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Cited by 480Neuroinflammation and Neurodegeneration MechanismsGut microbiota and healthTryptophan and brain disorders

Microbiome–microglia connections via the gut–brain axis

Open access
Abdel-Haq, Reem, Schlachetzki, Johannes C.M., Glass, Christopher K., Mazmanian, Sarkis K.·2019·Journal of Experimental Medicine
DOI 10.1084/jem.20180794PMC PMC6314531
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Abstract

Microglia, the resident immune cells in the brain, are essential for modulating neurogenesis, influencing synaptic remodeling, and regulating neuroinflammation by surveying the brain microenvironment. Microglial dysfunction has been implicated in the onset and progression of several neurodevelopmental and neurodegenerative diseases; however, the multitude of factors and signals influencing microglial activity have not been fully elucidated. Microglia not only respond to local signals within the brain but also receive input from the periphery, including the gastrointestinal (GI) tract. Recent preclinical findings suggest that the gut microbiome plays a pivotal role in regulating microglial maturation and function, and altered microbial community composition has been reported in neurological disorders with known microglial involvement in humans. Collectively, these findings suggest that bidirectional crosstalk between the gut and the brain may influence disease pathogenesis. Herein, we discuss recent studies showing a role for the gut microbiome in modulating microglial development and function in homeostatic and disease conditions and highlight possible future research to develop novel microbial treatments for disorders of the brain.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that the gut microbiota influences microglial maturation, identity, and function through gut–brain axis pathways including the vagus nerve, systemic circulation, and microbial metabolites. It argues that dysbiosis may contribute to microglial dysfunction in neurodevelopmental and neurodegenerative disorders such as autism spectrum disorder (ASD) and Parkinson’s disease (PD).

Key findings

  • Microglia make up ∼5–15% of total brain cells and mature stepwise from early to pre- to adult microglia. Germ-free (GF) mice show immature microglial gene expression and morphology, with impaired responses to LPS and lymphocytic choriomeningitis virus; a diverse microbiota—not just bacterial exposure—is required, and antibiotic depletion in adulthood reverts microglia toward an immature phenotype.
  • Gut–brain communication routes include the vagus nerve, intestinal barrier/peripheral immune signaling, and bacterial metabolites. Short-chain fatty acids (SCFAs; acetic, propionic, and butyric acid make up ∼95% of gut SCFAs) rescue the immature microglial phenotype in GF mice, while FFAR2-deficient SPF mice resemble GF mice. Other microbial neuroactive substances include serotonin (90% produced in the gut), tryptophan metabolites, GABA, and acetylcholine.
  • Disease associations include ASD, where GI symptoms occur in 23–70% of patients and fecal samples show increased Clostridium and Lactobacillus with decreased Bacteroidetes and Bifidobacterium; maternal immune activation models show microglial maturation disruption, and Bacteroides fragilis administration rescues behavioral and GI defects. In PD, >80% of patients report GI dysfunction 10–20 yr before motor symptoms, SIBO occurs in 25–54.5%, and GF α-synuclein-overexpressing mice show reduced motor deficits, GI dysfunction, and microglial activation; SCFA feeding restores deficits. Table 1 also lists schizophrenia, major depressive disorder, Alzheimer’s disease, amyotrophic lateral sclerosis, and multiple sclerosis as neuropathologies with both microglial dysfunction and microbial dysbiosis.

Methods

  • Narrative review; no primary data are reported. It synthesizes published human and animal studies on the gut microbiome, microglia, and gut–brain axis.
  • Evidence discussed includes GF and specific pathogen–free mice, antibiotic depletion, fecal microbiota transplant, probiotics/prebiotics, SCFA supplementation, vagotomy and vagus nerve stimulation, human postmortem brain tissue, PET imaging, and fecal microbiota analyses.
  • Main analysis is qualitative integration of mechanisms and disease associations; no systematic search strategy or meta-analysis is described.

Limitations

  • Stated in the paper: ASD pilot studies have small sample sizes; the maternal immune activation model has limitations in replicating complex ASD symptomatology; exact SCFA signaling pathways and how GI signals propagate to the CNS are poorly understood; whether disease-associated microbial alterations are a cause or consequence of altered brain function is unclear; the role of SCFAs in PD models is uncertain due to concentration- and region-dependent effects; interindividual variation in PD microbiota is high.
  • Evident from the text: as a narrative review, it does not systematically assess study quality or quantify effects; many conclusions rely on animal models and correlative human data, so causality in humans remains unestablished.

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

Integrity signals

Registry

Crossref · 10.1084/jem.20180794

Cites

212 of 212 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 126 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Microglial activity is influenced by factors originating outside the CNS, including the gut.

    “microglial activity is now known to be influenced by factors originating outside the CNS, including the gut.”
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    • cites Mayer et al., 2015 source

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    • cites Fung et al., 2017 source

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  • Interpretationnone given

    The gut microbiota can influence microglia via various mechanisms in both homeostatic and disease conditions.

    “This review highlights evidence demonstrating the various mechanisms by which the gut microbiota can influence microglia in both homeostatic and disease conditions.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Microglia from adult GF mice display differential expression of genes associated with microglial maturation, including down-regulation of genes that regulate cell activation and immune system defense pathways.

    “Microglia from adult GF mice also display differential expression of genes associated with microglial maturation, including down-regulation of genes that regulate cell activation and immune system defense pathways, such as Mapk8, IL-1α, Ly86, Jak3, and Stat1, all of which are normally highly expressed in adult microglia (Fig. 1; Erny et al., 2015; Matcovitch-Natan et al., 2016).”
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  • Premisecitation

    The gut-brain axis is critical for several facets of CNS physiology, including microglial development and function.

    “Sophisticated crosstalk between the CNS and the gut microbiome (known as the gut–brain axis) is critical for several facets of CNS physiology, including microglial development and function (Mayer et al., 2015; Fung et al., 2017).”
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  • Interpretationreasoning

    Input from gut microbiota is required for microglia to progress to later stages of cellular maturation and adequately fulfill their role in immune surveillance.

    “Taken together, the gene expression profile and behavior of microglia from GF mice or under microbiota-depleted conditions is reminiscent of an immature microglial phenotype, indicating that input from gut microbiota is required for microglia to progress to later stages of cellular maturation and adequately fulfill their role in immune surveillance.”
    Quote in the paperSubstantial claim
  • May combine two claims. 39
  • Classified as probably not a substantial claim. 11

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    Interpretationnone given

    The gut microbiome facilitates microglial maturation and shapes microglial physiology.

    “A role for the gut microbiome in facilitating microglial maturation and shaping microglial physiology has emerged in recent years.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Environmental factors and mechanisms shaping the developmental, homeostatic, and pathogenic program of microglia remain poorly understood.

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    Premisecitation

    Microglial development appears arrested in GF mice, as supported by high expression of genes characteristic of early and premicroglia in microglia from adult GF mice.

    “Microglial development appears arrested in GF mice, as supported by high expression of genes characteristic of early and premicroglia in microglia from adult GF mice.”
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    Premisecitation

    Tryptophan is a serotonin precursor.

    “Another microbial metabolite that influences microglia activity is tryptophan, a serotonin precursor.”
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    • cites Feng et al., 2017 source

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    Premisecitation

    In female offspring of GF dams, disruption was most notable in adults, and differentially expressed genes were primarily involved in immune and transcriptional signaling.

    “In female offspring, by contrast, disruption was most notable in adults, and differentially expressed genes were primarily involved in immune and transcriptional signaling (Thion et al., 2018).”
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    Premisecitation

    Once in the circulation, these substances activate a pro-inflammatory immune response mediated by peripheral T cells and macrophages and compromise the integrity of the BBB.

    “Once in the circulation, these substances activate a pro-inflammatory immune response mediated by peripheral T cells and macrophages and compromise the integrity of the BBB (Rochfort et al., 2014).”
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    Premisecitation

    SCFAs have been shown to activate sympathetic nervous system activity and alleviate intestinal inflammation.

    “SCFAs have been shown to activate sympathetic nervous system activity and alleviate intestinal inflammation, and altered SCFA production has been demonstrated in a variety of neuropathologies such as PD and ASD (Smith et al., 2013; MacFabe, 2015; Unger et al., 2016).”
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    Premisecitation

    Microglia from E18.5 embryos from GF mothers show an increased density in various brain regions, with increased numbers exhibiting a ramified morphology, indicative of a resting state.

    “For example, microglia from E18.5 embryos from GF mothers show an increased density in various brain regions, with increased numbers of microglia exhibiting a ramified morphology, indicative of a resting state.”
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    Premisecitation

    Approximately 70-80% of immune cells in the human body are found in the gut, allowing for direct gut-immune cell interactions.

    “Approximately 70–80% of immune cells in the human body are found in the gut, allowing for direct gut–immune cell interactions (Vighi et al., 2008).”
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    Premisecitation

    Vagus nerve stimulation combined with LPS challenge decreases microglial production of pro-inflammatory cytokines IL-6, IL-1β, and TNFα in the brain, an effect no longer observed following vagotomy.

    “Vagus nerve stimulation combined with LPS challenge has also been reported to decrease microglial production of the pro-inflammatory cytokines IL-6, IL-1β, and TNFα in the brain, an effect no longer observed following vagotomy (Meneses et al., 2016).”
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    Premisecitation

    Metabolism of tryptophan by activated microglia produces the neurotoxin quinolinic acid, an N-methyl-D-aspartate agonist implicated in several neurological conditions including Huntington's disease and depression.

    “Metabolism of tryptophan by activated microglia produces the neurotoxin quinolinic acid, an N-methyl-D-aspartate agonist implicated in several neurological conditions including Huntington’s disease and depression (Feng et al., 2017).”
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    Interpretationcitation

    Microglia are highly sensitive to perturbations in the gut microbial community during adulthood and require continual input from a complex gut microbiota to maintain homeostasis in the adult.

    “These findings suggest that microglia are highly sensitive to perturbations in the gut microbial community during adulthood and require continual input from a complex gut microbiota to maintain homeostasis in the adult.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SCFAs can exert physiological effects in the CNS via two primary mechanisms: activation of G protein-coupled receptors (GPCRs) expressed in the liver, spleen, and large intestine and inhibition of histone deacetylases.

    “SCFAs can exert physiological effects in the CNS via two primary mechanisms: activation of G protein–coupled receptors (GPCRs) expressed in the liver, spleen, and large intestine and inhibition of histone deacetylases (Kimura et al., 2011; Tan et al., 2014b).”
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    Premisecitation

    Among the most abundantly produced SCFAs are acetic acid, propionic acid, and butyric acid, which collectively make up ∼95% of SCFAs synthesized in the gut.

    “Among the most abundantly produced SCFAs are acetic acid, propionic acid, and butyric acid, which collectively make up ∼95% of SCFAs synthesized in the gut (Cook and Sellin, 1998).”
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    Interpretationnone given

    Information about the state of peripheral inflammation and GI health is received in the CNS via vagal afferents that innervate the GI tract and can influence microglial activation and neuroinflammation.

    “Information about the state of peripheral inflammation and GI health is received in the CNS via vagal afferents that innervate the GI tract and can influence microglial activation and neuroinflammation.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Altered microglial morphology and density, as well as attenuated inflammatory responses, are observed in offspring of GF dams immediately after birth.

    “Altered microglial morphology and density, as well as attenuated inflammatory responses, are also observed in offspring of GF dams immediately after birth, a time when microglia typically exhibit an activated phenotype (Castillo-Ruiz et al., 2018).”
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    Interpretationreasoning

    The heterogeneity of microglial behavior in response to both intrinsic and extrinsic factors provides further evidence of their complexity, with the gut microbiome representing a key contributing factor in microglial development and function.

    “The heterogeneity of microglial behavior in response to both intrinsic and extrinsic factors provides further evidence of their complexity, with the gut microbiome representing a key contributing factor in microglial development and function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In male offspring of GF dams, disruption of the transcriptomic profile and morphology of microglia was greatest during the embryonic phase of development, and differentially regulated genes were mostly associated with metabolic and translational pathways.

    “In male offspring of GF dams, disruption of the transcriptomic profile and morphology of microglia was greatest during the embryonic phase of development, and differentially regulated genes were mostly associated with metabolic and translational pathways (Thion et al., 2018).”
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    • cites Thion et al., 2018 source

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    Premisecitation

    SCFAs are metabolic byproducts of bacterial dietary fiber fermentation that can enter the systemic circulation and cross the BBB.

    “Short-chain fatty acids (SCFAs) are metabolic byproducts of bacterial dietary fiber fermentation that can enter the systemic circulation and cross the BBB (Conn et al., 1983).”
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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Gut-brain communication may influence microglia via two routes: the vagus nerve and the circulatory system.

    “Gut–brain communication may influence microglia via two routes: the vagus nerve and the circulatory system.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Fine-tuning of the intestinal barrier by gut microbiota and their interactions with gut immune cells modulates peripheral inflammation and can trigger downstream inflammatory responses in the CNS.

    “Fine-tuning of the intestinal barrier by gut microbiota and their interactions with gut immune cells modulates peripheral inflammation and can trigger downstream inflammatory responses in the CNS.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The critical role of gut-derived factors in regulating microglial function in the healthy state suggests that signals originating from the gut microbiota might also drive a pathogenic microglial phenotype that promotes disease.

    “First is the critical role of gut-derived factors in regulating microglial function in the healthy state, which suggests that signals originating from the gut microbiota might also drive a pathogenic microglial phenotype that promotes disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This dysbiosis is potentially sufficient to markedly disrupt microglial function and subsequently facilitate disease pathogenesis.

    “This dysbiosis is potentially sufficient to markedly disrupt microglial function and subsequently facilitate disease pathogenesis.”
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    Premisecitation

    These MIA offspring also exhibit increased intestinal permeability and intestinal inflammation, two GI symptoms commonly found in children with ASD.

    “These MIA offspring also exhibit increased intestinal permeability and intestinal inflammation, two GI symptoms commonly found in children with ASD (Hsiao et al., 2013; Chaidez et al., 2014).”
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    Premisecitation

    Vagotomy may be associated with reduced risk of developing PD in humans, potentially implicating peripheral influences on disease development.

    “While this pattern of α-synuclein spreading is not observed in all cases of sporadic PD, vagotomy may be associated with reduced risk of developing PD in humans, potentially implicating peripheral influences on disease development (Svensson et al., 2015; Liu et al., 2017).”
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    • cites Svensson et al., 2015 source

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    • cites Liu et al., 2017 source

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    Premisecitation

    Oral administration of Bacteroides fragilis to offspring of MIA mice at weaning rescues the integrity of the intestinal barrier, reduces anxiety, and improves communication and repetitive behaviors.

    “Similar to its ameliorative effect in colitis, oral administration of Bacteroides fragilis to offspring of MIA mice at weaning rescues the integrity of the intestinal barrier, reduces anxiety, and improves communication and repetitive behaviors (Hsiao et al., 2013).”
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    Premisecitation

    Mice lacking the fractalkine receptor Cx3cr1 demonstrate a temporary reduction in the number of microglia during early postnatal development, as well as increased synaptic density, immature brain circuitry, and signal transmission deficits that persist into adulthood.

    “Mice lacking the fractalkine receptor Cx3cr1 demonstrate a temporary reduction in the number of microglia during early postnatal development, as well as increased synaptic density, immature brain circuitry, and signal transmission deficits that persist into adulthood (Paolicelli et al., 2011; Zhan et al., 2014).”
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    Premisecitation

    Pathological hallmarks of PD include death of dopaminergic neurons of the substantia nigra pars compacta and intraneuronal accumulation of the α-synuclein protein.

    “Pathological hallmarks of PD include death of dopaminergic neurons of the substantia nigra pars compacta and intraneuronal accumulation of the α-synuclein protein (Goedert et al., 2013).”
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    Premisecitation

    Postmortem analysis of brain tissue collected from ASD patients show perturbations in microglial immune surveillance and synaptic remodeling, with evidence for heightened microglial activation, including increased expression of MHC II, elevated levels of pro- and anti-inflammatory cytokines, and increased microglial density.

    “Postmortem analysis of brain tissue collected from ASD patients show perturbations in microglial immune surveillance and synaptic remodeling, with evidence for heightened microglial activation, including increased expression of MHC II, elevated levels of pro- and anti-inflammatory cytokines, and increased microglial density (Vargas et al., 2005; Morgan et al., 2010; Voineagu et al., 2011; Gupta et”
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  • May combine two claims.

    Interpretationreasoning

    Studies of ASD and other neurodevelopmental disorders provide evidence for a potential pathogenic role for both dysbiosis and microglial dysfunction, and suggest that microglia may link early-life dysbiosis to long-lasting neurological abnormalities.

    “Studies of ASD and other neurodevelopmental disorders provide evidence for a potential pathogenic role for both dysbiosis and microglial dysfunction, and suggests that microglia may link early-life dysbiosis to long-lasting neurological abnormalities.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Children with ASD present with a wide range of cognitive and behavioral symptoms, including delayed language development, impaired social and communication skills, and repetitive behavior, depending on where they lie on the spectrum of disease severity.

    “Children with ASD present with a wide range of cognitive and behavioral symptoms, including delayed language development, impaired social and communication skills, and repetitive behavior, depending on where they lie on the spectrum of disease severity (Plauche Johnson, 2004).”
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    Premisecitation

    PD is the second most common neurodegenerative disorder and is defined by the presence of motor symptoms including bradykinesia, rigidity, and resting tremor.

    “PD is the second most common neurodegenerative disorder and is defined by the presence of motor symptoms including bradykinesia, rigidity, and resting tremor (Postuma et al., 2015).”
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    • cites Postuma et al., 2015 source

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    Premisecitation

    Cross-sectional studies comparing the gut microbiota composition between healthy and ASD individuals have revealed an altered microbiota profile in patients with ASD, with several studies reporting increased levels of Clostridium and Lactobacillus along with elevated levels of SCFAs, including propionic and butyric acid.

    “Cross-sectional studies comparing the gut microbiota composition between healthy and ASD individuals have revealed an altered microbiota profile in patients with ASD, with several studies reporting increased levels of Clostridium and Lactobacillus along with elevated levels of SCFAs, including propionic and butyric acid (Wang et al., 2012, 2013; De Angelis et al., 2013; Kang et al., 2013).”
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    • cites Wang et al., 2012, 2013

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    Premisecitation

    A complex interplay of genetic and environmental factors is thought to drive the pathogenesis of PD, eventually leading to mitochondrial and autophagic dysfunction.

    “A complex interplay of genetic and environmental factors is thought to drive the pathogenesis of PD, eventually leading to mitochondrial and autophagic dysfunction (Shulman et al., 2011).”
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  • May combine two claims.

    Study design and conductnone given

    The MIA model faithfully recapitulates abnormalities in both microglial behavior and GI function that are frequently observed in patients.

    “While the MIA model has limitations in terms of replicating the complex symptomatology of ASD, the model faithfully recapitulates abnormalities in both microglial behavior and GI function that are frequently observed in patients.”
    Quote in the paperNot a substantial claim

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    Interpretationreasoning

    This in turn could compromise neuronal function and eventually lead to synaptic degeneration and neuronal death.

    “This in turn could compromise neuronal function and eventually lead to synaptic degeneration and neuronal death.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Microglia from young MIA offspring show increased expression of inflammation-related genes typically associated with an adult microglial phenotype and down-regulation of genes expressed during earlier developmental stages (e.g., Pu.1 and Irf8).

    “Microglia from young MIA offspring show increased expression of inflammation-related genes typically associated with an adult microglial phenotype and down-regulation of genes expressed during earlier developmental stages (e.g., Pu.1 and Irf8), suggesting that maternal inflammation disrupts the timeline of normal microglial maturation (Matcovitch-Natan et al., 2016).”
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    Interpretationreasoning

    Microglia are believed to be involved in the pathogenesis of several neurodevelopmental and neurodegenerative disorders.

    “Given their wide spectrum of physiological functions and myriad roles in development and homeostasis, microglia are believed to be involved in the pathogenesis of several neurodevelopmental and neurodegenerative disorders.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Commensal symbiotic bacteria are critical for proper microglial maturation, and induction of infection in pregnant dams can have disruptive effects on the progression of microglial development in offspring.

    “While commensal symbiotic bacteria are critical for proper microglial maturation, induction of infection in pregnant dams can have disruptive effects on the progression of microglial development in offspring (Pratt et al., 2013; Matcovitch-Natan et al., 2016; Mattei et al., 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Pratt et al., 2013 source

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    • cites Matcovitch-Natan et al., 2016 source

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    • cites Mattei et al., 2017 source

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  • May combine two claims.

    Premisecitation

    Germ-free mice overexpressing human α-synuclein display reduced motor deficits, GI dysfunction, and microglial activation compared with mice with an intact gut microbiota.

    “These mice display reduced motor deficits, GI dysfunction, and microglial activation when compared with mice with an intact gut microbiota (Sampson et al., 2016).”
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    • cites Sampson et al., 2016 source

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  • May combine two claims.

    Interpretationreasoning

    The shift in microbial communities may contribute to the elevated levels of peripheral inflammation and intestinal permeability that are frequently seen in PD patients and might drive misfolding of α-synuclein in the gut and its retrograde propagation to the CNS.

    “The shift in microbial communities may contribute to the elevated levels of peripheral inflammation and intestinal permeability that are frequently seen in PD patients and might drive misfolding of α-synuclein in the gut and its retrograde propagation to the CNS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    While interindividual variation is high, PD patients often exhibit increased levels of Enterobacteriaceae and decreased levels of Bacteroidetes and Prevotellaceae.

    “While interindividual variation is high, PD patients often exhibit increased levels of Enterobacteriaceae and decreased levels of Bacteroidetes and Prevotellaceae (Keshavarzian et al., 2015; Unger et al., 2016).”
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    • cites Keshavarzian et al., 2015 source

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    Premisecitation

    Feeding germ-free transgenic mice overexpressing human α-synuclein a mixture of three SCFAs up-regulated microglial activation and induced motor deficits similar to those observed in colonized animals.

    “Feeding these GF transgenic mice a mixture of three SCFAs up-regulated microglial activation and induced motor deficits similar to those observed in colonized animals (Sampson et al., 2016).”
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    Premisecitation

    Studies show altered abundance of certain bacterial strains in patients with PD, changes that may correlate with severity of motor deficits.

    “Studies show altered abundance of certain bacterial strains in patients with PD, changes that may correlate with severity of motor deficits (Scheperjans et al., 2015; Mertsalmi et al., 2017).”
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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Signals originating from the gut microbiota and transmitted to the brain have the potential to alleviate or exacerbate disease pathogenesis, possibly through gut-mediated changes in microglial behavior.

    “Signals originating from the gut microbiota and transmitted to the brain have the potential to alleviate or exacerbate disease pathogenesis, changes that may operate through gut-mediated changes in microglial behavior.”
    Quote in the paperNot a substantial claim
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  • The paper relies on this without support.

    Environmental factors and mechanisms shaping the developmental, homeostatic, and pathogenic program of microglia remain poorly understood.

    “However, environmental factors and mechanisms shaping the developmental, homeostatic, and pathogenic program of microglia remain poorly understood.”

  • The paper relies on this without support.

    The womb is likely a sterile environment.

    “While the womb is likely a sterile environment”

  • The paper relies on this without support.

    BBB-permeable bacterial metabolites, including SCFAs, modulate microglial maturation.

    “BBB-permeable bacterial metabolites, including SCFAs, modulate microglial maturation through mechanisms that are yet to be determined.”
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Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Gut bacteria can affect CNS inflammation by binding to specific receptors, such as proinflammatory tachykinin/neurokinin receptors, in vagus nerve fiber.

    “Moreover, gut bacteria can also affect CNS inflammation by binding to specific receptors, such as the proinflammatory tachykinin/neurokinin receptors, in the vagus nerve fiber.104”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [104]

    In “The vagus nerve” (page unavailable), the paper says microbial products activate chemoreceptors at vagal nerve endings and that interactions between intestinal microbes and vagal afferents appear to influence CNS inflammation. It does not identify tachykinin/neurokinin receptors or say that gut bacteria themselves bind to those receptors. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Microbiota-microglia interactions are key mechanisms underlying microbiota-immune-brain interactions.

    “As alluded to in earlier sections microbiota-microglia interactions are receiving much attention of late as key mechanisms underlying microbiota-immune-brain interactions (Abdel-Haq et al., 2019;Rea et al., 2016;Vuong et al., 2017).”

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

  • Throughout the host lifespan, the gut microbiome provides essential signals to microglia during health and disease.

    “Throughout the host lifespan, the gut microbiome provides essential signals to microglia during health and disease.59,60,187,188”

    From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [187]

  • Interactions between the gut microbiome and the CNS innate immune system may modulate Alzheimer disease pathogenesis.

    “There is increasing evidence that interactions between the gut microbiome and the CNS innate immune system (gut-brain axis) may modulate AD pathogenesis.”

    From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Abdel-Haq et al., 2019

  • The microbiome regulates aspects of CNS physiology, including microglial maturation and function.

    “Various aspects of CNS physiology are regulated by the microbiome, including microglial maturation and function (Abdel-Haq et al., 2019).”

    From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Abdel-Haq et al., 2019

Self-check

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

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

  • Opposite directions reported for SCFA levels in ASD

    Major

    Table 1 says SCFA levels are decreased in ASD patients compared with healthy controls, whereas the ASD section says studies found elevated SCFA levels in patients with ASD.

  • Conflicting prevalence bounds for symptoms preceding PD motor symptoms

    Minor

    Table 1 says more than 80% of PD patients report GI dysfunction before motor symptoms. The PD section says nonmotor symptoms, including GI distress, precede motor symptoms in up to 80% of patients; the narrower GI group cannot exceed the stated bound for the broader nonmotor group.

2 of 2

Cites

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2 of the 214 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Abdel-Haq, R., Schlachetzki, J. C. M., Glass, C. K., & Mazmanian, S. K.
Affiliations
  • California Institute of Technology (US)
  • University of California San Diego (US)
Corresponding author
  • Abdel-Haq, Reem
  • Mazmanian, Sarkis K.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2018-11-01
Volume
216
Issue
1
Pages
41-59
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20180794
PMC
PMC6314531
OpenAlex
W2899046125
Cited by
471
References
214
Citations by year
2026: 51 · 2025: 78 · 2024: 70 · 2023: 76 · 2022: 77 · 2021: 46 · 2020: 38 · 2019: 33 · 2017: 1
FWCI
2.77
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
Funders
  • U.S. Department of Defense (PD160030)
  • Donna and Benjamin M. Rosen Bioengineering Center
  • National Institutes of Health (AG057706, NS096170, MH100556, NS085910)
  • Heritage Medical Research Institute
  • Simons Foundation (322839)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
gut microbiota, microglia, gut-brain axis, neuroinflammation, microglial maturation, neurodevelopmental disorders, neurodegenerative diseases, microbial treatment, brain microenvironment
MeSH terms
Gastrointestinal Microbiome, Animals, Brain, Humans, Intestines, Microglia, Neurodegenerative Diseases, Neurodevelopmental Disorders

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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

What counts as a claim ›How we measure confidence ›How we check this ›

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