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Principles and clinical implications of the brain-gut-enteric microbiota axis
Open accessAbstract
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.
Overview
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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.
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Claims the paper makes
72 Not checked yet · 40 Own interpretation · 1 No basis given
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the mechanisms that underlie the observed effects are poorly understood.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Introduction
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Introduction
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
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In the paper
“Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Abstract
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In the paper
“while accelerated intestinal transit, with an increased number of giant, migrating contractions, is seen in many diarrheal states, including diarrhea-predominant IBS.22”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
What the sources say
- Not checked yetcites [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
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
What the sources say
- Not checked yetcites [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
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In the paper
“Different types of psychological stressors modulate the composition and total biomass of the enteric microbiota in both adult15 and newborn animals.16”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Brain to enteric microbiota signaling
What the sources say
- Not checked yetcites [15] Schaedler, R. W. & Dubos, R. J. The fecal flora of various strains of mice. Its bearing on their susceptibility to endotoxin. J. Exp. Med. 115, 1149–1160 (1962). source
- Not checked yetcites [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
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In the paper
“In this case, the shedding of lactobacilli may have been related to the stress-induced acceleration of intestinal transit, since normal bacterial levels were restored 1 week after separation.16”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Brain to enteric microbiota signaling
What the sources say
- Not checked yetcites [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
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In the paper
“Although different types of psychological stressors, including early-life stress and sustained stress, have been recognized as risk factors or promoters of events that result in disease exacerbation in patients with ulcerative colitis2 and IBS,3”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Introduction
What the sources say
- Not checked yetcites [2] Levenstein, S. et al. Stress and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am. J. Gastroenterol. 95, 1213–1220 (2000). source
- Not checked yetcites [3] Whitehead, W. E., Crowell, M. D., Robinson, J. C., Heller, B. R. & Schuster, M. M. Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction. Gut 33, 825–830 (1992). source
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In the paper
“The activation of any of these systems, either alone or in combination, might influence enteric microbiota both indirectly, via changes in their environment, and directly, via host–enteric microbiota signaling.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Brain to enteric microbiota signaling
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In the paper
“Both sympathetic and parasympathetic nervous systems, which are part of the ANS, have a prominent role in the modulation of gut functions, such as motility, secretion of acid, bicarbonates and mucus, intestinal-fluid handling and mucosal immune response (reviewed elsewhere1).”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
What the sources say
- Not checked yetcites [1] Mayer, E. A. The neurobiology of stress and gastrointestinal disease. Gut 47, 861–869 (2000). source
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In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Abstract
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In the paper
“Interactions between pathogenic organisms and primary afferent neurons that innervate the gut are characterized as an important aspect of the pathophysiology that underlies Clostridium difficile colitis.5”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Introduction
What the sources say
- Not checked yetcites [5] Castagliuolo, I. et al. Neuronal involvement in the intestinal effects of Clostridium difficile toxin A and Vibrio cholerae enterotoxin in rat ileum. Gastroenterology 107, 657–665 (1994). source
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In the paper
“A reduced number of giant, migrating contractions in the colon has been reported in slow-transit constipation,21”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
What the sources say
- Not checked yetcites [21] Lembo, A. & Camilleri, M. Chronic constipation. N. Engl. J. Med. 349, 1360–1368 (2003). source
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In the paper
“The role of the central nervous system (CNS) in modulation of various gut functions, including motility, secretion, blood flow and gut-associated immune function in response to psychological and physical stressors, is well established by preclinical and clinical evidence1.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Introduction
What the sources say
- Not checked yetcites [1] Mayer, E. A. The neurobiology of stress and gastrointestinal disease. Gut 47, 861–869 (2000). source
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In the paper
“Regional and global changes in gastrointestinal transit can have profound effects on the delivery of important nutrients to the enteric microbiota (such as prebiotics, including resistant starches and certain dietary fibers) pH, and on the luminal environment in healthy and diseased states.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
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In the paper
“The ANS-mediated modulation of mucus secretion is likely to have important effects on the size and quality of the intestinal mucus layer, an important habitat for the biofilm, where the majority of the enteric microbiota reside.19”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
What the sources say
- Not checked yetcites [19] Macfarlane, S. & Dillon, J. F. Microbial biofilms in the human gastrointestinal tract. J. Appl. Microbiol. 102, 1187–1196 (2007). source
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In the paper
“Both norepinephrine and dynorphins are thought to be released into the gut lumen during perturbation of homeostasis.34”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
What the sources say
- Not checked yetcites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source
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In the paper
“In the enteric microbiota, these signaling mechanisms can mediate diverse physiological functions, including secondary metabolite production, bacterial motility, and pathogenicity.46”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [46] Irie, Y. & Parsek, M. R. Quorum sensing and microbial biofilms. Curr. Top. Microbiol. Immunol. 322, 67–84 (2008).
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In the paper
“The homology of the microbial autoinducer 3–QseC signaling system with the mammalian noradrenergic signaling system, which causes QseC to be activated also by norepinephrine, allows for interkingdom signaling with particular relevance for brain–gut interactions during stress (Figure 3).”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
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In the paper
“Disruption of the balance that exists between different enteric microbiota populations might, therefore, predispose the host to altered gut motility and secretion, which results in diarrhea or constipation.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
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In the paper
“Metabolic products of intestinal bacteria, such as short-chain fatty acids or chemotactic peptides (for example, N-formylmethionyl–leucine–phenylalanine) are able to stimulate the enteric nervous system and influence the rate of gut transit.38-40”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [38] Barbara, G. et al. Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am. J. Gastroenterol. 100, 2560–2568 (2005). source
- Not checked yetcites [39] Dass, N. B. et al. The relationship between the effects of short-chain fatty acids on intestinal motility in vitro and GPR43 receptor activation. Neurogastroenterol. Motil. 19, 66–74 (2007). source
- Not checked yetcites [40] Malbert, C. H. The ileocolonic sphincter. Neurogastroenterol. Motil. 17 (Suppl. 1), 41–49 (2005). source
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In the paper
“Norepinephrine release in the intestine during surgical trauma induces expression of virulent traits in Pseudomonas aeruginosa, which results in gut-derived sepsis.35”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
What the sources say
- Not checked yetcites [35] Alverdy, J. et al. Gut-derived sepsis occurs when the right pathogen with the right virulence genes meets the right host: evidence for in vivo virulence expression in Pseudomonas aeruginosa. Ann. Surg. 232, 480–489 (2000). source
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In the paper
“Bacteria use quorum sensing to regulate their own gene expression, not only in response to signals from other bacteria, but also in response to host signals.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [46] Irie, Y. & Parsek, M. R. Quorum sensing and microbial biofilms. Curr. Top. Microbiol. Immunol. 322, 67–84 (2008).
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In the paper
“Much like the nervous system, enteric microbiota can also modulate intestinal motility.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
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In the paper
“These changes are, in turn, likely to influence the balance of enteric microbiota.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
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In the paper
“The evidence from these in vitro studies may shed light on the reported association of stressful life events with the duration of gastroenteritis, and with the subsequent development of postinfectious IBS.37”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
What the sources say
- Not checked yetcites [37] Dunlop, S. P., Jenkins, D. & Spiller, R. C. Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am. J. Gastroenterol. 98, 1578–1583 (2003). source
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In the paper
“Microorganisms can communicate with mamma lian cells via so-called interkingdom signaling, which uses various hormones and hormone-like compounds: peptides and monoamines, such as the epidermal growth factor, and insulin and small, diffusible signaling molecules called autoinducers.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
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In the paper
“Perhaps the best-characterized microbial signaling system is analogous to the eukaryotic, noradrenergic signaling system and involves autoinducer 3—a molecule produced by the microbiota and the bacterial QseC receptor.34,44”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [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 yetcites [44] Reading, N. C. et al. A novel two-component signaling system that activates transcription of an enterohemorrhagic Escherichia coli effector involved in remodeling of host actin. J. Bacteriol. 189, 2468–2476 (2007). source
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In the paper
“Mast-cell products, such as tryptase and histamine, are secreted into the human jejunum in response to stress induced by cold pain,33”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
What the sources say
- Not checked yetcites [33] Santos, J. et al. Release of mast cell mediators into the jejunum by cold pain stress in humans. Gastroenterology 114, 640–648 (1998). source
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In the paper
“Enterohemorrhagic E. coli can sense luminal norepinephrine or adrenaline to express its virulence traits.45”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [45] Sperandio, V., Torres, A. G., Jarvis, B., Nataro, J. P. & Kaper, J. B. Bacteria–host communication: the language of hormones. Proc. Natl Acad. Sci. USA 100, 8951–8956 (2003). source
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In the paper
“A 2008 study in humans suggests that Paneth-cell secretion of α-defensin can be enhanced by stress.30”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
What the sources say
- Not checked yetcites [30] Alonso, C. et al. Maladaptive intestinal epithelial responses to life stress may predispose healthy women to gut mucosal inflammation. Gastroenterology 135, 163–172 (2008). source
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In the paper
“The signaling molecules used for communication by vertebrates, invertebrates and microbes share structural similarities.42,43”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [42] Mayer, E. A. & Baldi, J. P. Can regulatory peptides be regarded as words of a biological language? Am. J. Physiol. 261, G171–G184 (1991).
- Not checked yetcites [43] Roth, J. et al. Molecules of intercellular communication in vertebrates, invertebrates and microbes: do they share common origins? Prog. Brain Res. 68, 71–79 (1986). source
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In the paper
“Signals that originate from luminal micro-organisms and influence the gut epithelium have been studied extensively, and involve well-characterized mechanisms, such as Toll-like receptor signaling48,49 and signaling by bipeptides or tripeptides, such as N-formylmethionyl–leucyl–phenylalanine.50”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
What the sources say
- Not checked yetcites [48] Rhee, S. H., Keates, A. C., Moyer, M. P. & Pothoulakis, C. MEK is a key modulator for TLR5-induced interleukin-8 and MIP3alpha gene expression in non-transformed human colonic epithelial cells. J. Biol. Chem. 279, 25179–25188 (2004). source
- Not checked yetcites [49] Rhee, S. H., Kim, H., Moyer, M. P. & Pothoulakis, C. Role of MyD88 in phosphatidylinositol 3-kinase activation by flagellin/Toll-like receptor 5 engagement in colonic epithelial cells. J. Biol. Chem. 281, 18560–18568 (2006). source
- Not checked yetcites [50] Charrier, L. et al. hPepT1 mediates bacterial tripeptide fMLP uptake in human monocytes. Lab. Invest. 86, 490–503 (2006). source
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In the paper
“Enterochromaffin cells secrete serotonin and signaling peptides (for example, corticotropin-releasing hormone, cholecystokinin and somatostatin) in response to various physiological and pathological luminal stimuli,53-55 such as microbial factors or bacterial toxins,56-58 as well as central stimuli (see discussion above).31,32”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [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 yetcites [54] Gershon, M. D. & Tack, J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397–414 (2007). source
- Not checked yetcites [55] Gershon, M. D. Nerves, reflexes, and the enteric nervous system: athogenesis of the irritable bowel syndrome. J. Clin. Gastroenterol. 39, S184–S193 (2005). source
- Not checked yetcites [56] Grider, J. R., Kuemmerle, J. F. & Jin, J. G. 5-HT released by mucosal stimuli initiates peristalsis by activating 5-HT4/5-HT1p receptors on sensory CGRP neurons. Am. J. Physiol. 270, G778–G782 (1996). source
- Not checked yetcites [57] Peregrin, A. T., Ahlman, H., Jodal, M. & Lundgren, O. Involvement of serotonin and calcium channels in the intestinal fluid secretion evoked by bile salt and cholera toxin. Br. J. Pharmacol. 127, 887–894 (1999). source
- Not checked yetcites [58] Raybould, H. E. Visceral perception: sensory transduction in visceral afferents and nutrients. Gut 51 (Suppl. 1), i11–i14 (2002). source
- Not checked yetcites [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 yetcites [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).
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This location makes enterochromaffin cells uniquely suitable to function as bidirectional transducers of information between the intestinal lumen and the nervous system.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
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In the paper
“In pigs, psychological stress has been shown to reactivate subacute salmonella infection.47”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [47] Callaway, T. R. et al. Social stress increases fecal shedding of Salmonella typhimurium by early weaned piglets. Curr. Issues Intest. Microbiol. 7, 65–71 (2006).
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In the paper
“However, as outlined above, luminal micro-organisms produce a range of signaling molecules that can interact with receptors of other microbes, as well as those on host cells.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
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In the paper
“Even though such host to enteric bacteria signaling has only been character ized in detail for pathogenic organisms, and only for some molecules (such as norepinephrine, dynorphins and cytokines),34 similar mechanisms are likely to apply to molecules such as serotonin, somato statin, cholecysto kinin or corticotropin-releasing hormone.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source
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In the paper
“Signaling via α-2 adrenergic receptors has been suggested as a mechanism by which certain pathogenic bacteria could inhibit intestinal secretion, and thereby compromise the host’s ability to expel the pathogen.34”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
What the sources say
- Not checked yetcites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Through these various transduction mechanisms, enteric microbiota are likely to affect the nervous system via endocrine, immune and neural signaling mechanisms (Figure 4).”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
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In the paper
“One cell type that is uniquely qualified as a transducer for signals that arise in the gut lumen to afferent nerve terminals is the enterochromaffin cell (Figure 5).”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
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In the paper
“Information about the state of the luminal environment (for example, hyperosmolarity, carbohydrate levels, mechanical distortion of the mucosa, presence of cytostatic drugs and bacterial products) is transmitted to the CNS by the vagus nerve.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Vagal transmission of luminal signals
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In the paper
“Presence in the gastrointestinal tract of pathogenic bacteria, including E. coli, V. cholerae, or Salmonella typhimurium, has been associated with an increased secretion of serotonin into the lamina propria.62”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [62] Costedio, M. M. et al. Serotonin and its role in colonic function and in gastrointestinal disorders. Dis. Colon Rectum 50, 376–388 (2007). source
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In the paper
“In addition to the probable release of these products into the intestinal lumen, signaling molecules generated by Enterochromaffin cells can interact in a paracrine fashion with intrinsic and extrinsic primary, afferent nerve terminals that lie in close proximity to these cells.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
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In the paper
“Activation of intrinsic afferents results in neural reflexes that enhance the release of chloride ions and water into the intestinal lumen.65”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [65] Xue, J., Askwith, C., Javed, N. H. & Cooke, H. J. Autonomic nervous system and secretion across the intestinal mucosal surface. Auton. Neurosci. 133, 55–63 (2007). source
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In the paper
“As a consequence, serotonin receptors on enterocytes and on intrinsic and extrinsic, primary nerve endings are activated in a paracrine fashion.63,64”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [63] Spiller, R. C. Role of infection in irritable bowel syndrome. J. Gastroenterol. 42 (Suppl. 17), 41–47 (2007). source
- Not checked yetcites [64] Grondahl, M. L. et al. Effects of nitric oxide in 5-hydroxytryptamine-, cholera toxin-, enterotoxigenic Escherichia coli and Salmonella typhimurium-induced secretion in the porcine small intestine. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 141, 476–484 (2005). source
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Enterochromaffin cells also express a wide variety of receptors, including serotonin receptors, the pituitary adenylate-cyclase-activating peptide receptor, the α-adrenergic receptor, the β-adrenergic receptor, the cholinergic receptor, the corticotropin-releasing hormone receptor and the γ-aminobutyric acid receptor.59”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [59] Hansen, M. B. & Witte, A. B. The role of serotonin in intestinal luminal sensing and secretion. Acta Physiol. (Oxf.) 193, 311–323 (2008). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Anecdotal evidence and limited evidence from controlled clinical trials on IBS report improvements of certain symptoms following intestinal cleansing, antibiotic therapy, or administration of probiotic bacteria.12,80”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
What the sources say
- Not checked yetcites [12] Spiller, P. Review article: probiotics and prebiotics in irritable bowel syndrome (IBS). Aliment. Pharmacol. Ther. (2008).
- Not checked yetcites [80] Moayyedi, P. et al. The efficacy of probiotics in the therapy of irritable bowel syndrome: a systematic review. Gut [doi:10.1136/gut.2008.167270] (2008). source
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In the paper
“Inflammation-associated hyper algesia induced by a variety of stimuli, including administration of proinflammatory cytokines, was less intense in germ-free mice than in conventional mice.76”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [76] Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A departure from the physiological balance of the enteric microbiota has been suggested as a factor in the pathophysiology of IBS, a condition in which abnormal gastrointestinal motility and secretion is implicated as a cause of alterations in bowel habits.79”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
What the sources say
- Not checked yetcites [79] Kassinen, A. et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 133, 24–33 (2007). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The relative reduction in hyperalgesia in germ-free mice compared with conventional mice was associated with increased expression of the anti-inflammatory cytokine interleukin 10, and the pain reduction was reversed by the administration of an anti-interleukin 10 antibody.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [76] Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A departure from the physiological balance of the enteric microbiota has been suggested as a factor in the pathophysiology of IBS, a condition in which abnormal gastrointestinal motility and secretion is implicated as a cause of alterations in bowel habits.79”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
What the sources say
- Not checked yetcites [79] Kassinen, A. et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 133, 24–33 (2007). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Bidirectional microbe–to–brain signaling and alterations to it during chronic psychological stress may have an important role in the development of certain symptoms, particularly altered bowel habits and bloating.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The relative reduction in hyperalgesia in germ-free mice compared with conventional mice was associated with increased expression of the anti-inflammatory cytokine interleukin 10, and the pain reduction was reversed by the administration of an anti-interleukin 10 antibody.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [76] Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A possible role for gut infection in triggering brain responses, such as anxious behavior and mood changes, in the absence of overt gut inflammation or elevation of plasma cytokines has been described in mice.73”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The celiac branch of the vagus nerve innervates the small intestine, and a prominent role of afferents of this branch in the modulation of experimental knee-joint inflammation and pain sensitivity has been reported.74”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [74] Jänig, W., Khasar, S. G., Levine, J. D. & Miao, F. J. P. The role of visceral afferents in the control of nociception. In The Biological Basis for Mind Body Interactions 1st edn ( Eds Mayer, E. A. & Saper, C. B. ) 273–287 (Elsevier Science, Amsterdam, 2000). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Early evidence for a role of the enteric microbiota in the development of inflammatory somatic hyperalgesia has recently been reported.75”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [75] Amaral, F. A. et al. Commensal microbiota is fundamental for the development of inflammatory pain. Proc. Natl Acad. Sci. USA 105, 2193–2197 (2008). source
plainconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“IBS symptoms related to an imbalance in enteric microbiota could arise from alterations in gas-induced gut distention and the modulation of gastrointestinal motility and secretion.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“The celiac branch of the vagus nerve innervates the small intestine, and a prominent role of afferents of this branch in the modulation of experimental knee-joint inflammation and pain sensitivity has been reported.74”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [74] Jänig, W., Khasar, S. G., Levine, J. D. & Miao, F. J. P. The role of visceral afferents in the control of nociception. In The Biological Basis for Mind Body Interactions 1st edn ( Eds Mayer, E. A. & Saper, C. B. ) 273–287 (Elsevier Science, Amsterdam, 2000). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“As discussed above, stress-induced increases in norepi nephrine levels in the lumen of the gut may result in increased virulence of certain pathogenic organisms, including Campylobacter jejuni,36Salmonella82 and E. coli,34 which result in a prolongation of the symptoms of enteritis.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
What the sources say
- Not checked yetcites [36] Cogan, T. A. et al. Norepinephrine increases the pathogenic potential of Campylobacter jejuni. Gut 56, 1060–1065 (2007). source
- Not checked yetcites [82] Bailey, M. T. et al. In vivo adaptation of attenuated Salmonella typhimurium results in increased growth upon exposure to norepinephrine. Physiol. Behav. 67, 359–364 (1999). source
- Not checked yetcites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition to a possible influence of the gut microbiota on CNS functions, such as pain sensitivity, mood and affect in the adult organism, evidence for a role of intestinal microbes in the development of the hypothalamus–pituitary–adrenal axis has been observed in newborn mice.76”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [76] Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This evidence suggests a possible role for commensal enteric microbiota in the etiology of IBS in some patients.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Evidence for such mutual interaction has been demonstrated in gut inflammation,14 visceral pain,77 certain symptoms of IBS,12 and in obesity.78”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
What the sources say
- Not checked yetcites [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 yetcites [77] Rousseaux, C. et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13, 35–37 (2007). source
- Not checked yetcites [12] Spiller, P. Review article: probiotics and prebiotics in irritable bowel syndrome (IBS). Aliment. Pharmacol. Ther. (2008).
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, a growing body of evidence suggests that such signaling may also take place between the nervous system and the (nonpathogenic) commensal enteric microbiota, including probiotic bacteria.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although early results suggest that alterations might occur in the physiological balance of the enteric microbiota in patients with IBS, considerably more data than these are needed to establish a causative role for such changes in IBS symptoms.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Conclusions
hedged- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although early results suggest that alterations might occur in the physiological balance of the enteric microbiota in patients with IBS, considerably more data than these are needed to establish a causative role for such changes in IBS symptoms.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Conclusions
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Strong preclinical evidence suggests that the enteric microbiota has an important role in bidirectional interactions between the gut and the nervous system in health and in various disease models.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Conclusions
boostedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“In addition, stress-induced shedding of lactobacilli, similar to that observed in animal models of stress,16 may compromise gut homeostasis.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Our understanding of IBS pathophysiology is incomplete, and although the complexity of the network of interactions within the enteric microbiota and between it and the nervous system is now emerging, a few studies have provided evidence for biological mechanisms that may explain the improvements in IBS symptoms associated with the administration of probiotic bacteria.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Potential therapeutic implications
What the sources say
- Not checked yetcites [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 yetcites [83] O'Mahony, L. et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 128, 541–551 (2005). source
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In the paper
“Multiple mechanisms for bidirectional interaction between pathogenic bacteria and the gut–nervous system axis have been reported.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Conclusions
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In the paper
“For example, in a placebo-controlled, randomized study in patients with IBS and constipation, Agrawal et al. demonstrated that a 4-week intake of a preparation that contained Bifidobacterium lactis was associated with a significant reduction in abdominal distention (measured by abdominal inductance plethysmography).13”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Potential therapeutic implications
What the sources say
- Not checked yetcites [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).
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- It may state two separate claims as one. 31
- Probably not a substantial claim. 13
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Abstract
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In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Brain to enteric microbiota signaling
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Abstract
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In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Introduction
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In the paper
“Both pre natal17 and postnatal stress16 were associated with transient reductions in the levels of the enteric microbiota in rhesus monkeys.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Brain to enteric microbiota signaling
What the sources say
- Not checked yetcites [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 yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Brain to enteric microbiota signaling
What the sources say
- Not checked yetcites [19] Macfarlane, S. & Dillon, J. F. Microbial biofilms in the human gastrointestinal tract. J. Appl. Microbiol. 102, 1187–1196 (2007). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
What the sources say
- Not checked yetcites [23] Kiliaan, A. J. et al. Stress stimulates transepithelial macromolecular uptake in rat jejunum. Am. J. Physiol. 275, G1037–G1044 (1998).
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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
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In the paper
“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).”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Brain to enteric microbiota signaling
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In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
What the sources say
- Not checked yetcites [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 yetcites [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).
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“For example, Bifidobacterium bifidum and Lactobacillus acidophilus are able to promote motility, while Escherichia species can inhibit it.6”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [6] Mazmanian, S. K. et al. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS-related changes in gut environment
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In vitro norepinephrine stimulates the growth of several strains of enteric pathogens (reviewed elsewhere34) and magnifies the virulent properties of Campylobacter jejuni.36”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > CNS modulation of gut–microbe signaling
What the sources say
- Not checked yetcites [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 yetcites [36] Cogan, T. A. et al. Norepinephrine increases the pathogenic potential of Campylobacter jejuni. Gut 56, 1060–1065 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
hedged- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Bidirectional signaling
What the sources say
- Not checked yetcites [34] Hughes, D. T. & Sperandio, V. Inter-kingdom signalling: communication between bacteria and their hosts. Nat. Rev. Microbiol. 6, 111–120 (2008). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [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).
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similar mechanisms could have a role in the patho physiology of alterations in bowel habits for patients with IBS.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Microbe–gut–brain signaling
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This increase in luminal fluid in turn stimulates bowel motility, which ultimately helps remove intestinal contents, including pathogenic bacteria.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Nerve terminals of vagal afferents are located in close proximity to enterochromaffin cells, and these terminals express the serotonin-specific receptor 5-HT3R.67”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Vagal transmission of luminal signals
What the sources say
- Not checked yetcites [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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“A mechanism of this type might explain the reported upregulation of mucosal serotonin in a mouse model of postinfectious bowel dysfunction.66”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
What the sources say
- Not checked yetcites [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
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enterochromaffin cells as signal transducers
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Vagal transmission of luminal signals
What the sources say
- Not checked yetcites [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 yetcites [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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Evidence of activation of the afferent vagal system was reported, which suggests a possible vagus-mediated microbe to brain signaling pathway.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
What the sources say
- Not checked yetcites [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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, in healthy organisms, signaling via epithelial transducer cells, such as enterochromaffin cells, may be the predominant mechanism.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Enteric microbiota and homeostatic functions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
What the sources say
- Not checked yetcites [81] Gwee, K. A. et al. The role of psychological and biological factors in postinfective gut dysfunction. Gut 44, 400–406 (1999). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
- 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.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Potential therapeutic implications
What the sources say
- Not checked yetcites [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).
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Clinical impact of bidirectional signaling
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Principles and clinical implications of the brain–gut–enteric microbiota axis > Potential therapeutic implications
What the sources say
- Not checked yetcites [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 yetcites [12] Spiller, P. Review article: probiotics and prebiotics in irritable bowel syndrome (IBS). Aliment. Pharmacol. Ther. (2008).
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
In the citing paper
“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].”
In the citing paper
“There are evidence that the gut microbiota modulates the CNS via the ENS, the ANS, the HPA axis and vice versa [124,213]”
From Gut microbiota role in irritable bowel syndrome: New therapeutic strategies (2016) · cites this paper as [124]
In the citing paper
“Mounting evidence suggests that the gastrointestinal microbiota influences host behaviour via bi-directional communication through what has been coined the microbiota-gut-brain axis [17, 18, 20, 29, 50, 60, 71].”
From Distinct actions of the fermented beverage kefir on host behaviour, immunity and microbiome gut-brain modules in the mouse (2020) · cites this paper as [60]
In the citing paper
“It has been also lately recognized that the gut-brain interactions might be essentially influenced by the gut microbiota (Borre et al., 2014;Grenham et al., 2011;Rhee et al., 2009).”
From The Gut-Brain Axis in Parkinson’s Disease: Possibilities for Food-Based Therapies (2017) · cites this paper as Rhee et al., 2009
Citations
Cites
An obesity-associated gut microbiome with increased capacity for energy harvest
Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., & Gordon, J. I. (2006) · Nature · doi:10.1038/nature05414 · Cited by 12,444
Turnbaugh, P. J., Ley, R. E., Hamady, M., Fraser-Liggett, C. M., Knight, R., & Gordon, J. I. (2007) · Nature · doi:10.1038/nature06244 · Cited by 6,091
Gut flora in health and disease
Guarner, F., & Malagelada, J. (2003) · The Lancet · doi:10.1016/s0140-6736(03)12489-0 · Cited by 3,480 · cited 1×
“Approximately 10 11 bacterial cells can be found per gram of colon contents”
Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X., Kubo, C., & Koga, Y. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.063388 · Cited by 2,735 · cited 1×
“Inflammation-associated hyperalgesia induced by a variety of stimuli, including administration of proinflammatory cytokines, was less intense in germ-free mice than in conventional mice”
A microbial symbiosis factor prevents intestinal inflammatory disease
Mazmanian, S. K., Round, J. L., & Kasper, D. L. (2008) · Nature · doi:10.1038/nature07008 · Cited by 2,340 · cited 1×
“The human gut harbors 400–1,000 different bacterial species”
Elenkov, I. J., Wilder, R. L., Chrousos, G. P., & Vizi, E. S. (2000) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01470-4 · Cited by 2,252
Gershon, M. D., & Tack, J. (2007) · Gastroenterology · doi:10.1053/j.gastro.2006.11.002 · Cited by 1,563
O’Mahony, L., McCarthy, J., Kelly, P., Hurley, G., Luo, F., Chen, K., O’Sullivan, G. C., Kiely, B., Collins, J. K., Shanahan, F., et al. (2005) · Gastroenterology · doi:10.1053/j.gastro.2004.11.050 · Cited by 1,448
Cellular Control of the Synthesis and Activity of the Bacterial Luminescent System
Nealson, K. H., Platt, T., & Hastings, J. W. (1970) · Journal of Bacteriology · doi:10.1128/jb.104.1.313-322.1970 · Cited by 1,301 · cited 1×
“This pattern of mutual bacterial interaction is called quorum sensing”
Kassinen, A., Krogius-Kurikka, L., Mäkivuokko, H., Rinttilä, T., Paulin, L., Corander, J., Malinen, E., Apajalahti, J., & Palva, A. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.04.005 · Cited by 1,002 · cited 1×
“A departure from the physiological balance of the enteric microbiota has been suggested as a factor in the pathophysiology of IBS, a condition in which abnormal gastrointestinal motility and secretion is implicated as a cause of alterations in bowel habits”
Background
Cited by
Sorted by citations
Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., Codagnone, M. G., Cussotto, S., Fulling, C., Golubeva, A. V., et al. (2019) · Physiological Reviews · doi:10.1152/physrev.00018.2018 · Cited by 5,286
Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour
Cryan, J. F., & Dinan, T. G. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3346 · Cited by 4,572
Gut microbiota in health and disease
Sekirov, I., Russell, S. L., Antunes, L. C. M., & Finlay, B. B. (2010) · Physiological Reviews · doi:10.1152/physrev.00045.2009 · Cited by 4,182
“These observations prompted many to hypothesize on the role of the microbiota in the regulation of mood and behavior, and their contribution to the pathophysiology of mood disorders (47, 74, 211, 246).”
BackgroundBravo, J. A., Forsythe, P., Chew, M. V., Escaravage, E., Savignac, H. M., Dinan, T. G., Bienenstock, J., & Cryan, J. F. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102999108 · Cited by 3,888
The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication
Silva, Y. P., Bernardi, A., & Frozza, R. L. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00025 · Cited by 3,043
“Gut-brain communication can also be achieved through vagus nerve signaling (57).”
Background
Metadata
- Authors
- Rhee, S. H., Pothoulakis, C., & Mayer, E. A.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Mayer, Emeran A.
- Venue
- Nature Reviews Gastroenterology & Hepatology
- Published
- 2009-05
- Volume
- 6
- Issue
- 5
- Pages
- 306-314
- ISSN
- 1759-5045 (ISSN-L)
- 1759-5053
- 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
- green
- europepmc.org
- 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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
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