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Cited by 1,342Gut microbiota and healthGastrointestinal motility and disordersVagus Nerve Stimulation Research

Principles and clinical implications of the brain-gut-enteric microbiota axis

Open access
Rhee, Sang H., Pothoulakis, Charalabos, Mayer, Emeran A.·2009·Nature Reviews Gastroenterology & Hepatology
DOI 10.1038/nrgastro.2009.35PMC PMC3817714
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Abstract

While bidirectional brain–gut interactions are well known mechanisms for the regulation of gut function in both healthy and diseased states, a role of the enteric flora—including both commensal and pathogenic organisms—in these interactions has only been recognized in the past few years. The brain can influence commensal organisms (enteric microbiota) indirectly, via changes in gastrointestinal motility and secretion, and intestinal permeability, or directly, via signaling molecules released into the gut lumen from cells in the lamina propria (enterochromaffin cells, neurons, immune cells). Communication from enteric microbiota to the host can occur via multiple mechanisms, including epithelial-cell, receptor-mediated signaling and, when intestinal permeability is increased, through direct stimulation of host cells in the lamina propria. Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system. Vagal, afferent innervation of enterochromaffin cells provides a direct pathway for enterochromaffin-cell signaling to neuronal circuits, which may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions. Disruption of the bidirectional interactions between the enteric microbiota and the nervous system may be involved in the pathophysiology of acute and chronic gastrointestinal disease states, including functional and inflammatory bowel disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence for bidirectional signaling between the CNS and the enteric microbiota—the "brain–gut–enteric microbiota axis"—and proposes enterochromaffin cells as key bidirectional transducers. It argues that disruption of these interactions may contribute to functional and inflammatory bowel disorders, though causative roles remain unproven.

Key findings

  • The brain can influence commensal organisms indirectly (via ANS-mediated changes in motility, secretion, and intestinal permeability) and directly via signaling molecules (catecholamines, serotonin, dynorphin, cytokines) released into the gut lumen from neurons, immune cells, and enterochromaffin cells.
  • Microbe-to-host signaling occurs via epithelial receptor-mediated mechanisms (e.g., Toll-like receptors) and, when permeability is increased, through direct stimulation of lamina propria cells; the autoinducer-3–QseC system in enterohemorrhagic *E. coli* is activated by host norepinephrine, enabling interkingdom signaling during stress.
  • Enterochromaffin cells are positioned to act as bidirectional transducers: they secrete serotonin and peptides in response to luminal microbial factors and central stimuli, and vagal afferents expressing 5-HT3R lie in close proximity.
  • Germ-free mice showed less intense inflammation-associated hyperalgesia than conventional mice, associated with increased interleukin-10 expression, reversed by anti-interleukin-10 antibody; the human gut harbors 400–1,000 bacterial species with ~10¹¹ bacterial cells per gram of colon contents.
  • Two cited RCTs: 4-week *Bifidobacterium lactis* reduced abdominal distention and accelerated orocecal/colonic transit in IBS with constipation; 8-week *Bifidobacterium infantis* improved symptoms and normalized the plasma IL-10:IL-12 ratio.

Methods

  • Narrative review (not a primary study) summarizing preclinical and clinical evidence on bidirectional nervous system–enteric microbiota interactions.
  • Draws on animal models (rhesus monkeys, mice, rats, pigs), in vitro studies, and human clinical trials, including cited randomized controlled trials of probiotics in IBS.
  • Organizes evidence into brain-to-microbiota signaling, microbe-to-gut-to-brain signaling, enterochromaffin cell transduction, vagal transmission, homeostatic functions, and clinical/therapeutic implications.

Limitations

  • The paper states that evidence is "often sparse," that host-to-enteric bacteria signaling has been characterized in detail only for pathogenic organisms and only for some molecules (norepinephrine, dynorphins, cytokines), and that considerably more data are needed to establish a causative role for microbiota changes in IBS symptoms.
  • The paper notes most studies of CNS influence on microbiota used luminal bacterial populations from stool samples, with biofilm-adjacent organisms less well documented.
  • Evident from the text: this is a review without primary data or systematic search methodology, and several proposed mechanisms (e.g., enterochromaffin cell signaling to brain function, adrenergic receptors on epithelial brush border) are explicitly described as not yet studied in detail.

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

Integrity signals

Registry

Crossref · 10.1038/nrgastro.2009.35

Cites

87 of 87 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 105 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    The mechanisms that underlie the observed effects of psychological stressors on disease exacerbation in ulcerative colitis and IBS are poorly understood.

    “the mechanisms that underlie the observed effects are poorly understood.”
    Quote in the paperSubstantial claim
  • Premisecitation

    The enteric microbiota can directly influence gut homeostasis by the regulation of bowel motility and modulation of intestinal pain, immune responses, and nutrient processing.

    “The enteric microbiota can directly influence gut homeostasis by the regulation of bowel motility and modulation of intestinal pain, immune responses, and nutrient processing.8-10”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Husebye, E., Hellstrom, P. M., Sundler, F., Chen, J. & Midtvedt, T. Influence of microbial species on small intestinal myoelectric activity and transit in germ-free rats. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G368–G380 (2001). source

      Not checked in the free run.

    • cites [9] Rhee, S. H. et al. Pathophysiological role of Toll-like receptor 5 engagement by bacterial flagellin in colonic inflammation. Proc. Natl Acad. Sci. USA 102, 13610–13615 (2005). source

      Not checked in the free run.

    • cites [10] Ait-Belgnaoui, A. et al. Lactobacillus farciminis treatment suppresses stress induced visceral hypersensitivity: a possible action through interaction with epithelial cell cytoskeleton contraction. Gut 55, 1090–1094 (2006). source

      Not checked in the free run.

  • Interpretationnone given

    Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system.

    “Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Accelerated intestinal transit, with an increased number of giant migrating contractions, is seen in many diarrheal states, including diarrhea-predominant IBS.

    “while accelerated intestinal transit, with an increased number of giant, migrating contractions, is seen in many diarrheal states, including diarrhea-predominant IBS.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Chey, W. Y. et al. Colonic motility abnormality in patients with irritable bowel syndrome exhibiting abdominal pain and diarrhea. Am. J. Gastroenterol. 96, 1499–1506 (2001). source

      Not checked in the free run.

  • Premisecitation

    Impaired intestinal transit caused by compromised migrating motor complexes is associated with bacterial overgrowth in the small intestine.

    “Impaired intestinal transit caused by compromised, migrating motor complexes (a motor pattern characteristic of the fasting state of the gastrointestinal tract that is under parasympathetic control), is associated with bacterial overgrowth in the small intestine.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Van Felius, I. D. et al. Interdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis. Neurogastroenterol. Motil. 15, 267–276 (2003). source

      Not checked in the free run.

  • May combine two claims. 31
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Interpretationnone given

    The brain can influence commensal enteric microbiota indirectly via changes in gastrointestinal motility and secretion and intestinal permeability, or directly via signaling molecules released into the gut lumen from cells in the lamina propria.

    “The brain can influence commensal organisms (enteric microbiota) indirectly, via changes in gastrointestinal motility and secretion, and intestinal permeability, or directly, via signaling molecules released into the gut lumen from cells in the lamina propria (enterochromaffin cells, neurons, immune cells).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In maternal separation-induced postnatal stress, reduction in lactobacilli was associated with the appearance of stress-indicative behaviors, and affected animals were more susceptible than unstressed controls to opportunistic infection.

    “In maternal separation-induced, postnatal stress, reduction in lactobacilli was associated with the appearance of stress-indicative behaviors, and affected animals were more susceptible than unstressed controls to opportunistic infection.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Bailey, M. T. & Coe, C. L. Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev. Psychobiol. 35, 146–155 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Vagal afferent innervation of enterochromaffin cells provides a direct pathway for enterochromaffin-cell signaling to neuronal circuits, which may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions.

    “Vagal, afferent innervation of enterochromaffin cells provides a direct pathway for enterochromaffin-cell signaling to neuronal circuits, which may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The role of the enteric microbiota in bidirectional gut-brain interactions in health and disease has received little attention until the past 5 years or so.

    “the role of the enteric microbiota in bidirectional gut–brain interactions in health and disease has received little attention until the past 5 years or so.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both prenatal and postnatal stress were associated with transient reductions in the levels of the enteric microbiota in rhesus monkeys.

    “Both pre natal17 and postnatal stress16 were associated with transient reductions in the levels of the enteric microbiota in rhesus monkeys.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Bailey, M. T. et al. Prenatal stress alters bacterial colonization of the gut in infant monkeys. J. Pediatr. Gastroenterol. Nutr. 38, 414–421 (2004). source

      Not checked in the free run.

    • cites [16] Bailey, M. T. & Coe, C. L. Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys. Dev. Psychobiol. 35, 146–155 (1999). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bacteria located in the biofilm seem to be less affected by environmental alterations, such as changes in intestinal transit rate and luminal contents, than luminal populations are, but seem to have increased involvement in bidirectional signaling with the host.

    “In general, bacteria located in the biofilm seem to be less affected by environmental alterations, such as changes in intestinal transit rate and luminal contents, than luminal populations are, but seem to have increased involvement in bidirectional signaling with the host.19”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Macfarlane, S. & Dillon, J. F. Microbial biofilms in the human gastrointestinal tract. J. Appl. Microbiol. 102, 1187–1196 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stressful stimuli can enhance the permeability of the intestinal epithelium, which allows bacterial antigens to penetrate the gut epithelium and triggers an immune response in the intestinal mucosa.

    “For example, several studies have demonstrated that stressful stimuli can enhance the permeability of the intestinal epithelium, which allows bacterial antigens to penetrate the gut epithelium and triggers an immune response in the intestinal mucosa.23-27”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [23] Kiliaan, A. J. et al. Stress stimulates transepithelial macromolecular uptake in rat jejunum. Am. J. Physiol. 275, G1037–G1044 (1998).

      Not checked in the free run.

    • cites [24] Groot, J. et al. Stress-induced decrease of the intestinal barrier function. The role of muscarinic receptor activation. Ann. NY Acad. Sci. 915, 237–246 (2000). source

      Not checked in the free run.

    • cites [25] Yates, D. A., Santos, J., Soderholm, J. D. & Perdue, M. H. Adaptation of stress-induced mucosal pathophysiology in rat colon involves opioid pathways. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G124–G128 (2001). source

      Not checked in the free run.

    • cites [26] Soderholm, J. D. et al. Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am. J. Physiol. Gastrointest. Liver Physiol. 283, G1257–G1263 (2002). source

      Not checked in the free run.

    • cites [27] Jacob, C. et al. Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J. Biol. Chem. 280, 31936–31948 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The ANS affects epithelial mechanisms involved in immune activation of the gut, either directly through modulation of the response of gut immune cells to luminal bacteria, or indirectly through alteration of the access of luminal bacteria to gut immunocytes.

    “The ANS also affects epithelial mechanisms involved in immune activation of the gut, either directly, through modulation of the response of the gut immune cells (for example, macrophages and mast cells) to luminal bacteria, or indirectly, through alteration of the access of luminal bacteria to gut immunocytes (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Most studies that have examined the influence of CNS-related systems on enteric microbiota have been performed on luminal bacterial populations from stool samples, whereas the influence of these systems on organisms contained in the biofilm adjacent to the intestinal mucosa is less well documented.

    “Notably, most of the studies that have examined the influence of these systems on enteric microbiota have been performed on luminal bacterial populations from stool samples, whereas the influence of these systems on organisms contained in the biofilm adjacent to the intestinal mucosa are less well documented.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Serotonin secretion into the stomach lumen occurs in response to an intrathecal injection of TRP, an analog of thyrotropin-releasing hormone, and this secretion is probably mediated by vagal activation of gastric enterochromaffin cells.

    “For example, serotonin secretion into the stomach lumen has been reported in response to an intrathecal injection into the cerebrospinal fluid (central injection) of TRP, an analog of thyrotropin-releasing hormone, which is a central mediator of the stress response to cold temperatures.31,32 This secretion is probably mediated by vagal activation of gastric enterochromaffin cells.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Stephens, R. L. & Tache, Y. Intracisternal injection of a TRH analogue stimulates gastric luminal serotonin release in rats. Am. J. Physiol. 256, G377–G383 (1989).

      Not checked in the free run.

    • cites [32] Yang, H. et al. TRH analogue microinjected into specific medullary nuclei stimulates gastric serotonin secretion in rats. Am. J. Physiol. 262, G216–G222 (1992).

      Not checked in the free run.

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

    Premisecitation

    Secretion of antimicrobial peptides, such as defensins, by Paneth cells has an important role in host defense mechanisms against inflammatory and infectious diseases of the gut.

    “For example, secretion of antimicrobial peptides, such as defensins, by Paneth cells has an important role in host defense mechanisms against inflammatory and infectious diseases of the gut.29”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Salzman, N. H., Underwood, M. A. & Bevins, C. L. Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin. Immunol. 19, 70–83 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bifidobacterium bifidum and Lactobacillus acidophilus are able to promote motility, while Escherichia species can inhibit it.

    “For example, Bifidobacterium bifidum and Lactobacillus acidophilus are able to promote motility, while Escherichia species can inhibit it.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Mazmanian, S. K. et al. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Several signaling molecules used by the host for neuronal and neuroendocrine signaling are likely to be secreted into the gut lumen by neurons, immune cells and enterochromaffin cells, and the CNS is likely to have an important role in the release of these molecules.

    “Several signaling molecules used by the host for neuronal and neuroendocrine signaling (for example, catecholamines, serotonin, dynorphin, and cytokines) are also likely to be secreted into the gut lumen by neurons, immune cells and enterochromaffin cells, and the CNS is likely to have an important role in the release of these molecules.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Prokaryotes communicate with each other through hormones and hormone-like compounds, a pattern called quorum sensing.

    “Similarly to eukaryotes, prokaryotes communicate with each other through hormones and hormone-like compounds. This pattern of mutual bacterial inter action is called quorum sensing.41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Nealson, K. H., Platt, T. & Hastings, J. W. Cellular control of the synthesis and activity of the bacterial luminescent system. J. Bacteriol. 104, 313–322 (1970). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autoinducer 3 binds to the bacterial membrane receptor QseC, which results in its autophosphorylation; QseC then phosphorylates its response regulator QseB to initiate a signaling cascade that activates expression of bacterial genes associated with virulence and motility, including the gene that presides over flagellum development.

    “Autoinducer 3 binds to the bacterial membrane receptor QseC, which results in its autophosphorylation. QseC then phosphorylates its response regulator, QseB, to initiate a complex signaling cascade that activates the expression of bacterial genes associated with virulence and motility, including the gene that presides over flagellum development.34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Stress-induced changes in permeability involve activation of glial and mast cells in the gut, overproduction of interferon-γ and changes in the morphology of the colonic epithelium via reduced expression of tight junction protein 2 and by occlusion of important components of the intestinal tight junction.

    “Stress-induced changes in permeability involve activation of glial and mast cells in the gut, overproduction of interferon-γ and changes in the morphology of the colonic epithelium via reduced expression of tight junction protein 2 (zona occludens 2) and by occlusion of important components of the intestinal tight junction.28”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Demaude, J. et al. Phenotypic changes in colonocytes following acute stress or activation of mast cells in mice: implications for delayed epithelial barrier dysfunction. Gut 55, 655–661 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro norepinephrine stimulates the growth of several strains of enteric pathogens and magnifies the virulent properties of Campylobacter jejuni.

    “In vitro norepinephrine stimulates the growth of several strains of enteric pathogens (reviewed elsewhere34) and magnifies the virulent properties of Campylobacter jejuni.36”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source

      Not checked in the free run.

    • cites [36] Cogan, T. A. et al. Norepinephrine increases the pathogenic potential of Campylobacter jejuni. Gut 56, 1060–1065 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autoinducer 3 can stimulate norepinephrine receptors on the surface of eukaryotic cells, and α-2 receptors are present on the brush border of human enterocytes.

    “For example, autoinducer 3 can stimulate nor epinephrine receptors on the surface of eukaryotic cells, and α-2 receptors are present on the brush border of human enterocytes.51”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Valet, P. et al. Characterization and distribution of alpha 2-adrenergic receptors in the human intestinal mucosa. J. Clin. Invest. 91, 2049–2055 (1993). source

      Not checked in the free run.

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

    Interpretationnone given

    Although the effects of enteric microbiota to host signaling on various gut functions have been studied extensively, the possible effect of such microbial signaling beyond the gastrointestinal tract and on the nervous system has received little attention.

    “Although the effects of enteric microbiota to host signaling on various gut functions, including motility, secretion and immune function, have been studied extensively in healthy and diseased states, the possible effect of such microbial signaling beyond the gastro intestinal tract and on the nervous system has received little attention.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Microbial signaling molecules could interact directly with afferent nerve terminals in situations where intestinal permeability is enhanced, or their signal could be relayed to neurons within the intestinal wall by transducer cells in the epithelium.

    “Microbial signaling molecules could interact directly with afferent nerve terminals in situations where intestinal permeability is enhanced (for example, during inflammation or stress) or their signal could be relayed to neurons within the intestinal wall by ‘transducer cells’ in the epithelium.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    That signaling molecules are released by the host into the lumen of the gastrointestinal tract during stress and that receptors and intercellular signaling mechanisms for these same molecules are present on certain luminal microbes strongly suggests that the nervous system can also directly modulate microbial behavior.

    “That signaling molecules are released by the host into the lumen of the gastrointestinal tract during stress and that receptors and intercellular signaling mechanisms for these same molecules are present on certain luminal microbes34 strongly suggests that the nervous system can also directly modulate microbial behavior.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Enterochromaffin cells are distributed throughout the intestinal tract, and those located in the intestinal mucosa are accessible to the enteric microbiota on the intestinal lumen side, and are in contact with afferent and efferent nerve terminals located on the lamina propria.

    “Enterochromaffin cells are distributed throughout the intestinal tract,52 and, like intestinal epithelial cells, those located in the intestinal mucosa are accessible to the enteric microbiota on the intestinal lumen side, and are in contact with afferent and efferent nerve terminals located on the lamina propria.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Walsh, J. H. & Mayer, E. A. Gastrointestinal peptide hormones and signal transduction. In Gastrointestinal Disease: Pathophysiology, Diagnosis, Management 5th edn (Eds Sleizenger, M. & Fordtran, J.) 18–44 (WB Saunders, Philadelphia, 1993).

      Not checked in the free run.

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

    Interpretationreasoning

    Similar mechanisms could have a role in the pathophysiology of alterations in bowel habits for patients with IBS.

    “Similar mechanisms could have a role in the patho physiology of alterations in bowel habits for patients with IBS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Bacterial adrenergic agonist autoinducer 3 may mediate inhibition of intestinal fluid secretion-and thus delay transit rate-by binding to α-2 receptors on epithelial cells, while other microbial factors may stimulate serotonin release by enterochromaffin cells to enhance fluid secretion and accelerate transit rate.

    “Thus, whereas the bacterial adrenergic agonist autoinducer 3 may mediate inhibition of intestinal fluid secretion—and thus delay transit rate—by binding to α-2 receptors on epithelial cells, other microbial factors may stimulate serotonin release by enterochromaffin cells to enhance fluid secretion, and thus accelerate transit rate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The increase in luminal fluid stimulates bowel motility, which ultimately helps remove intestinal contents, including pathogenic bacteria.

    “This increase in luminal fluid in turn stimulates bowel motility, which ultimately helps remove intestinal contents, including pathogenic bacteria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Olfactory and taste receptors are expressed in enterochromaffin cells, and odorants present in the luminal environment are able to effect serotonin release by these cells.

    “Interestingly, olfactory and taste receptors are expressed in enterochromaffin cells, and odorants present in the luminal environment (probably produced by the enteric microbiota) are also able to effect serotonin release by these cells.53”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Braun, T., Voland, P., Kunz, L., Prinz, C. & Gratzl, M. Enterochromaffin cells of the human gut: sensors for spices and odorants. Gastroenterology 132, 1890–1901 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nerve terminals of vagal afferents are located in close proximity to enterochromaffin cells, and these terminals express the serotonin-specific receptor 5-HT3R.

    “Nerve terminals of vagal afferents are located in close proximity to enterochromaffin cells, and these terminals express the serotonin-specific receptor 5-HT3R.67”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Raybould, H. E., Cooke, H. J. & Christofi, F. L. Sensory mechanisms: transmitters, modulators and reflexes. Neurogastroenterol. Motil. 16 (Suppl. 1), 60–63 (2004). source

      Not checked in the free run.

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

    Interpretationcitation

    A mechanism of this type might explain the reported upregulation of mucosal serotonin in a mouse model of postinfectious bowel dysfunction.

    “A mechanism of this type might explain the reported upregulation of mucosal serotonin in a mouse model of postinfectious bowel dysfunction.66”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Wheatcroft, J. et al. Enterochromaffin cell hyperplasia and decreased serotonin transporter in a mouse model of postinfectious bowel dysfunction. Neurogastroenterol. Motil. 17, 863–870 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cholera toxin triggers intestinal-fluid secretion by binding to the GM1 ganglioside on the surface of enterochromaffin cells, and this interaction results in serotonin-mediated activation of secretomotor reflexes.

    “The cholera toxin, a secretory enterotoxin from Vibrio cholerae, is known to trigger intestinal-fluid secretion by binding to the GM1 ganglioside on the surface of enterochromaffin cells. This interaction results in serotonin-mediated activation of secretomotor reflexes.61”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Lencer, W. I. Microbes and microbial toxins: paradigms for microbial-mucosal toxins. V. Cholera: invasion of the intestinal epithelial barrier by a stably folded protein toxin. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G781–G786 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Inflammation-induced upregulation of serotonin signaling persists after the inflammation has receded, and in this postinflammatory, upregulated state, microbe to enterochromaffin cell signaling may result in persistent symptoms of bowel dysfunction in human postinfectious IBS.

    “Inflammation-induced upregulation of serotonin signaling persists after the inflammation has receded, and, in this post inflammatory, upregulated state, microbe to entero chromaffin cell signaling may result in persistent symptoms of bowel dysfunction in human, post infectious IBS.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The constellation of psychological symptoms associated with inflammation (fatigue, social withdrawal and loss of appetite) has been labeled the sickness behavior syndrome.

    “The influence on the brain of stimuli such as cytokines and vagal signaling has been well characterized in animal models of inflammation, and the constellation of psychological symptoms associated with inflammation (fatigue, social withdrawal and loss of appetite) has been labeled the sickness behavior syndrome.72”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Watkins, L. R. & Maier, S. F. The pain of being sick: implications of immune-to-brain communication for understanding pain. Annu. Rev. Psychol. 51, 29–57 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    As afferent nerves are not exposed to the luminal side of the intestine, under normal circumstances sensory neurons are indirectly activated by stimuli in the intestinal lumen via paracrine signaling, which is mediated by compounds such as serotonin, cholecystokinin, histamine, secretin, somatostatin, melatonin, uroguanylin, and corticotrophin-releasing factor, all of which can be released from ne

    “As afferent nerves are not exposed to the luminal side of the intestine, under normal circumstances sensory neurons are indirectly activated by stimuli in the intestinal lumen via paracrine signaling, which is mediated by compounds such as serotonin, cholecystokinin, histamine, secretin, somatostatin, melatonin, uroguanylin, and corticotrophin-releasing factor, all of which can be released from ne”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] Schonhoff, S. E., Giel-Moloney, M. & Leiter, A. B. Minireview: development and differentiation of gut endocrine cells. Endocrinology 145, 2639–2644 (2004). source

      Not checked in the free run.

    • cites [69] O'Hara, J. R., Ho, W., Linden, D. R., Mawe, G. M. & Sharkey, K. A. Enteroendocrine cells and 5-HT availability are altered in mucosa of guinea pigs with TNBS ileitis. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G998–G1007 (2004). source

      Not checked in the free run.

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

    Interpretationreasoning

    In the presence of increased intestinal permeability (caused, for instance, by stress or gut inflammation), access of various bacterial products and inflammatory mediators to nerve endings in the mucosa would be a plausible mechanism for microbe to brain communication.

    “As discussed earlier, in the presence of increased intestinal permeability (caused, for instance, by stress or gut inflammation), access of various bacterial products and inflammatory mediators to nerve endings in the mucosa would be a plausible mechanism for microbe to brain communication.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Possible mechanisms underlying such changes include effects secondary to the production of gas and short-chain fatty acids by enteric microbiota, and direct enteric microbiota to host signaling.

    “Possible mechanisms underlying such changes include effects secondary to the production of gas and short-chain fatty acids by enteric microbiota, and direct enteric microbiota to host signaling.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Evidence of activation of the afferent vagal system was reported, which suggests a possible vagus-mediated microbe to brain signaling pathway.

    “Evidence of activation of the afferent vagal system was reported, which suggests a possible vagus-mediated microbe to brain signaling pathway.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Lyte, M., Li, W., Opitz, N., Gaykema, R. P. & Goehler, L. E. Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol. Behav. 89, 350–357 (2006). source

      Not checked in the free run.

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

    Interpretationreasoning

    In healthy organisms, signaling via epithelial transducer cells, such as enterochromaffin cells, may be the predominant mechanism.

    “However, in healthy organisms, signaling via epithelial transducer cells, such as enterochromaffin cells, may be the predominant mechanism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In postinfectious IBS, major psychological stress around the time of gastroenteritis, trait anxiety, as well as extended duration of the infection, have been identified as risk factors for the persistence of symptoms.

    “In postinfectious IBS, major psychological stress around the time of gastroenteritis, trait anxiety, as well as extended duration of the infection, have been identified as risk factors for the persistence of symptoms.81”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Gwee, K. A. et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 44, 400–406 (1999). source

      Not checked in the free run.

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

    Interpretationnone given

    The epithelium-associated biofilm acts as a permanent bacterial reservoir whose presence allows prompt reconstitution of the physiological microbiota profile in the gut lumen following a decline in luminal microbiota.

    “One way to explain this resilience would be to consider the epithelium-associated biofilm as a permanent bacterial reservoir whose presence allows prompt reconstitution of the physiological microbiota profile in the gut lumen following a decline in luminal microbiota.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The gastrointestinal system is surprisingly resilient to transient changes in enteric microbiota induced by antibiotic treatment, colonic lavage, or, possibly, by spikes in psychological stress.

  • May combine two claims.

    Premisecitation

    The reduction in abdominal girth was associated with an acceleration of orocecal as well as colonic transit and with an overall improvement in symptoms.

    “This reduction in abdominal girth was associ ated with an acceleration of orocecal as well as colonic transit and with an overall improvement in symptoms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Agrawal, A. et al. Clinical trial: the effects of a fermented milk product containing Bifidobacterium lactis DN-173-010 on abdominal distension and gastrointestinal transit in irritable bowel syndrome with constipation. Aliment. Pharmacol. Ther. (In press).

      Not checked in the free run.

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

    Interpretationnone given

    Inflammation-induced upregulation of the mucosal serotonin signaling system would be expected to enhance the ability of the enteric microbiota to modulate gut motility through activation of peristaltic and secretomotor reflexes.

    “Inflammation-induced upregulation of the mucosal serotonin signaling system would be expected to enhance the ability of the enteric microbiota to modulate gut motility through activation of peristaltic and secretomotor reflexes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Modification of the enteric microbiota by administration of antibiotics, probiotic bacteria or prebiotic substances (for example, certain fibers or lactulose) are beneficial in the treatment of IBD and improve some symptoms of IBS.

    “Evidence suggests that modification of the enteric microbiota by administration of antibiotics, probiotic bacteria or prebiotic substances (for example, certain fibers or lactulose) are beneficial in the treatment of IBD14 and improve some symptoms of IBS.12”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Vanderpool, C., Yan, F. & Polk, D. B. Mechanisms of probiotic action: implications for therapeutic applications in inflammatory bowel diseases. Inflamm. Bowel Dis. 14, 1585–1596 (2008). source

      Not checked in the free run.

    • cites [12] Spiller, P. Review article: probiotics and prebiotics in irritable bowel syndrome (IBS). Aliment. Pharmacol. Ther. (2008).

      Not checked in the free run.

41 of 41

  • The paper relies on this without support.

    Little is known about the possible role of direct signaling by luminal microorganisms to the brain in healthy and diseased states.

    “However, little is known about the possible role of direct signaling by luminal microorganisms to the brain in healthy and diseased states.”

  • The paper relies on this without support.

    The gastrointestinal system is surprisingly resilient to transient changes in enteric microbiota induced by antibiotic treatment, colonic lavage, or, possibly, by spikes in psychological stress.

    “Notably, despite the intriguing possibility of adverse clinical consequences of long-term functional disruption in the brain–gut–microbe axis, the gastro intestinal system is surprisingly resilient to transient changes in enteric microbiota induced by antibiotic treatment, colonic lavage, or, possibly, by spikes in psychological stress.”
2 of 2

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?

  • Microbes can communicate with each other via metabolites, similar to those recognized by host cells, and can thereby interact with gut ANS synapses.

    “Microbes can communicate with each other via metabolites, similar to those recognized by host cells and can thereby interact with gut ANS synapses (Rhee et al., 2009).”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Rhee et al., 2009

    The ‘Bidirectional signaling’ section says microbes communicate through hormone-like compounds that resemble signaling molecules used by host cells. ‘Microbe–gut–brain signaling’ says microbial molecules could interact with afferent nerve terminals when intestinal permeability is increased, or reach neurons through epithelial transducer cells. It does not establish interaction with gut ANS synapses as an unqualified consequence of microbial communication. Page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The size and quality of the intestinal mucus layer is believed to be mediated by sympathetic innervation where mucosal immune system modulation and microbial composition and behavior alterations were seen.

    “The size and quality of the intestinal mucus layer is believed to be mediated by sympathetic innervation where mucosal immune system modulation (Elenkov et al., 2000) and microbial composition and behavior alterations (commensal and pathogenic) were seen (Macfarlane and Dillon, 2007;Rhee et al., 2009)”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Rhee et al., 2009

    In “CNS-related changes in gut environment” (page unavailable), the review says autonomic modulation of mucus secretion is likely to affect the intestinal mucus layer and that the autonomic nervous system also modulates gut immune responses. “Brain to enteric microbiota signaling” reports stress-associated changes in microbial composition. The review does not specifically establish sympathetic innervation as the mediator of mucus-layer changes, or show that those mucus changes produced the reported microbial alterations. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The concept of the microbiota-gut-brain axis emerged based upon the historical legacy of scientific figures.

    “The concept of the microbiota-gut-brain axis thus emerged (Cryan and O'Mahony, 2011;De Palma et al., 2014;Rhee et al., 2009) based upon the rich historical legacy of the illustrious scientific figures discussed above, amongst many others.”

    From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Rhee et al., 2009

    The Introduction (page unavailable) describes growing recognition of the microbiota’s role in bidirectional gut–brain interactions, supporting the reference to the concept’s emergence. It does not say that the concept emerged from the historical legacy of the scientific figures discussed in the citing paper. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Gut-brain communication can also be achieved through vagus nerve signaling.

    “Gut-brain communication can also be achieved through vagus nerve signaling (57).”

    From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [57]

  • The brain shapes the gut habitat and therefore selects for a distinct microbial profile by regulating gastrointestinal functions such as motility, nutrient absorption, acid production, and mucosal immunity.

    “By regulating gastrointestinal functions, e.g., motility, nutrient absorption, acid production and mucosal immunity, the brain shapes the gut habitat and therefore selects for a distinct microbial profile [62].”

    From Are the gut bacteria telling us to eat or not to eat? reviewing the role of gut microbiota in the etiology, disease progression and treatment of eating disorders (2017) · cites this paper as [62]

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Authors
Rhee, S. H., Pothoulakis, C., & Mayer, E. A.
Affiliations
University of California, Los Angeles (US)
Corresponding author
Mayer, Emeran A.
ORCID
Venue
Nature Reviews Gastroenterology & Hepatology
Publisher
Springer Science and Business Media LLC
Published
2009-05
Volume
6
Issue
5
Pages
306-314
ISSN
  • 1759-5045 (ISSN-L)
  • 1759-5053
DOI
10.1038/nrgastro.2009.35
PMC
PMC3817714
OpenAlex
W2076087096
Semantic Scholar
8d46dbee61595ddb88b690b9979d376a39c691fe
Cited by
1,342
References
87
Citations by year
2026: 66 · 2025: 107 · 2024: 112 · 2023: 130 · 2022: 122 · 2021: 127 · 2020: 114 · 2019: 90 · 2018: 84 · 2017: 94 · 2016: 77 · 2015: 48 · 2014: 55 · 2013: 45 · 2012: 33
FWCI
1.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Gastroenterology & Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (P01DK033506, P01 DK-33506, R01 DK072471, R01 DK 48351, R01DK048351, R01-DK47343, P50DK064539, P-50DK64539, R01DK047343, R01DK060729)
  • National Center for Complementary and Integrative Health (R24AT002681)
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 › Neurology › Vagus Nerve Stimulation Research
Keywords
gut-brain axis, gut microbiota, enteric microbiota, two-way communication, central nervous system, enterochromaffin cells, intestinal permeability, lamina propria, gastrointestinal motility, gastrointestinal secretion, functional bowel disorders, inflammatory bowel disease
MeSH terms
Brain, Humans, Intestines, Inflammatory Bowel Diseases, Enteric Nervous 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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