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Cited by 821Gut microbiota and healthTryptophan and brain disordersNeuroinflammation and Neurodegeneration Mechanisms

The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology

Open access
Rutsch, Andrina, Kantsjö, Johan B., Ronchi, Francesca·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2020.604179PMC PMC7758428
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Abstract

The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer’s and Parkinson’s diseases, but also anxiety and depressive-like disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer’s and Parkinson’s diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.

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Written from the paper’s full text.

TL;DR

This review synthesizes evidence that gut microbiota and microbial metabolites influence CNS physiology and neuroinflammation through the gut-brain axis, with the inflammasome proposed as an innate immune link. It highlights disease-specific findings in multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and neuropsychiatric disorders while emphasizing that causal mechanisms remain largely unresolved.

Key findings

  • The gut-brain axis involves the vagus nerve, immune system, bacterial metabolites, and products; dysbiosis is associated with altered blood-brain barrier permeability and neuroinflammation. Germ-free or antibiotic-treated mice show exaggerated HPA stress responses, impaired social behavior, reduced anxiety-like behavior, and increased motor/rearing activity, while SCFAs and tryptophan metabolites can restore microglia maturation, BBB integrity, and immune homeostasis.
  • In multiple sclerosis, transplanting MS-twin microbiota into germ-free EAE-susceptible mice promoted disease with significantly higher incidence than healthy-twin microbiota; IL-10–producing Tregs, *B. fragilis* polysaccharide A, SCFAs, and tryptophan-AhR signaling were protective. Inflammasome components caspase-1 and ASC are proposed biomarkers for MS onset, and IL-1β/IL-18/caspase-1 are upregulated in PBMCs and CSF; pertussis toxin–driven pyrin inflammasome IL-1β primes encephalitogenic Th17 cells.
  • In Alzheimer’s disease, patients show decreased Firmicutes and Actinobacteria and increased Bacteroidetes; germ-free APP/PS1 mice have reduced Aβ levels and amyloid load, while fecal transplant from conventionally raised APP/PS1 mice increases cerebral Aβ pathology. NLRP3, ASC, caspase-1, IL-1β, and IL-18 are elevated in AD patients, and *Porphyromonas gingivalis* gingipains are found in AD brains and increase Aβ production in mice.
  • In Parkinson’s disease, patients harbor depleted SCFA-producing bacteria; germ-free mice colonized with PD patient microbiota display physical impairments, and ASO germ-free mice show reduced α-synuclein aggregates that are restored by SCFA mixture. NLRP3/caspase-1/IL-1β are implicated, and NLRP3−/− mice are resistant to MPTP-induced loss of nigral dopaminergic neurons. In neuropsychiatric disorders, MDD patients have increased Enterobacteriaceae and *Alistipes* but reduced *Faecalibacterium*; schizophrenia patients show 77 differently expressed OTUs; MIA offspring show 67 different OTUs, and the metabolite 4EPS alone induces anxiety-like behavior.

Methods

  • Narrative review; no systematic review protocol, search strategy, inclusion/exclusion criteria, or meta-analysis is stated.
  • Synthesizes human observational/clinical studies and animal models, including germ-free, SPF, antibiotic-treated, gnotobiotic, transgenic, fecal microbiota transplantation, EAE, APP/PS1, 5xFAD, ASO, and MPTP models, plus in vitro studies.
  • Main analysis is qualitative synthesis of mechanisms, with a table summarizing inflammasome-dependent mechanisms in neurological disorders.

Limitations

  • The authors state that many mechanisms of microbial action and signaling pathways remain unknown, that causality between dysbiosis and disease is often unclear, and that translational approaches and larger clinical trials are needed to establish temporal and causal relationships.
  • The authors note conflicting findings on whether inflammasome deficiency shapes gut microbiota composition, with maternal-microbiota inheritance and cage effects having a more substantial impact in their conditions; they call for additional analyses under specific hygiene conditions.
  • Evident from the text: as a narrative review, it lacks a systematic search or quantitative synthesis and relies heavily on animal models and associative human data.

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

Integrity signals

Registry

Crossref · 10.3389/fimmu.2020.604179

Cites

288 of 288 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 329 cited sources checked · 0 supported · 0 flagged

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    Intestinal bacteria can affect central nervous system physiology and inflammation.

    “Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation.”
    Quote in the paperSubstantial claim
  • Premisenone given

    There is a reciprocal influence of microbiota and inflammasome activation in the brain.

    “Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    A relevant contribution of gut microbiota is not restricted to neuroinflammatory and psychiatric disorders but also extends to brain development.

    “Moreover, a relevant contribution of gut microbiota is not only restricted to neuroinflammatory and psychiatric disorders (23–32) but also to brain development (13).”
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    Gut microbial alteration (dysbiosis) is associated not only with gastrointestinal disorders but also with diseases affecting other distal organs, including the central nervous system.

    “Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Neuronal development is supported and shaped by maternal microbiota.

    “In this period, neuronal development takes place (73) and it is supported and shaped by maternal microbiota (74–79).”
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    Premisenone given

    During dysbiosis, gut-brain axis pathways are dysregulated and associated with altered blood-brain barrier permeability and neuroinflammation.

    “During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    The inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and anxiety and depressive-like disorders.

    “Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer’s and Parkinson’s diseases, but also anxiety and depressive-like disorders.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and leads to production of pro-inflammatory cytokines interleukin-1β and interleukin-18 and to pyroptosis.

    “The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis.”
    Quote in the paperNot a substantial claim

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    Functional immune cells can enter the CNS through the blood-brain barrier, choroid plexus, and lymphatic vessels and have been described beyond neuropathological conditions.

    “However, the idea that the CNS is an immune privileged organ has been reconsidered, as the functional immune cells can enter the CNS through the BBB, the choroid plexus, and the lymphatic vessels and have been described beyond neuropathological conditions (26, 35–47).”
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    Premisecitation

    Bacterial products and metabolites can pass the blood-brain barrier and shape CNS development and functions and the genesis of certain diseases.

    “Among the molecules that can pass the BBB are also bacterial products and metabolites shaping not only the CNS development and functions (6, 15) but also the genesis of certain diseases (33–42).”
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    Premisecitation

    The microbiota orchestrates the local immune system in the intestine and shapes immune and non-immune cells located at distal sites and acting systemically.

    “Notably, the microbiota orchestrates the local immune system in the intestine (67), and shapes immune and non-immune cells located in distal sites and acting systemically (68, 69).”
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    Premisecitation

    Under healthy conditions, the microbiota influences numerous physiological processes within the host, including protection against pathogens, nutrient digestion and absorption, development, and education of multiple host organs and the immune system.

    “Under healthy conditions, the microbiota influences numerous physiological processes within the host, such as protection against pathogens, nutrient digestion and absorption, development, and education of multiple host organs and the immune system (3–6).”
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    Premisecitation

    The inflammasome plays a role in depressive- and anxiety-like behaviors and locomotor activity.

    “Among those pathways, researchers showed that the inflammasome plays a role in depressive- and anxiety-like behaviors, and locomotor activity (57).”
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    Compared to colonized mice, germ-free mice show exaggerated hypothalamic-pituitary-adrenal stress reaction, impaired social behaviors, reduced anxiety-like behavior, and increased motor and rearing activity.

    “In details, compared to colonized mice, GF mice showed exaggerated hypothalamic–pituitary–adrenal (HPA) restrain stress reaction (10), impared social behaviors (12, 15, 82), reduced anxiety-like behavior (7, 81–83) and increased motor and rearing activity (80, 84).”
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    Premisecitation

    Antibiotic treatment results in reduced expression of the tight-junction forming proteins occludin and claudin-5 in the brain, increased blood-brain barrier permeability, reduced anxiety-like behaviors, and elevated exploratory behavior and home-cage activity.

    “Antibiotic treatment results in reduced expression of the tight-junction forming proteins, occludin, and claudin-5, in the brain, increased BBB permeability, reduced anxiety-like behaviors, and elevated exploratory behavior and home-cage activity (35).”
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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.

    “More recently, it has also been reported that 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 (90).”
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    Premisecitation

    Colonizing germ-free animals post-weaning was sufficient to restore tryptophan levels in the periphery and reduce anxiety in germ-free animals, but insufficient to reverse CNS neurochemical consequences present in adult germ-free animals.

    “Interestingly, colonizing GF animals post-weaning was sufficient to restore the levels of tryptophan in the periphery and to reduce anxiety in GF animals, but was insufficient to reverse the CNS neurochemical consequences present in adult GF animals (7).”
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    Premisecitation

    Treatment with L. johnsonii restored a healthy gut microbiota composition and attenuated both colitis and E. coli-induced memory impairment.

    “In contrast, the treatment with L. johnsonii restored a healthy gut microbiota composition and attenuated both colitis and E. coli-induced memory impairment (95, 96).”
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    Treatment of mice with E. coli isolated from colitic mice caused colitis and brain memory impairment.

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    Premisecitation

    A small fraction of short-chain fatty acids reaches the systemic circulation and can cross the blood-brain barrier using their own transporters located on brain vascular epithelial cells.

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    Short-chain fatty acids maintain gut health by promoting intestinal barrier integrity, mucus production, and supporting a tolerogenic response over inflammation.

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    Propionate and butyrate can influence cell signaling via modification of intracellular potassium levels and regulate expression of tryptophan 5-hydroxylase 1 and tyrosine hydroxylase.

    “Propionate and butyrate can influence the cell signaling system via modification of the intracellular potassium levels (104), and they regulate the expression levels of tryptophan 5-hydroxylase 1, involved in the synthesis of serotonin, and tyrosine hydroxylase, which is involved in the biosynthesis of dopamine, adrenaline, and noradrenaline (105).”
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    Premisecitation

    Multiple sclerosis patients with active disease have an altered microbiota compared to patients in the remission phase, who have a microbiota more similar to healthy controls.

    “Interestingly, even MS patients with active disease have an altered microbiota compared to patients in the remission phase, which in turn have a microbiota more similar to healthy controls (25, 134–138).”
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    Premisecitation

    Probiotic supplementations have therapeutic potential to ameliorate multiple sclerosis, improving disability status, mental health, and some inflammatory and metabolic parameters compared to placebo.

    “Moreover, probiotics supplementations have a therapeutic potential to ameliorate MS, improving the disability status, the mental health, and some inflammatory and metabolic parameters, compared to the placebo group (148, 149).”
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    Premisecitation

    Fecal microbiota transplantation in three multiple sclerosis patients to treat severe constipation reverted the intestinal illness and improved multiple sclerosis symptoms.

    “In an additional relevant study, three MS patients underwent multiple fecal microbiota transplantations (FMT) to treat severe constipation. This treatment reverted the intestinal illness and improved the MS symptoms (147), proving the existence of a gut-brain connection.”
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    Premisecitation

    Multiple sclerosis patients treated with minocycline have a reduced rate of relapses and amelioration of several immunological parameters such as IL-12p40, metalloproteinase-9, and soluble vascular cell adhesion molecule-1.

    “Additionally, MS patients that were treated with the antibiotic minocycline, a broad-spectrum tetracycline, have reduced rate of relapses and amelioration of several immunological parameters (such as IL-12p40, metalloproteinase-9, and soluble vascular cell adhesion molecule-1) (145, 146).”
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    Interpretationcitation

    The intestinal microbiota was responsible for disease severity and the modulation of the adaptive immune response during experimental autoimmune encephalomyelitis development.

    “This effect suggested that the intestinal microbiota was responsible for the disease severity and the modulation of the adaptive immune response during disease development (18).”
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    Premisecitation

    Mice treated with antibiotics alone or recolonized with the PSA-wild-type strain of B. fragilis were protected against experimental autoimmune encephalomyelitis, whereas mice recolonized with ΔPSA B. fragilis and vehicle-treated controls developed the disease.

    “Mice treated with antibiotics alone or recolonized with the PSA-wild-type strain of B. fragilis were protected against disease, whereas the mice recolonized with ΔPSA B. fragilis and as well the vehicle-treated control group developed the disease (116).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [116] Ochoa-Repáraz, 2010, Central Nervous System Demyelinating Disease Protection by the Human Commensal Bacteroides fragilis Depends on Polysaccharide A Expression, J Immunol source

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  • May combine two claims.

    Premisecitation

    Multiple sclerosis patients during active relapse had less IgA specific for intestinal bacteria compared to patients in remission, suggesting the capacity of IgA-producing cells to migrate from the gut to the central nervous system during disease relapses.

    “Remarkably, MS patients during active relapse had less IgA specific for intestinal bacteria compared to patients in remission, suggesting the capacity of IgA-producing cells to migrate from the gut to the central nervous system during disease relapses, as in the mouse system (151).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Rojas, 2019, Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10, Cell source

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    Premisecitation

    Germ-free mice colonized with only SFB developed experimental autoimmune encephalomyelitis and a T helper 17 pathogenic immune response in the gut and CNS.

    “Strikingly, GF mice colonized with only a single bacterium, the SFB, developed EAE, and a T helper (Th)-17 pathogenic immune response in the gut and in the CNS (117).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Kyung, 2011, Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis, PNAS source

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    Premisecitation

    Commensal-reactive IgA-producing cells expressed IL-10, and production of IL-10 (partially together with iNOS, but not IgA itself) was essential to ameliorate experimental autoimmune encephalomyelitis.

    “Briefly, commensal-reactive IgA-producing cells expressed IL-10, and the production of IL-10 (partially together with iNOS, but not IgA itself) was essential to ameliorate EAE (151).”
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    • cites [151] Rojas, 2019, Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10, Cell source

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  • May combine two claims.

    Premisecitation

    IL-10- and IgA-producing plasma cells have a role in ameliorating experimental autoimmune encephalomyelitis in mice and correlate with relapse in multiple sclerosis patients.

    “In the recent milestone study from the groups of Gommerman J. and Baranzini SE., IL-10- and IgA-producing plasma cells have been suggested to have a role in ameliorating EAE in mice and to correlate with relapse in MS patients (151).”
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    • cites [151] Rojas, 2019, Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10, Cell source

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  • May combine two claims.

    Premisecitation

    Bi-colonization with Allobaculum and L. reuteri together activated MOG-specific T cells toward a pathogenic Th17 phenotype and worsened experimental autoimmune encephalomyelitis, with demyelination and cell infiltration in the spinal cord.

    “However, the bi-colonization with Allobaculum and L. reuteri together activated MOG-specific T cells toward a pathogenic Th17 phenotype and worsened EAE, with demyelination and cell infiltration in the spinal cord (152).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Miyauchi, 2020, Gut microorganisms act together to exacerbate inflammation in spinal cords, Nature source

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  • May combine two claims.

    Premisecitation

    Ampicillin administration alone ameliorated experimental autoimmune encephalomyelitis development with a reduction of proliferating CD4+ autoreactive T cells.

    “Lately, in the classical acute EAE model, ampicillin administration alone ameliorated the EAE development (152) with a reduction of proliferating CD4+ autoreactive T cells.”
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    • cites [152] Miyauchi, 2020, Gut microorganisms act together to exacerbate inflammation in spinal cords, Nature source

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  • May combine two claims.

    Premisecitation

    Supplementation of a cocktail of five probiotics (IRT5) before or after experimental autoimmune encephalomyelitis onset in rodents is associated with delay of disease onset or suppression of disease progression, respectively.

    “The supplementation of a cocktail of five probiotics (IRT5) before or after the EAE onset in rodents is associated with the delay of the disease onset or suppression of the disease progression, respectively (154).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Kwon, 2013, Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response, Clin Immunol source

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  • May combine two claims.

    Premisecitation

    Amelioration of experimental autoimmune encephalomyelitis upon probiotic treatment was associated with a higher abundance of Treg cells, higher production of IL-10 by CD4+ T cells, B cells, and CD11c+ cells, together with suppression of the pro-inflammatory Th-1/Th-17 response.

    “The amelioration of the disease upon probiotic treatment was associated with a higher abundance of Treg cells, higher production of IL-10 by CD4+ T cells, B cells, and CD11c+ cells, together with the suppression of the pro-inflammatory Th-1/Th-17 response (154).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Kwon, 2013, Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response, Clin Immunol source

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  • May combine two claims.

    Premisecitation

    Prophylactic antibiotic treatment before clinical onset of spontaneous experimental autoimmune encephalomyelitis led to a significant reduction of susceptibility, accompanied by altered intestinal microbial composition and a decrease in Th-17 cell development.

    “Prophylactic antibiotic treatment (at 1–3 weeks before the clinical onset of the disease, starting from 2–4 weeks of age) led to a significant reduction of susceptibility to spontaneous EAE, accompanied by altered intestinal microbial composition and a decrease in Th-17 cell development (153).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [153] Gödel, 2020, Perturbation of gut microbiota decreases susceptibility but does not modulate ongoing autoimmune neurological disease, J Neuroinflammation source

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  • May combine two claims.

    Premisecitation

    Short-chain fatty acids favor enhancement of acetyl-CoA metabolism, histone acetylation, preservation of spinal cord lipid content, suppression of demyelination, and oligodendrocyte maturation and differentiation.

    “Mechanistically, SCFAs favor the enhancement of acetyl-CoA metabolism, histone acetylation, preservation of spinal cord lipid content, suppression of demyelination, oligodendrocyte maturation and differentiation (157, 158).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [157] Chevalier, 2017, Increasing acetyl-CoA metabolism attenuates injury and alters spinal cord lipid content in mice subjected to experimental autoimmune encephalomyelitis, J Neurochemistry source

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    • cites [158] Chen, 2019, Butyrate suppresses demyelination and enhances remyelination, J Neurol source

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  • May combine two claims.

    Interpretationreasoning

    Microbiota modulation in early life stages or prophylactic treatments in subjects genetically prone to autoimmune diseases such as multiple sclerosis could be efficient approaches to ameliorate disease susceptibility and/or delay onset.

    “These results suggest that microbiota modulation in early life stages or prophylactic treatments in subjects that are genetically prone to develop certain autoimmune diseases, such as MS, could be efficient approaches to ameliorate the disease susceptibility and/or to delay the onset of the disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Several microbial factors have been linked to Alzheimer's disease pathogenesis, and a few studies suggested alteration in the commensal microbiota and pathogenic infections as potential causes of Alzheimer's disease.

    “Several microbial factors have been linked to the AD pathogenesis (140, 141), and a few studies suggested alteration in the commensal microbiota and pathogenic infections as potential causes of AD (142).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [140] Geuking, 2011, Intestinal Bacterial Colonization Induces Mutualistic Regulatory T Cell Responses, Immunity source

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    • cites [141] Atarashi, 2011, Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species, Science (80-) source

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    • cites [142] Jia, 2017, Anti-diabetic Effects of Clostridium butyricum CGMCC0313.1 through Promoting the Growth of Gut Butyrate-producing Bacteria in Type 2 Diabetic Mice, Sci Rep source

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  • May combine two claims.

    Premisecitation

    In vitro stimulation with indoxyl-3-sulfate activated the AhR signaling pathway in primary human microglia, leading to suppression of pro-inflammatory pathways via TNF-α, IL-6, IL-12A, NOS2, and VEGF-β expression and promotion of anti-inflammatory responses such as IL-10 and TGF-α expression.

    “Moreover, using primary human microglia, they showed that the in vitro stimulation with I3S activated the AhR signaling pathway leading to the suppression of pro-inflammatory pathways (via TNF-α, IL-6, IL-12A, NOS2, VEGF-β expression), and the promotion of anti-inflammatory responses (such as IL-10 and TGF-α expression) (89).”
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    • cites [89] Rothhammer, 2018, Microglial control of astrocytes in response to microbial metabolites, Nature source

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  • May combine two claims.

    Premisecitation

    5xFAD mice recapitulate significant Alzheimer's disease and fecal microbial composition features that evolve with age.

    “Additionally, 5xFAD mice (over-expressing in the brain the mutant human APP carrying Swedish, Florida, and London Familial Alzheimer’s Disease (FAD) mutations along with human PS1 harboring two FAD mutations) recapitulate significant AD and fecal microbial composition features that evolve with age (162, 163).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [162] Brandscheid, 2017, Altered Gut Microbiome Composition and Tryptic Activity of the 5xFAD Alzheimer’s Mouse Model, J Alzheimers Dis source

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    • cites [163] Wang, 2019, Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression, Cell Res source

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  • May combine two claims.

    Premisecitation

    Germ-free APP/PS1 transgenic mice have reduced Aβ levels in the brain and blood and reduced amyloid load compared to conventionally-raised APP/PS1 mice.

    “Importantly, GF-APP/PS1 transgenic mice have reduced Aβ levels in the brain and blood and reduced amyloid load compared to conventionally-raised APP/PS1 mice (161).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Harach, 2017, Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota, Sci Rep source

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  • May combine two claims.

    Premisecitation

    Neuroinflammatory modifications were strikingly dependent on microbiota ones, and depletion of intestinal microbes via antibiotic treatment ameliorated the recruitment and priming of anti-inflammatory microglia and Th-1 cells.

    “The neuroinflammatory modifications were, in fact, strikingly dependent on the microbiota ones, and the depletion of intestinal microbes via antibiotic treatment ameliorated the recruitment and priming of anti-inflammatory microglia and Th-1 cells (163).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Wang, 2019, Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression, Cell Res source

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  • May combine two claims.

    Premisecitation

    At the age of seven months, when signs of synaptic degeneration appear, Firmicutes became the predominant phylum, with a marked decrease in abundance of Bacteroidetes and Verrucomicrobia.

    “At the age of seven months, when the signs of synaptic degeneration appear, Firmicutes became the predominant phylum, with a marked decrease in abundance of Bacteroidetes and Verrucomicrobia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These variations over time were absent in wild-type mice, which had a much more stable microbiota throughout the lifespan.

    “These variations over time were absent in wild-type mice, which had a much more stable microbiota throughout the lifespan (163).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Wang, 2019, Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression, Cell Res source

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  • May combine two claims.

    Premisecitation

    At 2 to 3 months of age, both pro-inflammatory and anti-inflammatory microglia expanded, while in the following months only the first subset continued to grow, along with recruitment of Th-1 CD4+ proinflammatory cells, reaching a peak at seven-nine months.

    “In fact, at 2 to 3 months of age, both pro-inflammatory and anti-inflammatory microglia expanded, while in the following months, only the first subset continued to grow, along with the recruitment of Th-1 CD4+ proinflammatory cells, reaching a peak at seven-nine months.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Premisecitation

    Feces from oligomannate-treated 5xFAD mice transferred protection from neuroinflammatory events to recipient wild-type mice pre-treated with Aβ aggregate injections.

    “The feces isolated from oligomannate-treated 5xFAD mice transferred protection from neuroinflammatory events in recipient animals (163).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Wang, 2019, Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression, Cell Res source

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  • May combine two claims.

    Premisecitation

    Sodium oligomannate suppressed neuroinflammation, Aβ plaque deposition, and cognition impairment.

    “The usage of a sodium oligomannate, with known cognition improvement effect in humans, suppressed neuroinflammation, Aβ plaque deposition, and cognition impairment (164).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Dong, 2019, Drug development for alzheimer’s disease: Microglia induced neuroinflammation as a target, Int J Mol Sci source

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  • May combine two claims.

    Interpretationcitation

    Modifications of intestinal flora impact several metabolic pathways in AD mouse models, potentially leading to cognitive defects, amyloid deposition, and intestinal abnormalities.

    “Therefore, modifications of the intestinal flora impact several metabolic pathways in AD mouse models, that could be leading to cognitive defects, amyloid deposition, and intestinal abnormalities (165).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [165] Zhang, 2017, Altered Gut Microbiota in a Mouse Model of Alzheimer’s Disease, J Alzheimers Dis source

      Not checked in the free run.

    • Rests on an assumption: In AD mice, intestinal microbiota diversity is altered and SCFA levels are reduced compared to wild-type control mice.

  • May combine two claims.

    Premisecitation

    FMT from wild-type animals into ADLPAPT mice ameliorated formation of Aβ plaques, neurofibrillary tangles, glial reactivity, and cognitive impairment in recipient mice.

    “Upon fecal microbial transplantations from WT animals into ADLPAPT mice, formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment were ameliorated in the recipients mice (166).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Kim, 2020, Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model, Gut source

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  • May combine two claims.

    Premisecitation

    Oral Bifidobacterium longum NK46 in 5xFAD mice changed intestinal microbiota composition, increasing Bacteroides and reducing Firmicutes and Proteobacteria phyla.

    “The human isolate Bifidobacterium longum (NK46) was orally administered in 5xFAD mice and induced anti-inflammatory effects (decrease in lipopolysaccharide (LPS) levels, NF-κB activation, and TNF-α expression), changes in the intestinal microbiota composition of the recipients (increase in Bacteroides and reduction in Firmicutes and Proteobacteria phyla), and suppression of Aβ accumulation in the”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Lee, 2019, Suppression of gut dysbiosis by Bifidobacterium longum alleviates cognitive decline in 5XFAD transgenic and aged mice, Sci Rep source

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  • May combine two claims.

    Premisecitation

    Mice that received gingipains-deficient P. gingivalis or synthetic gingipains inhibitors had significantly less P. gingivalis DNA detectable in the brain, less Aβ production, reduced neuroinflammation, and increased number of healthy neurons in the hippocampus.

    “On the other hand, mice that received gingipains-deficient P. gingivalis or synthetic gingipains inhibitors had significantly less P. gingivalis DNA detectable in the brain, less Aβ production, reduced neuroinflammation, and increased number of healthy neurons in the hippocampus (120).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Dominy, 2019, Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors, Sci Adv source

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  • May combine two claims.

    Premisecitation

    Butyrate-producing bacteria are associated with a decrease in the dopamine metabolite and lower quality of life and signs of depression.

    “Those butyrate-producing bacteria are also associated with a decrease in the dopamine metabolite and lower quality of life and signs of depression (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Valles-Colomer, 2019, The neuroactive potential of the human gut microbiota in quality of life and depression, Nat Microbiol source

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  • May combine two claims.

    Premisecitation

    The ASO mouse model of PD develops progressive deficits in motor function as well as in gut motility.

    “Importantly, ASO (overexpressing a-synuclein under Thy1 promoter) mouse model of PD develops progressive deficits in motor function as well as in gut motility (182, 183).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [182] Chesselet, 2012, A Progressive Mouse Model of Parkinson’s Disease: The Thy1-aSyn (“Line 61”) Mice, Neurotherapeutics source

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    • cites [183] Rockenstein, 2002, Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters, J Neurosci Res source

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  • May combine two claims.

    Premisecitation

    ASO GF mice show reduced signs of PD and diminished α-synuclein aggregates in the frontal cortex, but not in the cerebellum, compared to their SPF counterparts.

    “ASO GF mice show reduced signs of PD and diminished α-synuclein aggregates in the frontal cortex, but not in the cerebellum, compared to their SPF counterparts (103).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Frost, 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nat Commun source

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  • May combine two claims.

    Premisecitation

    PD is characterized by a disrupted intestinal barrier, which leads to systemic dissemination of microbial products like LPS and an increase in expression of intestinal pro-inflammatory genes.

    “Another important characteristic of the disease is a disrupted intestinal barrier, which leads to the systemic dissemination of microbial products like LPS and an increase in expression of intestinal pro-inflammatory genes (181).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Perez-Pardo, 2018, Role of TLR4 in the gut-brain axis in Parkinson’s disease: A translational study from men to mice, Gut source

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  • May combine two claims.

    Interpretationreasoning

    A PD-typical microbiota composition could be associated with less dopamine production and PD.

    “This finding suggests that a PD-typical microbiota composition could be associated with less dopamine production and PD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from mouse models of AD, PD, and neuropsychiatric disorders can be generalized to human disease.

  • May combine two claims.

    Premisecitation

    ASO-GF mice treated with SCFA mixture showed mature microglia, formation of α-syn-aggregates, GI deficits, and significantly impaired performance in several motor tasks, as ASO-SPF mice.

    “Remarkably, ASO-GF mice treated with SCFAs mixture showed again mature microglia, formation of α-syn-aggregates, GI deficits, and significantly impaired performance in several motor tasks, as ASO-SPF mice (103).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Frost, 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nat Commun source

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  • May combine two claims.

    Premisecitation

    Microglia phenotype and gastrointestinal function (measured as fecal output) were significantly improved in antibiotic-treated animals but diminished in GF mice recolonized with SPF flora.

    “Importantly, the microglia phenotype and also the gastrointestinal function (measured as fecal output) were significantly improved in antibiotic-treated animals but diminished in GF mice recolonized with SPF flora (103).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Frost, 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nat Commun source

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  • May combine two claims.

    Premisecitation

    Repeated oral administration of Proteus mirabilis or its derived LPS to MPTP-treated or young mice was sufficient to induce a PD-like phenotype with motor deficit, loss of dopaminergic neurons in the nigra, brain and gut inflammation with disruption of the intestinal epithelial barrier, and formation of α-syn inclusions in the brain and in the colon.

    “In the end, in a differently induced model of PD, the repeated oral administration of Proteus mirabilis or its derived LPS to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated or young mice was sufficient to induce a PD-like phenotype with motor deficit, loss of dopaminergic neurons in the nigra, brain and gut inflammation with disruption of the intestinal epithelial barrier, and formation of α”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [185] Choi, 2018, Oral administration of Proteus mirabilis damages dopaminergic neurons and motor functions in mice, Sci Rep source

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  • May combine two claims.

    Premisecitation

    Treatment with minocycline reduced inflammation, α-syn-aggregates, and improved motor function.

    “Moreover, the simple treatment with minocycline was adequate to reduce inflammation, α-syn-aggregates, and improve motor function (103).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Frost, 2014, The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism, Nat Commun source

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  • May combine two claims.

    Premisecitation

    MDD patients had increased fecal α-diversity, with increased levels of Enterobacteriaceae and Alistipes but reduced levels of Faecalibacterium, compared to drug-responder MDD patients and healthy controls.

    “Patients suffering from major depressive disorder (MDD) had increased fecal α-diversity (increased levels of Enterobacteriaceae and Alistipes but reduced levels of Faecalibacterium) compared to drug-responders-MDD patients and healthy controls.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [186] Jiang, 2015, Altered fecal microbiota composition in patients with major depressive disorder, Brain Behav Immun source

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  • May combine two claims.

    Premisecitation

    In a Flemish population cohort, butyrate-producing Faecalibacterium and Coprococcus bacteria were associated with high quality of life, and Bacteroides enterotype 2 with low quality of life and signs of depression.

    “From a large microbiome study on a Flemish population cohort, some bacteria have been associated with high quality of life, such as butyrate-producing Faecalibacterium, Coprococcus bacteria, and others with low quality of life and signs of depression, such as Bacteroides enterotype 2 (22).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Valles-Colomer, 2019, The neuroactive potential of the human gut microbiota in quality of life and depression, Nat Microbiol source

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  • May combine two claims.

    Premisecitation

    Studies showing the importance of microbiota in ASD pathogenesis are few and mostly inconsistent, with some exceptions concerning differences in bacteria such as Prevotella, Firmicutes, Clostridiales (like Clostridium perfringens), and Bifidobacterium species between ASD patients and controls.

    “Regarding human autism spectrum disorder (ASD), studies showing the importance of the microbiota in the pathogenesis are few and mostly inconsistent, with some exceptions concerning the differences observed for bacteria, such as Prevotella, Firmicutes, Clostridiales, like Clostridium perfringens, and Bifidobacterium species (188), between the ASD patients and the controls.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [188] Ho, 2020, Gut microbiota changes in children with autism spectrum disorder: a systematic review, Gut Pathog source

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  • May combine two claims.

    Premisecitation

    In mice, genetic deficiency of caspase-1 is associated with a decrease of innate and stress-induced depressive- and anxiety-like behaviors and affects chronic restraint stress response, with possible involvement of the intestinal microbiota.

    “As mentioned earlier, in mice, the genetic deficiency of caspase-1, the effector molecule of the inflammasome, is associated with a decrease of innate and stress-induced depressive- and anxiety-like behaviors and affects chronic restraint stress response with a possible involvement of the intestinal microbiota (190).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Wong, 2016, Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition, Mol Psychiatry source

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  • May combine two claims.

    Premisecitation

    Administration of Bacteroides fragilis (and Bacteroides thetaiotaomicron but not Enterococcus faecalis) improved gut dysbiosis, intestinal barrier integrity, metabolic profile, and communicative, repetitive, anxiety-like, and sensorimotor behaviors in the MIA model.

    “The pure administration of two bacterial strains as probiotic treatment, such as Bacteroides fragilis (and Bacteroides thetaiotaomicron but not Enterococcus faecalis), could improve the gut dysbiosis, intestinal barrier integrity, the metabolic profile of the animals, and the communicative, repetitive, anxiety-like, and sensorimotor behaviors in the MIA model (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Hsiao, 2013, Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell source

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  • May combine two claims.

    Premisecitation

    Offspring from MIA dams showed intestinal microbial dysbiosis with 67 different OTUs compared to the control group, dysregulation of intestinal barrier integrity with increased permeability, and alteration in their metabolomic profile.

    “Interestingly, offspring coming from MIA dams showed intestinal microbial dysbiosis with 67 different OTUs compared to the control group, dysregulation of the intestinal barrier integrity with increased permeability, as reported already in children affected by ASD (189), and alteration in their metabolomic profile (20).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [189] Lefter, 2020, A descriptive review on the prevalence of gastrointestinal disturbances and their multiple associations in autism spectrum disorder, Med source

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    • cites [20] Hsiao, 2013, Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell source

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  • May combine two claims.

    Premisecitation

    In the MIA model, 4-ethylphenylsulfate, indole pyruvate, serotonin, glycolate, imidazole propionate, and N-acetylserine were enormously increased in the serum of MIA offspring and entirely restored by single B. fragilis treatment.

    “Concerning the metabolites that could be induced by the intestinal bacteria under certain pathological conditions, in the MIA model, 4-ethylphenylsulfate (4EPS), indole pyruvate, serotonin, glycolate, imidazole propionate, and N-acetylserine were enormously increased in the serum of MIA offspring and entirely restored by the single B. fragilis treatment (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Hsiao, 2013, Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders, Cell source

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

    Premisecitation

    Caspase-1-deficient mice, compared to wild-type mice, showed decreased floating time in the forced swim test, decreased anxiety-like behavior in the elevated plus-maze, decreased latency to feed in the novelty suppressed feeding test, buried fewer marbles, produced less fecal pellets, showed increased locomotion, and performed faster at the rotarod test.

    “Caspase-1–deficient mice, compared to wild-type mice, showed decreased floating time in the forced swim test, decreased anxiety-like behavior as measured by the unaltered open/closed arms time ratio in the elevated plus-maze (190).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [190] Wong, 2016, Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition, Mol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with minocycline or chronic restraint stress for 21 consecutive days changed the gut microbiota composition of mice compared with mice not undergoing these procedures.

    “Upon treating the mice with either the minocycline antibiotic, which suppresses inflammasome activation and alters the microbiota composition, or after chronic restraint stress experiment for 21 consecutive days, the gut microbiota composition of these mice changed, compared with mice which do not undergo these procedures (190).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Wong, 2016, Inflammasome signaling affects anxiety- and depressive-like behavior and gut microbiome composition, Mol Psychiatry source

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  • May combine two claims.

    Premisecitation

    Under physiological conditions, AIM2 inflammasome is activated during neurodevelopment and contributes to CNS physiology acting through gasdermin-D regulation, and not through IL-1β and IL-18 production.

    “Under physiological conditions, AIM2 inflammasome is activated during neurodevelopment and contributes to CNS physiology acting through gasdermin-D regulation, and not through IL-1β and IL-18 production (205).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [205] Lammert, 2020, AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment, Nature source

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  • May combine two claims.

    Interpretationnone given

    Several microbial factors can activate the intestinal inflammasome, which might have a distal effect on the brain.

    “Several microbial factors can activate the intestinal inflammasome, which might have a distal effect on the brain.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In the intestine under physiological conditions, resident microbes constantly stimulate inflammasomes.

  • May combine two claims.

    Premisecitation

    SlrP also promotes survival of the host and microbial transmission to other hosts.

    “It also promotes survival of the host, and from the microbial point of view microbial transmission to other hosts (212).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [212] Rao, 2017, Pathogen-Mediated Inhibition of Anorexia Promotes Host Survival and Transmission, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several microbial metabolites, such as taurine, spermine, and histamine, can affect NLRP6 inflammasome activation in the gut and play an important role, if properly balanced, in host-microbial mutualism at the level of the intestine.

    “Several microbial metabolites, such as taurine, spermine, and histamine, can affect the NLRP6 inflammasome activation in the gut and play an important role, if properly balanced, in host-microbial mutualism at the level of the intestine (213).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [213] Blacher, 2017, Microbiome-Modulated Metabolites at the Interface of Host Immunity, J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Salmonella leucine-rich repeat protein (SlrP) inhibits Salmonella virulence and the typical host anorexic response induced by the infection.

    “An evidence for intestinal inflammasome activation and its effects on the brain comes from the discovery that Salmonella leucine-rich repeat protein (SlrP) inhibits Salmonella virulence and the typical host anorexic response induced by the infection (212).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [212] Rao, 2017, Pathogen-Mediated Inhibition of Anorexia Promotes Host Survival and Transmission, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Environmental (bacterial) factors can affect the priming of autoreactive pathogenic T cells, providing insights into pathogenic mechanisms of MS and other immune-mediated diseases.

    “We therefore suggested that environmental (bacterial) factors can also affect the priming of autoreactive pathogenic T cells providing new insights into the pathogenic mechanisms of MS and other immune-mediated diseases, including neurological disorders.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models and in vitro studies of neurological disease are relevant to human disease.

  • May combine two claims.

    Premisecitation

    Priming of the pathogenic CD4+ T helper subset was dependent on ASC-dependent IL-1β production, and not on IL-12p35 or IL-12p40.

    “The priming of this pathogenic subset of T helper CD4+ T cells was dependent on ASC-dependent IL-1β production, and not on IL-12p35 or IL-12p40 (132).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Ronchi, 2016, Experimental priming of encephalitogenic Th1/Th17 cells requires pertussis toxin-driven IL-1β production by myeloid cells, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP/PS1 mice lacking ASC, caspase-1, or NLRP3 had significantly reduced hippocampal and cortical amyloid plaque deposition and ameliorated disease outcome.

    “Animal studies confirmed this significant involvement of NLRP activation, as APP/PS1 mice, lacking the expression of ASC, caspase-1, or NLRP3 had significantly reduced hippocampal and cortical amyloid plaque deposition and ameliorated disease outcome (229, 230).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [229] Venegas, 2017, Microglia-derived ASC specks crossseed amyloid-β in Alzheimer’s disease, Nature source

      Not checked in the free run.

    • cites [230] Heneka, 2013, NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tau22 mice lacking ASC or NLRP3 expression had lower levels of aggregated and hyperphosphorylated tau in the hippocampus, and their spatial memory deficits were rescued.

    “Consistent with this, Tau22 mice lacking ASC or NLRP3 expression had lower levels of aggregated and hyperphosphorylated tau in the hippocampus, and their typical spatial memory deficits were rescued (197).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Ising, 2019, NLRP3 inflammasome activation drives tau pathology, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ accumulation activates microglia and promotes pro-inflammatory mediator production and impairment of their phagocytic function.

    “Aβ accumulation activates the microglia and promotes pro-inflammatory mediators’ production and impairment of their phagocytic function (232, 233).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [232] Sarlus, 2017, Microglia in Alzheimer’s disease, J Clin Invest source

      Not checked in the free run.

    • cites [233] Shi, 2018, Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight, Nat Rev Immunol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Inflammasome activation in AD pathogenesis could be downstream of Aβ deposit formation and could amplify neuroinflammation linked to the disease.

    “All these evidences suggest that the inflammasome activation in AD pathogenesis could be downstream the Aβ deposits formation, and it could then amplify the neuroinflammation linked to the disease.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Findings from animal models and in vitro studies of neurological disease are relevant to human disease.

  • May combine two claims.

    Premisecitation

    Injection of caspase-1 inhibitor Ac-YVAD-CMK reduced expression of NLRP inflammasome signaling proteins and improved number of dopaminergic neurons in LPS- and 6-hydroxydopamine-induced PD in rats.

    “Injection of the caspase-1 inhibitor Ac-YVAD-CMK was shown to reduce the expression of NLRP inflammasome signaling proteins and improve the number of dopaminergic neurons in LPS- and 6-hydroxydopamine-induced PD in rats (242).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [242] Mao, 2017, The NLRP3 Inflammasome is Involved in the Pathogenesis of Parkinson’s Disease in Rats, Neurochem Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In α-synuclein A53T transgenic mouse model of PD, elevated midbrain IL-1β was measured, and lack of endogenous caspase-1 significantly reduced microglia activation.

    “In the α-synuclein A53T transgenic mouse model of PD (which overexpress the mutant human A53/α-synuclein), elevated levels of IL-1β in midbrain were measured, but when the mice lack the endogenous expression of caspase-1, this significantly reduced the activation of microglia (243).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [243] Fan, 2016, MicroRNA-7 Enhances Subventricular Zone Neurogenesis by Inhibiting NLRP3/Caspase-1 Axis in Adult Neural Stem Cells, Mol Neurobiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fibrillar, but not monomeric, α-synuclein induced NLRP3- and caspase-1-mediated IL-1β secretion in human monocytes and BV2 microglial cell line, or via TLR-2 signaling in rodent microglial cells.

    “The fibrillar, but not monomeric, form of α-synuclein induced NLRP3- and caspase-1–mediated IL-1β secretion in human monocytes and BV2 microglial cell line (238), or via TLR-2 signaling pathway in rodents microglial cells (250).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [238] Codolo, 2013, Triggering of inflammasome by aggregated α-synuclein, an inflammatory response in synucleinopathies, PloS One source

      Not checked in the free run.

    • cites [250] Kim, 2013, Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic expression of IL-1β in substantia nigra of rats induced progressive death of dopaminergic neurons and motor impairments.

    “Moreover, the chronic expression of IL-1β in substantia nigra of rats induced progressive death of dopaminergic neurons and resulted in motor impairments (241).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Ferrari, 2006, Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1β in the substantia nigra, Neurobiol Dis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLRP3−/− mice were resistant to loss of nigral dopaminergic neurons induced by MPTP, associated with reduction in caspase-1 activation and IL-1β and IL-18 secretion.

    “Moreover, NLRP3−/− mice were resistant to the loss of nigral dopaminergic neurons induced by treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and this was associated with a reduction in caspase-1 activation and IL-1β and IL-18 secretion (244).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [244] Yan, 2015, Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a small cohort of MDD patients, NLRP3 mRNA and protein levels are increased in PBMCs, as are caspase-1 and IL-1β, and normalize to healthy levels upon antidepressant treatment.

    “A study involving a relatively small cohort of MDD patients and healthy volunteers reported that NLRP3 mRNA and protein levels are increased in peripheral blood mononuclear cells in MDD patients, as caspase-1 and IL-1β, and normalized to healthy levels upon antidepressant treatment (245).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [245] Alcocer-Gómez, 2016, Stress-Induced Depressive Behaviors Require a Functional NLRP3 Inflammasome, Mol Neurobiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with SSD had higher levels of IL-18, IL-1Ra, TNF, and IL-6; OCD patients had higher levels of IL-18, IL-1Ra, and TNF, compared to healthy controls.

    “In details, patients with SSD had higher levels in IL-18, IL-1Ra, TNF, and IL-6; whereas OCD patients had higher levels of IL-18, IL-1Ra, and TNF, compared to the healthy controls (248).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [248] Hylén, 2020, Increased inflammasome activity in markedly ill psychiatric patients: An explorative study, J Neuroimmunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The increased inflammasome/cytokine effects in psychiatric patients were not caused by functional mutations of inflammasome components or products, BMI, age at disease onset, depression, or treatment with psychotropic drugs.

    “Importantly, these effects were not caused by the presence of functional mutations of inflammasome components or products, which could lead to increased inflammasome activity and cytokine release, neither by the body mass index (BMI), age at disease onset, depression, or treatment with psychotropic drugs (248).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [248] Hylén, 2020, Increased inflammasome activity in markedly ill psychiatric patients: An explorative study, J Neuroimmunol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    BHB exerts antidepressant-like effects, possibly by anti-inflammatory mechanisms that inhibit or are led by NLRP3-induced neuroinflammation in the hippocampus.

    “These findings suggest that BHB exerts antidepressant-like effects, possibly by anti-inflammatory mechanisms that inhibits or are led by NLRP3-induced neuro-inflammation in the hippocampus (255).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [255] Yamanashi, 2017, Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses, Sci Rep source

      Not checked in the free run.

    • Rests on an assumption: Findings from animal models and in vitro studies of neurological disease are relevant to human disease.

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

    Interpretationnone given

    The inflammasome is a signaling pathway that might be activated in the presence of certain bacteria and bacterial molecules.

    “The inflammasome is a signaling pathway that might be activated in the presence of certain bacteria and bacterial molecules.”
    Quote in the paperNot a substantial claim
87 of 87

  • The paper relies on this without support.

    A significant gap of knowledge exists in understanding the exact mechanisms involved in communication between the gut and the brain during health and disease.

    “Despite growing evidence, a significant gap of knowledge still exists in understanding the exact mechanisms involved in the communication between gut and brain during health and disease.”

  • The paper relies on this without support.

    For the majority of pathological conditions, it is not known whether dysbiosis is the cause or the consequence of the disease.

    “We are at the initial phases of this discovery path, and for the majority of the pathological conditions, we still do not know if the dysbiosis is the cause or rather the consequence of it.”

  • The paper relies on this without support.

    In AD mice, intestinal microbiota diversity is altered and SCFA levels are reduced compared to wild-type control mice.

    “In addition, the intestinal microbiota diversity was altered and the levels of SCFAs were reduced in AD mice compared to wild-type control mice.”

  • The paper relies on this without support.

    In the intestine under physiological conditions, resident microbes constantly stimulate inflammasomes.

    “In the intestine, under physiological conditions, constant stimulation of inflammasomes is happening due to the resident trillions of microbes.”

  • The paper relies on this without support.

    Findings from mouse models of AD, PD, and neuropsychiatric disorders can be generalized to human disease.

    “An essential role of the microbiota in PD pathogenesis has been shown in animal models.”

  • The paper relies on this without support.

    The composition and function of the gut microbiota in mice and humans are sufficiently similar for mouse FMT or colonization results to inform human disease mechanisms.

    “GF mice colonized with microbiota from PD patients display physical impairments compared to GF mice colonized with microbiota from healthy human donors (111).”

  • The paper relies on this without support.

    Findings from animal models and in vitro studies of neurological disease are relevant to human disease.

    “Animal studies confirmed this significant involvement of NLRP activation, as APP/PS1 mice, lacking the expression of ASC, caspase-1, or NLRP3 had significantly reduced hippocampal and cortical amyloid plaque deposition and ameliorated disease outcome (229, 230).”
7 of 7

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?

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

    “In the gut, the GM and its metabolites have been shown to modulate gastrointestinal functions via their effects on intestinal permeability (32–35), mucosal immune function (36–38), intestinal motility and sensitivity (39, 40), and the enteric nervous system (ENS) (21, 24, 25, 41).”

    From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [33]

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.

  • Tau22 mice are assigned two different ages for the same comparison

    Minor

    The table places the increase in cleaved caspase-1 and ASC at 22 months relative to 3 months, while the text places it at 11 months relative to 3 months.

  • Table assigns Ronchi et al. the wrong reference number

    Minor

    The EAE table cites Ronchi et al. as reference 113, but the reference list identifies 113 as Sharon et al. and 132 as Ronchi et al.

2 of 2

Cites

1 retracted

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Cited by

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Related

Authors
Rutsch, A., Kantsjö, J. B., & Ronchi, F.
Affiliations
University of Bern (CH)
Corresponding author
Ronchi, Francesca
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-12-10
Volume
11
Pages
604179-604179
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2020.604179
PMC
PMC7758428
OpenAlex
W3111897458
Semantic Scholar
29a07f4cb9063457f53723c6a4328c6b5202423e
Cited by
821
References
288
Citations by year
2026: 111 · 2025: 196 · 2024: 188 · 2023: 168 · 2022: 120 · 2021: 37 · 2020: 1
FWCI
7.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • BORIS (University Library Bern) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Open Access CRIS of the University of Bern
Funders
Novartis Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
gut-brain axis, gut microbiota, dysbiosis, inflammasome, neuroinflammation, blood-brain barrier permeability, vagus nerve, bacterial metabolites, IL-1β, IL-18, pyroptosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, neuropsychiatric disorders, anxiety, depression, brain development
MeSH terms
Gastrointestinal Microbiome, Animals, Bacteria, Mental Disorders, Brain, Brain Diseases, Humans, Intestines, Host-Pathogen Interactions, Inflammasomes, Dysbiosis

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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.

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