physiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Microbiota-gut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling.

    “Microbiotagut peptide interactions are poised to be of great significance in the regulation of gut-brain signaling.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Following secretion, gut peptides diffuse throughout the lamina propria, which is occupied by a variety of immune cells, ultimately to reach the bloodstream, to stimulate sensory neurons and potentially to act on the vagus nerve, thereby creating an intersection for gut peptidergic signaling to the brain.

    “Following secretion, gut peptides diffuse throughout the lamina propria, which is occupied by a variety of immune cells, ultimately to reach the bloodstream, to stimulate sensory neurons and potentially to act on the vagus nerve, thereby creating an intersection for gut peptidergic signaling to the brain [111].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [111] Okano-Matsumoto, 2011, Electrophysiological evidence for distinct vagal pathways mediating CCK-evoked motor effects in the proximal versus distal stomach, J Physiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Owing to the wide expression of peptides and their receptors in both brain and gut, in addition to their facilitated transit into the bloodstream, it seems reasonable to assume that these peptides can act beyond their primary signaling function, suggesting a possible role (most likely indirect) of the gut peptides in neuropsychiatric disorders.

    “Owing to the wide expression of peptides and their receptors in both brain and gut, in addition to their facilitated transit into the bloodstream, it seems reasonable to assume that these peptides can act beyond their primary signaling function, suggesting a possible role (most likely indirect) of the gut peptides in neuropsychiatric disorders [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Latorre, 2016, Enteroendocrine cells: a review of their role in brain-gut communication, Neurogastroenterol Motil source

      Not checked in the free run.

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

    Interpretationreasoning

    Owing to their privileged location in the GI tract, it is possible that those peptides may be influenced by changes in the gut microbiota and modulate (directly or indirectly) upstream signaling to the brain.

    “Owing to their privileged location in the GI tract, it is possible that those peptides may be influenced by changes in the gut microbiota and modulate (directly or indirectly) upstream signaling to the brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The blood-brain barrier selectively facilitates the transport of some peptides in the blood-to-brain direction, suggesting a direct pathway for some gut peptides that are not quickly degraded after their release.

    “In a complementary manner, the blood-brain barrier (BBB) selectively facilitates the transport of some peptides in the blood-to-brain direction, suggesting a direct pathway for some gut peptides that are not quickly degraded after their release [112][113][114][115].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112][113][114][115]

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  • May combine two claims.

    Interpretationreasoning

    The dynamic profile of gut peptides, including their direct link with mood disorders, and their broad role in the gut suggests that the microbiota-gut peptide-brain communication axis can be a target for psychobiotics to prevent and treat such disorders.

    “The dynamic profile of gut peptides, including their direct link with mood disorders, and their broad role in the gut suggests that the microbiota-gut peptide-brain communication axis can be a target for psychobiotics to prevent and treat such disorders (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Depression and anxiety are often accompanied by changes in colonic motility, which, in turn, alters the composition and stability of the gut microbiota, as well as the colonic physiology and morphology.

    “Depression and anxiety are often accompanied by changes in colonic motility, which, in turn, alters the composition and stability of the gut microbiota, as well as the colonic physiology and morphology [137-140].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [137] Bailey, 1999, Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys, Dev Psychobiol source

      Not checked in the free run.

    • cites [138] Park, 2013, Altered colonic function and microbiota profile in a mouse model of chronic depression, Neurogastroenterol Motil source

      Not checked in the free run.

    • cites [139] Rodes, 2011, Transit time affects the community stability of LactobacillusBifidobacterium species in an in vitro model of human colonic microbiotia, Artif Cells Blood Substit Immobil Biotechnol source

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    • cites [140] O'Malley, 2010, Distinct alterations in colonic morphology and physiology in two rat models of enhanced stress-induced anxiety and depression-like behaviour, Stress source

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    Premisecitation

    SCFA act on G-protein-coupled receptors located along the GI tract to regulate energy homeostasis via the stimulation of leptin production in adipocytes, and the secretion of gut peptides from colonic EECs.

    “SCFA act on G-protein-coupled receptors [free fatty acid (FFA) receptors] located along the GI tract to regulate energy homeostasis via the stimulation of leptin production in adipocytes, and the secretion of gut peptides from colonic EECs [84][85][86][87].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84][85][86][87]

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

    Premisecitation

    Since the expression of gut-derived peptides is likely to be modulated by changes in the gut microbiota, it has been proposed that these peptide hormones may have an important role in gut-brain communication.

    “Since the expression of these gut-derived peptides is likely to be modulated by changes in the gut microbiota, it has been proposed that these peptide hormones may have an important role in gut-brain communication [21,[25][26][27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21,[25][26][27]

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  • May combine two claims.

    Interpretationreasoning

    Although the altered gut microbiota and its effects on host metabolic phenotype during psychiatric illness remains unknown, these observations highlight the potential association of the gut microbiota with host depression and anxiety.

    “Although the altered gut microbiota and its effects on host metabolic phenotype during psychiatric illness remains unknown, these observations highlight the potential association of the gut microbiota with host depression and anxiety.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In IBS, a correlation was found between gut microbiota composition and brain volumes in patients with IBS with early life trauma, suggesting a shift in the Firmicutes/Bacteroidetes ratio, with Firmicutes increased and Bacteroidetes decreased.

    “Likewise, in IBS, a disease linked to alterations in the immune system [144], a correlation was found between gut microbiota composition and brain volumes in patients with IBS with early life trauma, suggesting a shift in the Firmicutes/Bacteroidetes ratio, with Firmicutes increased and Bacteriodetes decreased [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Labus, 2017, Differences in gut microbial composition correlate with regional brain volumes in irritable bowel syndrome, Microbiome source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Antidepressants are well known to have antimicrobial effects, modulating the pathophysiology of anxiety and depression by reshaping not only brain biochemistry, but also the gut microbiota.

    “Antidepressants are well known to have antimicrobial effects, modulating the pathophysiology of the anxiety and depression by reshaping not only brain biochemistry, but also the gut microbiota [159,160].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [159] Lieb, 2004, The immunostimulating and antimicrobial properties of lithium and antidepressants, J Infect source

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    • cites [160] Munoz-Bellido, 2000, Antimicrobial activity of psychotropic drugs. Selective serotonin reuptake inhibitors, Int J Antimicrob Agents source

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

    Premisecitation

    NPY is the most abundant peptide in the brain and is expressed from the medullary brainstem to the cerebral cortex.

    “NPY is the most abundant peptide in the brain and is expressed from the medullary brainstem to the cerebral cortex (for review, see [175]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Kask, 2002, The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y, Neurosci Biobehav Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both PYY and PP are able to cross the BBB by transmembrane diffusion and bind cognate receptors located in the area postrema.

    “Both PYY and PP are able to cross the BBB by transmembrane diffusion and bind cognate receptors located in the area postrema [115,178].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [115] Nonaka, 2003, Characterization of blood-brain barrier permeability to PYY3-36 in the mouse, J Pharmacol Exp Ther source

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    • cites [178] Dumont, 2007, Distribution of peripherally injected peptide YY ([125I] PYY (3-36)) and pancreatic polypeptide ([125I] hPP) in the CNS: enrichment in the area postrema, J Mol Neurosci source

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  • May combine two claims.

    Premisecitation

    Stress-related disorders can also alter the intestinal barrier, triggering a leaky gut, which could allow a microbiota-driven proinflammatory response through the translocation of certain bacterial products from the gut.

    “Stress-related disorders can also alter the intestinal barrier, triggering a Bleaky gut^, which could allow a microbiota-driven proinflammatory response through the translocation of certain bacterial products from the gut [141-143].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [141] Kelly, 2015, Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders, Front Cell Neurosci source

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    • cites [142] Maes, 2012, Increased IgA and IgM responses against gut commensals in chronic depression: Further evidence for increased bacterial translocation or leaky gut, J Affect Disord source

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    • cites [143] Maes, 2008, The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression, Neuro Endocrinol Lett

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  • May combine two claims.

    Premisecitation

    Stressed mice have been shown to have greater populations of the genus Clostridium, which agrees with the gut microbiota profile in maternally separated rodents.

    “Stressed mice also have been shown to have greater populations of the genus Clostridium, which agrees with the gut microbiota profile in maternally separated rodents [149-151].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [149] Bailey, 2011, Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation, Brain Behav Immun source

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    • cites [150] De Palma, 2015, Microbiota and host determinants of behavioural phenotype in maternally separated mice, Nat Commun source

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    • cites [151] O'Mahony, 2011, Strain differences in the neurochemical response to chronic restraint stress in the rat: relevance to depression, Pharmacol Biochem Behav source

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  • May combine two claims.

    Premisecitation

    Yu et al. found that depressive-like rats had the relative abundances of Bacteroidetes significantly increased, whereas that of Firmicutes was markedly decreased.

    “Yu et al. [148] found that depressive-like rats had the relative Stomach Small intestine Colon abundances of Bacteroidetes significantly increased, whereas that of Firmicutes was markedly decreased.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Yu, 2017, Variations in gut microbiota and fecal metabolic phenotype associated with depression by 16S rRNA gene sequencing and LC/MS-based metabolomics, J. Pharm Biomed Anal source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although plasma PYY is increased after oligofructose treatment in healthy rats, oligofructose did not alter plasma PYY levels in obese mice.

    “Although plasma PYY is increased after oligofructose treatment in healthy rats [202,203], oligofructose did not alter plasma PYY levels in obese mice [204].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [202] Hong, 2016, Evaluation of prebiotic effects of high-purity galactooligosaccharides in vitro and in vivo, Food Technol Biotechnol source

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    • cites [203] Cluny, 2015, Interactive effects of oligofructose and obesity predisposition on gut hormones and microbiota in diet-induced obese rats, Obesity source

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    • cites [204] Steensels, 2017, Supplementation of oligofructose, but not sucralose, decreases high-fat diet induced body weight gain in mice independent of gustducin-mediated gut hormone release, Mol Nutr Food Res source

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  • May combine two claims.

    Premisecitation

    By activating Y4 receptors in the gut, PP reduces intestinal motor activity and facilitates nutrient absorption, an effect likewise exerted by PYY.

    “By activating Y 4 receptors in the gut, PP reduces intestinal motor activity and facilitates nutrient absorption, an effect likewise exerted by PYY [24,188,190].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Holzer, 2012, Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis, Neuropeptides source

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    • cites [188] Fujimiya, 2000, Peptidergic regulation of gastrointestinal motility in rodents, Peptides source

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    • cites [190] Tough, 2006, Y(4) receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa, J Pharmacol Exp Ther source

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  • May combine two claims.

    Interpretationreasoning

    Although the gut microbiota was not investigated in these studies, the results strongly suggest a potential role for gut-brain communication through Y4 signaling.

    “Although the gut microbiota was not investigated in these studies, the results strongly suggest a potential role for gut-brain communication through Y 4 signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Schéle et al. found that administration of leptin reduced NPY expression in germ-free mice but not in conventionally raised mice, suggesting that the gut microbiota may decrease leptin sensitivity, effects that are dependent on vagal signaling.

    “In addition, Schéle et al. [116] found that administration of leptin reduced NPY expression in germ-free mice but not in conventionally raised mice, suggesting that the gut microbiota may decrease leptin sensitivity, effects that are dependent on vagal signaling [192].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [116] Schéle, 2013, The gut microbiota reduces leptin sensitivity and the expression of the obesity-suppressing neuropeptides proglucagon (Gcg) and brain-derived neurotrophic factor (Bdnf) in the central nervous system, Endocrinology source

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    • cites [192] De Lartigue, 2010, EGR1 is a target for cooperative interactions between cholecystokinin and leptin, and inhibition by ghrelin, in vagal afferent neurons, Endocrinology source

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  • May combine two claims.

    Premisecitation

    The SCFA butyrate can increase the expression of receptors that sense microbial compounds (Toll-like receptors), which, in turn, increases the expression of PYY.

    “Moreover, the SCFA butyrate can increase the expression of receptors that sense microbial compounds (Toll-like receptors), which, in turn, increases the expression of PYY [201].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Larraufie, 2017, TLR ligands and butyrate increase Pyy expression through two distinct but inter-regulated pathways, Cell Microbiol source

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

    Interpretationreasoning

    Given the importance of microbiota-generated SCFAs such as butyrate, the role of the SCFA in mediating PYY expression through immune cells could be an important link in microbial-host communication and PYY signaling.

    “Given the importance of microbiota-generated SCFAs such as butyrate, the role of the SCFA in mediating PYY expression through immune cells could be an important link in microbial-host communication and PYY signaling.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Despite the interspecies variability, the contrasting results found in humans and animals could be owing to the selective spectrum of bacteria that can modulate PYY expression.

    “Despite the interspecies variability, the contrasting results found in humans and animals could be owing to the selective spectrum of bacteria that can modulate PYY expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recently, it was shown that the depletion of the gut microbiota in adult mice upregulated NPY expression within the amygdala and hypothalamus, followed by cognitive deficits.

    “Recently, it was shown that the depletion of the gut microbiota in adult mice upregulated NPY expression within the amygdala and hypothalamus, followed by cognitive deficits [25], an effect also observed in rats housed in environmental enrichment [213].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Fröhlich, 2016, Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication, Brain Behav Immun source

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    • cites [213] Lach, 2016, Short-term enriched environment exposure facilitates fear extinction in adult rats: the NPY-Y1 receptor modulation., Neuropeptides source

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  • May combine two claims.

    Premisecitation

    Circulating levels of plasma PYY and NPY are also enhanced in patients with IBD, suggesting that the epithelial levels of NPY and PYY are exhausted by excessive release of these peptides from EECs and intestinal neurons.

    “Moreover, circulating levels of plasma PYY and NPY are also enhanced in patients with IBD, suggesting that the epithelial levels of NPY and PYY are exhausted by excessive release of these peptides from EECs and intestinal neurons [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] El-Salhy, 2016, The role of the neuropeptide Y (NPY) family in the pathophysiology of inflammatory bowel disease (IBD), Neuropeptides source

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

    Premisecitation

    In the brain, GLP-1 is present in the NTS and the olfactory bulb.

    “In the brain, GLP-1 is present in the NTS and the olfactory bulb [5,224].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] Latorre, 2016, Enteroendocrine cells: a review of their role in brain-gut communication, Neurogastroenterol Motil source

      Not checked in the free run.

    • cites [224] Vrang, 2010, Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: role of peripherally secreted and centrally produced peptides, Prog Neurobiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rajpal et al. investigated selective spectrum antibiotics and found that only an alteration of Gram-negative bacteria (which, in turn, increased the population of Firmicutes) improved metabolic aspects, including PYY, in rodents.

    “For this, Rajpal et al. [207] investigated selective spectrum antibiotics and found that only an alteration of Gramnegative bacteria (which, in turn, increased the population of Firmicutes) improved metabolic aspects, including PYY, in rodents.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [207] Rajpal, 2015, Selective spectrum antibiotic modulation of the gut microbiome in obesity and diabetes rodent models, PLOS ONE source

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  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Thus, in addition to the literature mentioned above, this indicates that NPY, PYY, and PP somehow participate in the reciprocal interaction between the brain, the gut, and the immune system, therefore warranting investigation of their pathophysiological implications within the context of the microbiota-gut-brain axis.

    “Thus, in addition to the literature mentioned above, this indicates that NPY, PYY, and PP somehow participate in the reciprocal interaction between the brain, the gut, and the immune system, therefore warranting investigation of their pathophysiological implications within the context of the microbiota-gut-brain axis.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    GLP-1, an incretin hormone, is a 30 amino-acid peptide derived from the post-translational processing of preproglucagon, which is involved in the neural regulation of food intake, body weight, the modulation of the hypothalamic-pituitary-adrenal (HPA) axis, and overall response to stress via activation of the GLP-1 receptor.

    “GLP-1, an incretin hormone, is a 30 amino-acid peptide derived from t he post-translational processing of preproglucagon, which is involved in the neural regulation of food intake, body weight, the modulation of the hypothalamic-pituitary-adrenal (HPA) axis, and overall response to stress via activation of the GLP-1 receptor (for review, see [220][221][222][223]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [220][221][222][223]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NPY and PYY are also antimicrobial peptides, influencing the composition and function of the gut microbiota.

    “Finally, NPY and PYY are also antimicrobial peptides, influencing the composition and function of the gut microbiota [219].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] El Karim, 2008, Antimicrobial activity of neuropeptides against a range of micro-organisms from skin, oral, respiratory and gastrointestinal tract sites, J Neuroimmunol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    As the NTS projects GLP-1 neurons directly to the paraventricular nucleus of the hypothalamus, it is plausible to affirm that GLP-1 restricts feeding behavior, which is dependent of the vagal pathway.

    “As the NTS projects GLP-1 neurons directly to the paraventricular nucleus of the hypothalamus, it is plausible to affirm that GLP-1 restricts feeding behavior, which is dependent of the vagal pathway [230][231][232].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230][231][232]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anxiety-like behavior in diabetic mice was blunted by a GLP-1 receptor agonist, whereas in nondiabetic animals, the impact of a GLP-1 receptor agonist was less clear in reducing anxiety-like behavior.

    “Moreover, anxiety-like behavior in diabetic mice was blunted by a GLP-1 receptor agonist [247, 248], whereas in nondiabetic animals, the impact of a GLP-1 receptor agonist was less clear in reducing anxiety-like behavior [249-251].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [247] Komsuoglu Celikyurt, 2014, Exenatide treatment exerts anxiolytic- and antidepressant-like effects and reverses neuropathy in a mouse model of type-2 diabetes, Med Sci Monit Basic Res source

      Not checked in the free run.

    • cites [248] Sharma, 2015, Glucagon-like peptide-1 (GLP-1) receptor agonist prevents development of tolerance to anti-anxiety effect of ethanol and withdrawal-induced anxiety in rats, Metab Brain Dis source

      Not checked in the free run.

    • cites [249] Kinzig, 2003, CNS glucagon-like peptide-1 receptors mediate endocrine and anxiety responses to interoceptive and psychogenic stressors, J Neurosci source

      Not checked in the free run.

    • cites [250] Krass, 2015, GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment, Acta Neuropsychiatr source

      Not checked in the free run.

    • cites [251] Möller, 2002, Anxiogenic-like action of centrally administered glucagon-like peptide-1 in a punished drinking test, Prog Neuropsychopharmacol Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vagal afferent neurons express the GLP-1 receptor, activation of which induces firing of the respective vagal afferent neurons and most likely stimulation of NTS.

    “Indeed, vagal afferent neurons express the GLP-1 receptor, activation of which induces firing of the respective vagal afferent neurons and most likely stimulation of NTS [228,229].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [228] Kakei, 2002, Glucagon-like peptide-1 evokes action potentials and increases cytosolic Ca2+ in rat nodose ganglion neurons, Auton Neurosci source

      Not checked in the free run.

    • cites [229] Katsurada, 2014, Endogenous GLP-1 acts on paraventricular nucleus to suppress feeding: projection from nucleus tractus solitarius and activation of corticotropin-releasing hormone, nesfatin-1 and oxytocin neurons, Biochem Biophys Res Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the NTS, GLP-1 fibers directly innervate hypophysiotrophic CRF neurons in the paraventricular nucleus (PVN), where GLP-1 activates the HPA axis response.

    “In the NTS, GLP-1 fibers directly innervate hypophysiotrophic CRF neurons in the paraventricular nucleus (PVN), where GLP-1 activates the HPA axis response [225].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [225] Rinaman, 1999, Interoceptive stress activates glucagon-like peptide-1 neurons that project to the hypothalamus, Am J Physiol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP-1 levels in the lymph were found to be higher, lasting longer than in the bloodstream, supporting a plausible model where GLP-1 does reach the brain given its transport via the lymph.

    “GLP-1 levels in the lymph were found to be higher, lasting longer than in the bloodstream, supporting a plausible model where GLP-1 does reach the brain given its transport via the lymph [233].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] D'Alessio, 2007, Fasting and postprandial concentrations of GLP-1 in intestinal lymph and portal plasma: evidence for selective release of GLP-1 in the lymph system, Am J Physiol Regul Integr Comp Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The densities of CCK cells are reduced in IBD, which may lower the levels of gastric secretion, such as bicarbonate, pancreatic enzymes, and bile salts, resulting in the development of IBS.

    “The densities of CCK cells are reduced in IBD, which may lower the levels of gastric secretion, such as bicarbonate, pancreatic enzymes, and bile salts, resulting in the development of IBS [283,284].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [283] Hsu, 2016, Gut-derived cholecystokinin contributes to visceral hypersensitivity via nerve growth factor-dependent neurite outgrowth, J Gastroenterol Hepatol source

      Not checked in the free run.

    • cites [284] El-Salhy, 2015, Reduction in duodenal endocrine cells in irritable bowel syndrome is associated with stem cell abnormalities, World J Gastroenterol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    As CCK has been reported to have anti-inflammatory effects, reduced expression of CCK in the gut may have an impact on gut inflammatory diseases, with subsequent consequences in IBD or IBS comorbidity.

    “As CCK has been reported to have anti-inflammatory effects, reduced expression of CCK in the gut may have an impact on gut inflammatory diseases, with subsequent consequences in IBD or IBS comorbidity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Systemic administration of CCK-8 elevated the levels of brain-derived neurotrophic factor in the rat hippocampus, suggesting a neuroplasticity-related effect mediated by CCK.

    “Moreover, systemic administration of CCK-8 elevated the levels of brain-derived neurotrophic factor in the rat hippocampus, suggesting a neuroplasticity-related effect mediated by CCK [276].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [276] Tirassa, 2007, CCK-8 induces NGF and BDNF synthesis and modulates TrkA and TrkB expression in the rat hippocampus and septum: effects on kindling development, Neurochem Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vagotomy in mice attenuates the effects of CCK on gastric emptying, whereas the administration of LPS abolishes CCK-induced inhibition of food intake.

    “Indeed, vagotomy in mice attenuates the effects of CCK on gastric emptying, whereas the administration of LPS abolishes CCK-induced inhibition of food intake [281,282].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [281] de La Serre, 2015, Chronic exposure to low dose bacterial lipopolysaccharide inhibits leptin signaling in vagal afferent neurons, Physiol Behav source

      Not checked in the free run.

    • cites [282] Bauer, 2016, Regulation of energy balance by a gut–brain axis and involvement of the gut microbiota, Cell Mol Life Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A GLP-1 receptor agonist was able to reverse LPS-induced depressive-like behavior without directly affecting inflammatory cytokines.

    “Furthermore, a GLP-1 receptor agonist was able to reverse LPS-induced depressive-like behavior without directly affecting inflammatory cytokines [256].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [256] Ventorp, 2017, Exendin-4 treatment improves LPS-induced depressive-like behavior without affecting pro-inflammatory cytokines, J Parkinsons Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with mood disorders and the presence of cognitive deficits, 4-week treatment with a GLP-1 agonist reverted the cognitive deficits without affecting metabolic parameters, suggesting GLP-1 target offers beneficial effects in some symptoms that can be overrepresented in psychiatric disorders.

    “In patients with mood disorders and the presence of cognitive deficits, it was found that 4-week treatment with a GLP-1 agonist reverted the cognitive deficits without affecting metabolic parameters, suggesting GLP-1 target offers beneficial effects in some symptoms that can be overrepresented in psychiatric disorders [267].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [267] Mansur, 2017, Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study, J Affect Disord source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic systemic stimulation of GLP-1 receptors promoted antidepressant-like effects in rodents, coupled with increasing hippocampal neurogenesis, suggesting plasticity-related effects could underpin such effects.

    “However, chronic systemic stimulation of GLP-1 receptors promoted antidepressant-like effects in rodents, coupled with increasing hippocampal neurogenesis, suggesting plasticity-related effects could underpin such effects [252][253][254][255].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [252][253][254][255]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Taken together, the localization of GLP-1 and the GLP-1 receptors in the gut-brain axis underscores the importance of the microbiota in the modulatory role for GLP-1 in the central regulation of energy homeostasis, which may influence depression and anxiety associated with metabolic dysfunctions.

    “Taken together, the localization of GLP-1 and the GLP-1 receptors in the gut-brain axis underscores the importance of the microbiota in the modulatory role for GLP-1 in the central regulation of energy homeostasis, which may influence depression and anxiety associated with metabolic dysfunctions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CCK is the first peptide released postprandially to reduce food intake in both obese and lean individuals, remaining in the bloodstream for about 3 h.

    “CCK is the first peptide released postprandially to reduce food intake in both obese and lean individuals, remaining in the bloodstream for about 3 h [277, 278].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [277] Mishra, 2016, Obesity: an overview of possible role(s) of gut hormones, lipid sensing and gut microbiota, Metabolism source

      Not checked in the free run.

    • cites [278] Rehfeld, 2001, The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33, J Clin Endocrinol Metab

      Not checked in the free run.

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

    Premisecitation

    Ghrelin is the endogenous ligand of growth hormone secretagogue receptor type 1a.

    “Ghrelin is the endogenous ligand of the growth hormone secretagogue receptor type 1a and was first discovered for its stimulation of growth hormone secretion from the pituitary [293].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [293] Kojima, 1999, Ghrelin is a growth-hormone-releasing acylated peptide from stomach, Nature source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Ghrelin crosses BBB via active transport and direct diffusion, making ghrelinergic system ideally placed to play important role in stress response.

    “Ghrelin crosses the BBB via active transport and direct diffusion, making the ghrelinergic system ideally placed to play an important role in the stress response [112,297,302].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [112] Banks, 2002, Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure, J Pharmacol Exp Ther source

      Not checked in the free run.

    • cites [297] Schellekens, 2012, Ghrelin signalling and obesity: at the interface of stress, mood and food reward, Pharmacol Ther source

      Not checked in the free run.

    • cites [302] Schaeffer, 2013, Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons, Proc Natl Acad Sci U S A source

      Not checked in the free run.

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

    Interpretationreasoning

    The importance of microbiota in CCK's modulatory role in central regulation of energy homeostasis may influence depression and anxiety associated with obesity and represent a potential target.

    “The importance of the microbiota in the modulatory role for CCK in the central regulation of energy homeostasis may influence depression and anxiety associated with obesity and represent a potential target in this specific aspect of emotionality.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Antagonists of GHS receptor administered during repeated stressors prevented fear memory formation, as well as anxiety and depression-like phenotypes in mice.

    “antagonists of GHS receptor administered during repeated stressors prevented fear memory formation, as well as anxiety and depression-like phenotypes in mice [296,315].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [296] Huang, 2017, Ghrelin alleviates anxiety- and depression-like behaviors induced by chronic unpredictable mild stress in rodents, Behav Brain Res source

      Not checked in the free run.

    • cites [315] Meyer, 2014, A ghrelin-growth hormone axis drives stress-induced vulnerability to enhanced fear, Mol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ghrelin enhances release of NPY onto GABAergic nerve terminals adjacent to CRH neurons, disinhibiting these neurons and stimulating CRF release into pituitary-hypophyseal portal circulation, driving increased ACTH secretion from pituitary.

    “Nevertheless, it appears that in addition to its effects on feeding, ghrelin enhances the release of NPY onto GABAergic nerve terminals adjacent to CRH neurons, disinhibiting these neurons and stimulating CRF release into the pituitary-hypophyseal portal circulation, driving increased ACTH secretion from the pituitary [28,308].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Cowley, 2003, The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis, Neuron source

      Not checked in the free run.

    • cites [308] Arvat, 2001, Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone, J Clin Endocrinol Metab

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice lacking GHS receptors are more susceptible to stress and exhibit anxiety- and depressive-like behavior.

    “Moreover, mice lacking growth hormone secretagogue (GHS) receptors are more susceptible to stress and exhibit anxiety-and depressive-like behavior [309,312].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [309] Lutter, 2008, The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress, Nat Neurosci source

      Not checked in the free run.

    • cites [312] Walker, 2015, The P7C3 class of neuroprotective compounds exerts antidepressant efficacy in mice by increasing hippocampal neurogenesis, Mol Psychiatry source

      Not checked in the free run.

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

    Premisecitation

    After fasting, germ-free mice have higher plasma ghrelin concentrations than conventionally colonized mice, which could reflect direct effect of fasting and not microbiota profile on ghrelin release.

    “However, after a period of fasting, germ-free mice have higher plasma ghrelin concentrations than conventionally colonized mice, which could reflect a direct effect of fasting and not the microbiota profile on ghrelin release [121].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [121] Khosravi, 2015, Helicobacter pylori infection can affect energy modulating hormones and body weight in germ free mice, Sci Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dietary capsaicin increases Firmicutes/Bacteroidetes ratio, associated with decreased plasma ghrelin levels and increase in butyrate.

    “The use of dietary capsaicin was shown to increase the Firmicutes/Bacteroidetes ratio, which was associated with decreased plasma ghrelin levels and an increase in butyrate [325].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [325] Kang, 2016, Healthy subjects differentially respond to dietary capsaicin correlating with specific gut enterotypes, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ghrelin decreases in response to prebiotic supplementation inulin and oligofructose uniquely in obese and lean rodents, with obese rats showing attenuated ghrelin levels.

    “Ghrelin has also been shown to decrease in response to the prebiotic supplementation inulin and oligofructose uniquely in obese and lean rodents, with obese rats showing attenuated ghrelin levels [117, 122, 127].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [117] Parnell, 2012, Prebiotic fibres dose-dependently increase satiety hormones and alter Bacteroidetes and Firmicutes in lean and obese JCR:LA-cp rats, Br J Nutr source

      Not checked in the free run.

    • cites [122] Cani, 2004, Inulin-type fructans modulate gastrointestinal peptides involved in appetite regulation (glucagon-like peptide-1 and ghrelin) in rats, Br J Nutr source

      Not checked in the free run.

    • cites [127] Cani, 2005, Oligofructose promotes satiety in rats fed a high-fat diet: involvement of glucagon-like peptide-1, Obes Res source

      Not checked in the free run.

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

    Premisecitation

    ACTH passes into systemic circulation to cause release of cortisol (humans) or corticosterone (rodents) from adrenal glands.

    “Then, ACTH passes into systemic circulation to cause the release of cortisol (in humans) or corticosterone (in rodents) from the adrenal glands [328,330].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [328] Turnbull, 1997, Corticotropin-releasing factor (CRF) and endocrine responses to stress: CRF receptors, binding protein, and related peptides, Proc Soc Exp Biol Med source

      Not checked in the free run.

    • cites [330] Tsatsanis, 2007, The corticotropin-releasing factor (CRF) family of peptides as local modulators of adrenal function, Cell Mol Life Sci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Since gut microbiota strongly affects immune system, intestinal diseases where gut microbiota is changed, such as IBS and IBD, may induce expression of inflammatory cells, which can increase expression of glucocorticoids but not CRF.

    “Since the gut microbiota strongly affects the immune system, intestinal diseases where the gut microbiota is changed, such as IBS and IBD, may induce the expression of inflammatory cells, which, in turn, can increase expression of glucocorticoids but not CRF.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The gut microbiota strongly affects the immune system.

  • May combine two claims.

    Premisecitation

    In humans, relative abundance of bacterial taxa such as Bacteroides was negatively correlated with plasma ghrelin, which in obese patients was increased.

    “In humans, the relationship between the gut microbiota and ghrelin levels seems to mirror that in rodents where the relative abundance of bacterial taxa such as Bacteroides was negatively correlated with plasma ghrelin, which, in obese patients, was increased [130,197,292].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [130] Glintborg, 2006, Evaluation of metabolic risk markers in polycystic ovary syndrome (PCOS). Adiponectin, ghrelin, leptin and body composition in hirsute PCOS patients and controls, Eur J Endocrinol source

      Not checked in the free run.

    • cites [197] Liu, 2017, Dysbiosis of gut microbiota associated with clinical parameters in polycystic ovary syndrome, Front Microbiol

      Not checked in the free run.

    • cites [292] Federico, 2016, Gastrointestinal hormones, intestinal microbiota and metabolic homeostasis in obese patients: effect of bariatric surgery, In Vivo

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Plasma ghrelin did not return to levels found in normal weight individuals after obese patients underwent bariatric surgery, despite postoperative increase of Lactobacillus and Streptococcus.

    “Interestingly, plasma ghrelin did not return to levels found in normal weight individuals after obese patients underwent bariatric surgery, despite a postoperative increase of Lactobacillus and Streptococcus [292].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [292] Federico, 2016, Gastrointestinal hormones, intestinal microbiota and metabolic homeostasis in obese patients: effect of bariatric surgery, In Vivo

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SCFA butyrate, as well as physical exercise, reduce serum ghrelin levels through involvement of FFA3 receptor.

    “Moreover, the SCFA butyrate, as well as physical exercise, reduce serum ghrelin levels through involvement of FFA3 receptor [105, 318].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [105] Lin, 2012, Butyrate and propionate protect against diet-induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms, PLOS ONE

      Not checked in the free run.

    • cites [318] Queipo-Ortuño, 2013, Gut microbiota composition in male rat models under different nutritional status and physical activity and its association with serum leptin and ghrelin levels, PLOS ONE source

      Not checked in the free run.

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

    Premisecitation

    CRF-binding protein is thought to play inhibitory role by binding CRF to prevent activation of CRF receptors.

    “CRFbinding protein is thought to play an inhibitory role in which it binds CRF to prevent the activation of CRF receptors [336].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336] Seasholtz, 2002, Corticotropin-releasing hormone-binding protein: Biochemistry and function from fishes to mammals, J Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Depletion of gut microbiota via antibiotic treatment in mice from weaning onward does not alter hypothalamic mRNA CRF expression in adulthood, even when mice underwent acute restraint stress, suggesting gut microbiota-mediated CRF signaling may occur during early life.

    “Interestingly, the depletion of the gut microbiota via antibiotic treatment in mice from weaning onward does not alter hypothalamic mRNA CRF expression in adulthood, even when mice underwent acute restraint stress [21], suggesting gut microbiota-mediated CRF signaling may occur during early life.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Desbonnet, 2015, Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour, Brain Behav Immun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sun et al. observed changes in gut microbiota composition, which was reverted with probiotic supplement.

    “Sun et al. [131] also observed changes in gut microbiota composition, which was reverted with a probiotic supplement.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Sun, 2013, Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice, Gastroenterology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Absence of CRF1 receptors impairs basal and stress-induced HPA axis response and induces anxiolytic- and antidepressant-like effect.

    “Whereas the absence of CRF 1 receptors impairs basal and stress-induced HPA axis response and induces an anxiolytic-and antidepressant-like effect [329, 340, 341]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [329] Aubry, 2013, CRF system and mood disorders, J Chem Neuroanat source

      Not checked in the free run.

    • cites [340] Habib, 2000, Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates, Proc Natl Acad Sci U S A source

      Not checked in the free run.

    • cites [341] Smith, 1998, Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development, Neuron source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prenatal stress induced depressive-like behavior in adulthood mice, which led to long-lasting change of enteric microbiota composition associated with exaggerated HPA axis response to stress.

    “Prenatal stress induced depressive-like behavior in adulthood mice, which led to a long-lasting change of the enteric microbiota composition associated with an exaggerated HPA axis response to stress [353][354][355].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [353] 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.

    • cites [354] Golubeva, 2015, Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [355] Abe, 2007, Prenatal psychological stress causes higher emotionality, depression-like behavior, and elevated activity in the hypothalamo-pituitary-adrenal axis, Neurosci Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Germ-free rodents have increased hypothalamic CRF gene expression, as well as circulating levels of ACTH and corticosterone to acute restraint stress in adulthood.

    “Germ-free rodents have increased hypothalamic CRF gene expression, as well as circulating levels of ACTH and corticosterone to acute restraint stress in adulthood [27,216].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Crumeyrolle-Arias, 2014, Absence of the gut microbiota enhances anxiety-like behavior and neuroendocrine response to acute stress in rats, Psychoneuroendocrinology source

      Not checked in the free run.

    • cites [216] 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.

  • May combine two claims.

    Premisecitation

    Central administration of CRF in rodents induces depressive and anxiolytic-like behavior, followed by changes in intestinal microbial community.

    “The central administration of CRF in rodents induces depressive and anxiolytic-like behavior, which was followed by changes in the intestinal microbial community [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Park, 2013, Altered colonic function and microbiota profile in a mouse model of chronic depression, Neurogastroenterol Motil source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early-life stress such as maternal separation results in changes in gut microbiota followed by increase in stress reactivity, including decrease in Lactobacillus in adult mice.

    “Early-life stress such as maternal separation results in changes in the gut microbiota followed by an increase in stress reactivity, including a decrease in Lactobacillus in adult mice [137].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Bailey, 1999, Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys, Dev Psychobiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Healthy participants who ingested Lactobacillus helveticus and Bifidobacterium longum showed less self-reported negative mood and decreased urinary cortisol.

    “In yet another study, healthy participants who ingested Lactobacillus helveticus and Bifidobacterium longum showed less self-reported negative mood and decreased urinary cortisol [50,390].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Messaoudi, 2011, Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers, Gut Microbes source

      Not checked in the free run.

    • cites [390] Messaoudi, 2010, 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

    Oleoylethanolamide excites vagal afferent neurons and stimulates both axonal and somatodendritic oxytocin secretion.

    “Oleoylethanolamide, a product of fat absorption, which has antidepressant-like and neuroimmune properties [380,381], excites vagal afferent neurons and stimulates both axonal and somatodendritic oxytocin secretion [382][383][384].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [382] Gaetani, 2010, The fat-induced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin, J Neurosci source

      Not checked in the free run.

    • cites [383] Romano, 2013, The satiety signal oleoylethanolamide stimulates oxytocin neurosecretion from rat hypothalamic neurons, Peptides source

      Not checked in the free run.

    • cites [384] Wang, 2005, Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1, J Physiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These patients also presented reduced degree of anxiety before surgery, suggesting effect of probiotics in mediating CRF expression to modulate stress reactivity.

    “These patients also presented a reduced degree of anxiety before surgery, suggesting an interesting effect of probiotics in mediating CRF expression to modulate stress reactivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [361] Yang, 2016, Probiotics reduce psychological stress in patients before laryngeal cancer surgery, Asia Pac J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Plasticity in oxytocin system is likely a protective coping mechanism in response to stress shaped by gut microbiota during early life stage, mainly through maternal exchange, which can contribute to depressive phenotypes when offspring become adults.

    “Nonetheless, plasticity in the oxytocin system is likely a protective coping mechanism in response to stress shaped by the gut microbiota during the early life stage, mainly through maternal exchange, which can contribute to depressive phenotypes when offspring become adults.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Decreased oxytocin levels have been linked with depression (not only postpartum depression) and maternal neglect.

    “Although oxytocin facilitates parturition and lactation in females, decreased oxytocin levels have been linked with depression (not only postpartum depression) and maternal neglect [362,363].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [362] Leng, 2015, Intranasal oxytocin: myths and delusions, Biol Psychiatry source

      Not checked in the free run.

    • cites [363] Neumann, 2012, Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors, Trends Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is little evidence that oxytocin is modulated by gut bacteria, although gut microbiota seems to influence oxytocin in brain.

    “There is little evidence that oxytocin is modulated by gut bacteria, although gut microbiota seems to influence oxytocin in the brain [21,26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Desbonnet, 2015, Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour, Brain Behav Immun source

      Not checked in the free run.

    • cites [26] Buffington, 2016, Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lowered oxytocin levels observed in nonweaned rats induces depressive-like phenotype, which correlates positively with changes in gut bacterial taxa.

    “whereas lowered oxytocin levels observed in nonweaned rats induces a depressive-like phenotype, which correlates positively with changes in the gut bacterial taxa [378].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [378] Farshim, 2016, Maternal weaning modulates emotional behavior and regulates the gut-brain axis, Sci Rep source

      Not checked in the free run.

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

    Interpretationnone given

    Microbiota-derived metabolites might be able directly to modify gut-peptide receptors, displaying gut-peptide mimicry.

    “Interestingly, microbiota-derived metabolites might be able directly to modify gut-peptide receptors, displaying gut-peptide mimicry.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Antimicrobials such as bacteriocins may help gain terrain over neighbor competitors.

    “antimicrobials such as bacteriocins may help gain terrain over neighbor competitors.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The nature of bacteria that occupy overlapping niches is to compete for the same nutrients.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Generation of specialized psychobiotics to modify gut hormone secretion from EECs may represent feasible and therapeutic microbiota-based strategies for treatment of depression and anxiety disorders.

    “The generation of specialized psychobiotics to modify gut hormone secretion from EECs may represent feasible and therapeutic microbiota-based strategies for the treatment of depression and anxiety disorders.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    There is significant anatomical and functional overlap of peptides released in gut and brain, suggesting these peptides exert common downstream effects on neural systems involved in mental health.

    “There is significant anatomical and functional overlap of peptides released in the gut and brain, suggesting that these peptides exert common downstream effects on neural systems involved in mental health.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationreasoning

    Manipulation of gut peptides via psychobiotics may represent promising opportunity to target mental disorders from site of GI tract.

    “Therefore, the manipulation of gut peptides via psychobiotics may represent a promising opportunity to target mental disorders from the site of the GI tract.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There are major challenges associated with development of peptide therapeutics, including limited peptide stability, short duration of action, and ability to cross BBB.

    “There are major challenges associated with the development of peptide therapeutics, including limited peptide stability, a short duration of action, and the ability to cross the BBB [394,395].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [394] Rafferty, 2016, Peptide therapeutics and the pharmaceutical industry: barriers encountered translating from the laboratory to patients, Curr Med Chem source

      Not checked in the free run.

    • cites [395] Yin, 2017, Protein based therapeutic delivery agents: contemporary developments and challenges, Biomaterials source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    There is already strong evidence to support influence of enteric microbiome on brain function in health and disease, suggesting gut microbiome plays crucial role in normal brain development and modulation of host physiological systems important in stress-related disorders.

    “However, there is already strong evidence to support the influence of the enteric microbiome on brain function in health and disease, suggesting the gut microbiome plays a crucial role in normal brain development, as well as modulation of host physiological systems important in stress-related disorders.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Since stress can alter gut microbiota composition, there is interaction between oxytocin and gut microbiome.

    “Since stress can alter the gut microbiota composition, it is not surprising that there is interaction between oxytocin and the gut microbiome.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Stress can alter the gut microbiota composition.

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

    Premisecitation

    Bacteriocins are ribosomally synthesized peptides produced by bacteria to eliminate neighboring cells through toxic and immune functions, while protecting itself and progeny.

    “Bacteriocins are ribosomally synthesized peptides that are produced by bacteria to eliminate neighboring cells through toxic and immune functions, while protecting itself and its progeny [399-402].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [399] Walsh, 2015, In silico identification of bacteriocin gene clusters in the gastrointestinal tract, based on the Human Microbiome Project's reference genome database, BMC Microbiol source

      Not checked in the free run.

    • cites [400] Zheng, 2015, Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way?, Neuropharmacology source

      Not checked in the free run.

    • cites [401] Kommineni, 2015, Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract, Nature source

      Not checked in the free run.

    • cites [402] Corr, 2007, Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118, Proc Natl Acad Sci U S A source

      Not checked in the free run.

87 of 87

  • The paper relies on this without support.

    Some patients are resistant to the therapeutic effects of conventional pharmacological therapies.

    “Conversely, some patients are resistant to the therapeutic effects of conventional pharmacological therapies.”

  • The paper relies on this without support.

    Alterations in gut microbiota cause changes in gut peptide release that are sufficient to affect brain function and behavior.

    “Evidence of direct involvement interaction between the NPY system and the gut microbiota modulating behavior is lacking.”

  • The paper relies on this without support.

    The gut microbiota strongly affects the immune system.

    “Since the gut microbiota strongly affects the immune system”

  • The paper relies on this without support.

    Stress can alter the gut microbiota composition.

    “Since stress can alter the gut microbiota composition”

  • The paper relies on this without support.

    The nature of bacteria that occupy overlapping niches is to compete for the same nutrients.

    “Since the nature of bacteria that occupy overlapping niches is to compete for the same nutrients”
5 of 5

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?

  • Disturbances in the composition of the microbiome have been linked to anxiety, and treatments aimed at normalising these disturbances using specific probiotics have been proposed.

    “Disturbances in the composition of the microbiome have been linked to anxiety (Lach et al., 2018;Leclercq et al., 2016) and treatments aimed at normalising these disturbances using specific probiotics have been proposed (Yang, Wei, Ju, & Chen, 2019).”

    From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Lach et al., 2018

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Related

Authors
Lach, G., Schellekens, H., Dinan, T. G., & Cryan, J. F.
Affiliations
University College Cork (IE)
Corresponding author
Cryan, John F.
ORCID
Venue
Neurotherapeutics
Publisher
Elsevier BV
Published
2018-01
Volume
15
Issue
1
Pages
36-59
ISSN
1878-7479 (ISSN-L)
DOI
10.1007/s13311-017-0585-0
PMC
PMC5794698
OpenAlex
W2769787189
Semantic Scholar
be5e28f3ea23394eef9edebbb176acf8dd5b68ff
Cited by
573
References
421
Citations by year
2026: 34 · 2025: 59 · 2024: 74 · 2023: 97 · 2022: 82 · 2021: 91 · 2020: 76 · 2019: 38 · 2018: 19 · 2017: 1
FWCI
3.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurotherapeutics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Science Foundation Ireland (SFI/12/RC/, 12/RC/2273, 12/RC/, SFI/12/RC/2273.)
  • APC Microbiome Institute (SFI/12/RC/2273)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
gut microbiota, gut-brain axis, anxiety, depression, gut peptides, gastrointestinal hormones, neuropeptide Y, peptide YY, pancreatic polypeptide, cholecystokinin, glucagon-like peptide, corticotropin-releasing factor, oxytocin, ghrelin, vagus nerve, stress-related psychiatric disorders
MeSH terms
Gastrointestinal Microbiome, Anxiety, Brain, Cholecystokinin, Corticotropin-Releasing Hormone, Depression, Endocrine System, Humans, Neuropeptide Y, Oxytocin, Peptide Hormones, Glucagon-Like Peptide 1, Ghrelin

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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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