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Cited by 457Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

The endotoxin hypothesis of neurodegeneration

Open access
Brown, Guy C.·2019·Journal of Neuroinflammation
DOI 10.1186/s12974-019-1564-7PMC PMC6744684
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Abstract

The endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid β and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer’s disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer’s disease. Intestinal permeability increases early in Parkinson’s disease, and injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson’s disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.

AI snapshot

Written from the paper’s full text.

TL;DR

The endotoxin hypothesis proposes that lipopolysaccharide (LPS/endotoxin), largely from gut and other mucosal sources, causes or contributes to neurodegeneration by driving systemic and brain inflammation. The review argues the hypothesis is plausible and supported by associations and animal models, but remains unproven because causality in human neurodegenerative disease has not been established.

Key findings

  • Blood endotoxin is elevated in several neurodegenerative and inflammatory conditions: healthy humans 10 ± 20 pg/ml, Alzheimer’s disease 60 pg/ml, amyotrophic lateral sclerosis 45 pg/ml, liver cirrhosis 60 pg/ml, HIV/AIDS 70 pg/ml, and sepsis about 500 pg/ml.
  • In healthy humans, intravenous injection of 1 ng LPS/kg (equivalent to about 15 pg/ml distributed through blood) increased blood cytokines, sickness behaviour, and decreased motivation within 1–3 h, and caused robust brain microglial activation measured by PET at 3 h.
  • In rodents, a single intraperitoneal injection of 5 mg LPS/kg caused acute microglial activation persisting at least 12 months and loss of dopaminergic neurons in the substantia nigra 10 months later; multiple doses of 1 mg LPS/kg over several days caused more rapid neurodegeneration.
  • Endotoxin promotes amyloid β, tau, α-synuclein, and TDP-43 aggregation/neuropathology, and APOE4 both sensitises to endotoxin and predisposes to Alzheimer’s disease, suggesting endotoxin may synergise with different aggregable proteins to produce different neurodegenerative diseases.

Methods

  • Design: narrative review and explicit statement of the endotoxin hypothesis of neurodegeneration; no primary experimental data are reported.
  • Data/sample: synthesis of published human, animal, and in vitro studies, including a table of plasma endotoxin levels in different conditions and endotoxin doses causing effects.
  • Main analysis: qualitative literature review and mechanistic synthesis; no systematic review, meta-analysis, or statistical analysis is described.

Limitations

  • The paper states the endotoxin hypothesis is unproven: increased endotoxin is associated with neurodegenerative disease and can cause neurodegeneration in models, but whether human neurodegenerative disease is caused by increased endotoxin is not known.
  • The paper notes extrapolation problems: rodent LPS doses used are lethal in humans, E. coli LPS is often used because it is highly inflammatory, and acute responses to LPS do not easily predict chronic responses because of priming, tolerance, and epigenetic changes.
  • Evident from the text: this is a narrative review without systematic search or primary data, and endotoxin measurement is complicated by LAL assay activity units, blood interference, and species differences in sensitivity and basal levels.

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

Integrity signals

Registry

Crossref · 10.1186/s12974-019-1564-7

Cites

116 of 116 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 167 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    Liver failure, as occurs in cirrhosis, elevates blood endotoxin levels to roughly the same level as occurs in Alzheimer's disease.

    “liver failure, as occurs in cirrhosis, elevates blood endotoxin levels to roughly the same level as occurs in Alzheimer’s disease (Table 1)”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Intestinal permeability increases early in Parkinson's disease.

    “Intestinal permeability increases early in Parkinson’s disease”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Forsyth CB, Shannon KM, Kordower JH, et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One. 2011;6:e28032. source

      Not checked in the free run.

  • Premisecitation

    Blood plasma endotoxin levels are normally low in healthy humans.

    “Blood plasma levels of endotoxin are normally low”
    • Also stated in: § Serum endotoxin · plain
      “Endotoxin is present in plasma of all healthy humans at very variable levels between 0.01 and 0.5 EU/ml (mean 0.1 ± 0.2 EU/ml), equivalent to about 1 and 50 pg/ml [7, 8].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Nádházi Z, Takáts A, Offenmüller K, Bertók L. Plasma endotoxin level of healthy donors. Acta Microbiol Immunol Hung. 2002;49:151–7. source

      Not checked in the free run.

    • cites [8] Wiedermann CJ, Kiechl S, Dunzendorfer S, et al. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol. 1999;34:1975–81. source

      Not checked in the free run.

  • Premisecitation

    Endotoxin binds directly to APOE.

    “Endotoxin binds directly to APOE”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Rensen PC, Oosten M, Bilt E, Eck M, Kuiper J, Berkel TJ. Human recombinant apolipoprotein E redirects lipopolysaccharide from Kupffer cells to liver parenchymal cells in rats In vivo. J Clin Invest. 1997;99:2438–45. source

      Not checked in the free run.

    • cites [82] Van Oosten M, Rensen PC, Van Amersfoort ES, Van Eck M, Van Dam AM, Breve JJ, Vogel T, Panet A, Van Berkel TJ, Kuiper J. Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality. A new therapeutic approach to treat gram-negative sepsis. J Biol Chem. 2001;276:8820–4. source

      Not checked in the free run.

  • Premisecitation

    Endotoxin promotes amyloid β and tau aggregation and neuropathology.

    “Endotoxin promotes amyloid β and tau aggregation and neuropathology”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [66] Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, Hong JT. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation. 2008;5:37. source

      Not checked in the free run.

    • cites [67] Asti A, Gioglio L. Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation? J Alzheimers Dis. 2014;39:169–79. source

      Not checked in the free run.

    • cites [68] Gardner LE, White JD, Eimerbrink MJ, et al. Imatinib methanesulfonate reduces hyperphosphorylation of tau following repeated peripheral exposure to lipopolysaccharide. Neuroscience. 2016;331:72–7. source

      Not checked in the free run.

    • cites [69] Bhaskar K, Konerth M, Kokiko-Cochran ON, et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68:19–31. source

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  • May combine two claims. 57
  • Classified as probably not a substantial claim. 13
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra.

    “injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [70] Kim C, Lv G, Lee JS, et al. Exposure to bacterial endotoxin generates a distinct strain of α- synuclein fibril. Sci Rep. 2016;6:30891. source

      Not checked in the free run.

    • cites [71] Wang W, Nguyen LTT, Burlak C, et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc Natl Acad Sci. 2016;113:9587–92. source

      Not checked in the free run.

    • cites [99] Kelly LP, Carvey PM, Keshavarzian A, Shannon KM, Shaikh M, Bakay RA, Kordower JH. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson’s disease. Mov Disord. 2014;29:999–1009. source

      Not checked in the free run.

    • cites [42] Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55:453–62. source

      Not checked in the free run.

    • cites [43] Qin L, Liu Y, Hong J-S, et al. NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia. 2013;61:855–68. source

      Not checked in the free run.

    • cites [44] Tufekci KU, Genc S, Genc K. The endotoxin-induced neuroinflammation model of Parkinson’s disease. Parkinsons Dis. 2011;2011:487450.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer's disease.

    “the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer’s disease.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Gale SC, Gao L, Mikacenic C, Coyle SM, Rafaels N, Murray Dudenkov T, Madenspacher JH, Draper DW, Ge W, Aloor JJ, Azzam KM, Lai L, Blackshear PJ, Calvano SE, Barnes KC, Lowry SF, Corbett S, Wurfel MM, Fessler MB. APOε4 is associated with enhanced in vivo innate immune responses in human subjects. J Allergy Clin Immunol. 2014;134:127–34. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood and brain endotoxin levels are elevated in Alzheimer's disease.

    “Blood and brain endotoxin levels are elevated in Alzheimer’s disease”
    • Also stated in: § Endotoxin and Alzheimer’s disease · plain
      “Mean blood endotoxin levels are increased threefold in AD patients [10].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Zhang R, Miller RG, Gascon R, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2009;206:121–4. source

      Not checked in the free run.

    • cites [78] Zhao Y, Jaber V, Lukiw WJ. Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): detection of lipopolysaccharide (LPS) in AD hippocampus. Front Cell Infect Microbiol. 2017;7:318. source

      Not checked in the free run.

    • cites [79] Zhan X, Stamova B, Jin L-W, et al. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology. 2016;87:2324–32. source

      Not checked in the free run.

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

    Premisecitation

    Endotoxin is a lipopolysaccharide (LPS) that constitutes much of the outer membrane of gram-negative bacteria and is present at high concentrations in gut, gums, skin, and other tissues during bacterial infection.

    “Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection.”
    • Also stated in: § Endotoxin structure and function · plain
      “Endotoxin is a type of lipopolysaccharide (LPS), consisting of lipid A (usually 6 acyl chains attached to a phosphorylated disaccharide), attached to the ‘core’ (a short sugar chain with various modifications), which is attached to the O-antigen (a long linear chain of sugars of variable length).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Needham BD, Trent MS. Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat Rev Microbiol. 2013;11:467–81. source

      Not checked in the free run.

    • cites [6] Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14:e1002533. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adding endotoxin at levels found in disease to blood of healthy humans induces systemic inflammation and brain microglial activation.

    “Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Sandiego CM, Gallezot JD, Pittman B, Nabulsi N, Lim K, Lin SF, Matuskey D, Lee JY, O'Connor KC, Huang Y, Carson RE, Hannestad J, Cosgrove KP. Imaging robust microglial activation after lipopolysaccharide administration in humans with PET. Proc Natl Acad Sci U S A. 2015;112:12468–73. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood endotoxin levels are elevated during infections, gut inflammation, gum disease, and neurodegenerative disease.

    “but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Zhang R, Miller RG, Gascon R, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2009;206:121–4. source

      Not checked in the free run.

    • cites [11] Raparelli V, Basili S, Carnevale R, Napoleone L, Del Ben M, Nocella C, Bartimoccia S, Lucidi C, Talerico G, Riggio O, Violi F. Low-grade endotoxemia and platelet activation in cirrhosis. Hepatology. 2017;65:571–81. source

      Not checked in the free run.

    • cites [12] Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12:1365–71. source

      Not checked in the free run.

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    Premisecitation

    Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits, and loss of brain synapses and neurons.

    “Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42] Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55:453–62. source

      Not checked in the free run.

    • cites [43] Qin L, Liu Y, Hong J-S, et al. NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia. 2013;61:855–68. source

      Not checked in the free run.

    • cites [44] Tufekci KU, Genc S, Genc K. The endotoxin-induced neuroinflammation model of Parkinson’s disease. Parkinsons Dis. 2011;2011:487450.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple doses of 1 mg LPS/kg (over several days), or chronic endotoxin, cause more rapid neurodegeneration and have been used as models of Parkinson's or Alzheimer's disease.

    “Multiple doses of 1 mg LPS/kg (over several days), or chronic endotoxin, cause more rapid neurodegeneration and have been used as models of Parkinson’s or Alzheimer’s disease [44, 45].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Tufekci KU, Genc S, Genc K. The endotoxin-induced neuroinflammation model of Parkinson’s disease. Parkinsons Dis. 2011;2011:487450.

      Not checked in the free run.

    • cites [45] Zakaria R, Wan Yaacob WM, Othman Z, Long I, Ahmad AH, Al-Rahbi B. Lipopolysaccharide-induced memory impairment in rats: a model of Alzheimer’s disease. Physiol Res. 2017;66:553–65. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endotoxin causes inflammatory activation mainly via activating TLR4 (with co-receptor MD2) on the cell surface, resulting in NF-κB transcriptional activation of hundreds of inflammatory genes, including pro-inflammatory cytokines such as TNFα, IL-6 and pro-IL-1β.

    “Endotoxin causes inflammatory activation mainly via activating TLR4 (with co-receptor MD2) on the cell surface, resulting in NF-κB transcriptional activation of hundreds of inflammatory genes, including pro-inflammatory cytokines such as TNFα, IL-6 and pro-IL-1β [4, 17, 18].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Hajjar AM, Ernst RK, Tsai JH, Wilson CB, Miller SI. Human toll-like receptor 4 recognizes host-specific LPS modifications. Nat Immunol. 2002;3:354–9. source

      Not checked in the free run.

    • cites [17] Morris MC, Gilliam EA, Li L. Innate immune programing by endotoxin and its pathological consequences. Front Immunol. 2015;5:680. source

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    • cites [18] Bryant CE, Spring DR, Gangloff M, et al. The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol. 2010;8:8–14. https://doi.org/10.1038/nrmicro2266 . source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Endotoxin is present in all humans, but blood levels are very variable and correlate with neurodegeneration.

    “Endotoxin is present in all of us, but levels in blood are very variable and correlate with neurodegeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In rodents, a single intraperitoneal injection of 5 mg LPS/kg causes acute microglial activation in the brains that persists for at least 12 months, and results in loss of dopaminergic neurons in the substantia nigra 10 months later.

    “In rodents, a single intraperitoneal injection of 5 mg LPS/kg causes acute microglial activation in the brains that persists for at least 12 months, and results in loss of dopaminergic neurons in the substantia nigra 10 months later [42, 43].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007;55:453–62. source

      Not checked in the free run.

    • cites [43] Qin L, Liu Y, Hong J-S, et al. NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration. Glia. 2013;61:855–68. source

      Not checked in the free run.

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    Premisecitation

    There is a strong non-genetic contribution to the risk of neurodegenerative diseases, which is poorly understood.

    “Genetics affects the risk of these diseases, but there is a strong non-genetic contribution to the risk, which is poorly understood [1, 2].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] VanItallie TB. Alzheimer’s disease: innate immunity gone awry? Metabolism. 2017;69S:S41–9. source

      Not checked in the free run.

    • cites [2] Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Curr Treat Options Neurol. 2018;20:54. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low and medium doses of endotoxin do not change blood-brain barrier permeability and only minimally enter the brain, suggesting that peripheral LPS may induce brain inflammation indirectly by (i) LPS activation of peripheral nerves acting centrally; (ii) LPS activation of the blood-brain barrier, which then releases cytokines within the brain, or recruiting immune cells into the brain; or (iii) LP

    “Low and medium doses of endotoxin do not change blood-brain barrier permeability and only minimally enter the brain [52], suggesting that peripheral LPS may induce brain inflammation indirectly by (i) LPS activation of peripheral nerves acting centrally; (ii) LPS activation of the blood-brain barrier, which then releases cytokines within the brain, or recruiting immune cells into the brain; or (ii”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Banks WA, Robinson SM. Minimal penetration of lipopolysaccharide across the murine blood-brain barrier. Brain Behav Immun. 2010;24:102–9. source

      Not checked in the free run.

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    Premisecitation

    LPS toxicity varies depending on lipid A composition, and this depends on bacterial species, strain and environmental conditions.

    “LPS toxicity varies depending on lipid A composition, and this depends on bacterial species, strain and environmental conditions [3–5].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Needham BD, Trent MS. Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat Rev Microbiol. 2013;11:467–81. source

      Not checked in the free run.

    • cites [4] Hajjar AM, Ernst RK, Tsai JH, Wilson CB, Miller SI. Human toll-like receptor 4 recognizes host-specific LPS modifications. Nat Immunol. 2002;3:354–9. source

      Not checked in the free run.

    • cites [5] Vatanen T, Kostic AD, d'Hennezel E, Siljander H, Franzosa EA, Yassour M, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell. 2016;165:1551. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sustained brain inflammation in response to blood endotoxin requires brain TLR4, which may be on microglia, endothelium, perivascular macrophages, meninges or circumventricular organs.

    “However, sustained brain inflammation in response to blood endotoxin requires brain TLR4, which may be on microglia, endothelium, perivascular macrophages, meninges or circumventricular organs [55].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Chakravarty S, Herkenham M. Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci. 2005;25:1788–96. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endotoxin promotes TDP-43 aggregation and neuropathology.

    “endotoxin promotes TDP-43 aggregation and neuropathology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Correia AS, Patel P, Dutta K, Julien JP. Inflammation induces TDP-43 mislocalization and aggregation. PLoS One. 2015;10:e0140248. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High doses of endotoxin in blood cause a 'cytokine storm', septic shock and death, via activating TLR4, RAGE and caspases.

    “High doses of endotoxin in blood (endotoxemia) cause a ‘cytokine storm’, septic shock and death, via activating TLR4, RAGE and caspases [16, 18, 20, 21].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [16] Fink MP. Animal models of sepsis. Virulence. 2014;5:143–5. source

      Not checked in the free run.

    • cites [18] Bryant CE, Spring DR, Gangloff M, et al. The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol. 2010;8:8–14. https://doi.org/10.1038/nrmicro2266 . source

      Not checked in the free run.

    • cites [20] Pfalzgraff A, Weindl G. Intracellular lipopolysaccharide sensing as a potential therapeutic target for sepsis. Trends Pharmacol Sci. 2019;40:187–97. source

      Not checked in the free run.

    • cites [21] Yamamoto Y, Harashima A, Saito H, Tsuneyama K, Munesue S, Motoyoshi S, et al. Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol. 2011;186:3248–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the absence of infection, endotoxin crosses the mucosal membranes of gut, gums, nose or lungs, the main source being intestinal permeability.

    “However, in the absence of infection, endotoxin still crosses the mucosal membranes of gut, gums, nose or lungs, the main source being intestinal permeability [36, 37].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Bischoff SC, Barbara G, Buurman W, et al. Intestinal permeability – a new target for disease prevention and therapy. BMC Gastroenterol. 2014;14:189. source

      Not checked in the free run.

    • cites [37] Brenchley JM, Douek DC. Microbial translocation across the GI tract. Annu Rev Immunol. 2012;30:149–73. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Serum endotoxin levels are elevated in patients with severe autism, liver cirrhosis, diabetes, cardiovascular disease, chronic infection and ageing, amyotrophic lateral sclerosis and Alzheimer's disease.

    “Serum endotoxin levels are elevated in patients with severe autism [30], liver cirrhosis [11], diabetes [31], cardiovascular disease [8], chronic infection and ageing [32], amyotrophic lateral sclerosis and Alzheimer’s disease [10].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30] Emanuele E, Orsi P, Boso M, Broglia D, Brondino N, Barale F, di Nemi SU, Politi P. Low-grade endotoxemia in patients with severe autism. Neurosci Lett. 2010;471:162–5. source

      Not checked in the free run.

    • cites [11] Raparelli V, Basili S, Carnevale R, Napoleone L, Del Ben M, Nocella C, Bartimoccia S, Lucidi C, Talerico G, Riggio O, Violi F. Low-grade endotoxemia and platelet activation in cirrhosis. Hepatology. 2017;65:571–81. source

      Not checked in the free run.

    • cites [10] Zhang R, Miller RG, Gascon R, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2009;206:121–4. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is very roughly 1 g of endotoxin in the human gut, whereas 100 ng of endotoxin injected into blood induces inflammatory activation of the body and brain.

    “There is very roughly 1 g of endotoxin in the human gut [6], whereas 100 ng of endotoxin injected into blood induces inflammatory activation of the body and brain (Table 1).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14:e1002533. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons.

    “Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] Kinsner A, Boveri M, Hareng L, Brown GC, Coecke S, Hartung T, Bal-Price A. Highly purified lipoteichoic acid induced pro-inflammatory signalling in primary culture of rat microglia through Toll-like receptor 2: selective potentiation of nitric oxide production by muramyl dipeptide. J Neurochem. 2006;99:596–607. source

      Not checked in the free run.

    • cites [59] Neher JJ, Neniskyte U, Zhao JW, Bal-Price A, Tolkovsky AM, Brown GC. Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J Immunol. 2011;186:4973–83. source

      Not checked in the free run.

    • cites [60] Fricker M, Neher JJ, Zhao JW, Théry C, Tolkovsky AM, Brown GC. MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation. J Neurosci. 2012;32:2657–66. source

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    Premisecitation

    Endotoxin is released by bacteria and its toxicity is due to the host's inflammatory over-reaction rather than an intrinsic toxicity to animal cells.

    “we now know that (i) endotoxin is released by bacteria and (ii) the toxicity of endotoxin is due to the host’s inflammatory over-reaction to it, rather than an intrinsic toxicity to animal cells [3, 16, 18].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Needham BD, Trent MS. Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. Nat Rev Microbiol. 2013;11:467–81. source

      Not checked in the free run.

    • cites [16] Fink MP. Animal models of sepsis. Virulence. 2014;5:143–5. source

      Not checked in the free run.

    • cites [18] Bryant CE, Spring DR, Gangloff M, et al. The molecular basis of the host response to lipopolysaccharide. Nat Rev Microbiol. 2010;8:8–14. https://doi.org/10.1038/nrmicro2266 . source

      Not checked in the free run.

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

    Premisenone given

    Injection of endotoxin into animals can induce neurodegeneration.

    “Injection of endotoxin into animals can induce neurodegeneration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    E. coli LPS induces a strong inflammatory response via MD2/TLR4, whereas B. dorei LPS does not, and B. dorei LPS can inhibit the inflammatory response to E. coli LPS.

    “E. coli LPS induces a strong inflammatory response via MD2/TLR4, whereas B. dorei LPS does not [5]. Moreover, because B. dorei LPS binds but does not activate the MD2/TLR4 receptor complex, it can inhibit the inflammatory response to E. coli LPS [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Vatanen T, Kostic AD, d'Hennezel E, Siljander H, Franzosa EA, Yassour M, et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell. 2016;165:1551. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endotoxin is present in plasma of all healthy humans at very variable levels between 0.01 and 0.5 EU/ml (mean 0.1 ± 0.2 EU/ml), equivalent to about 1 and 50 pg/ml.

    “Endotoxin is present in plasma of all healthy humans at very variable levels between 0.01 and 0.5 EU/ml (mean 0.1 ± 0.2 EU/ml), equivalent to about 1 and 50 pg/ml [7, 8].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Nádházi Z, Takáts A, Offenmüller K, Bertók L. Plasma endotoxin level of healthy donors. Acta Microbiol Immunol Hung. 2002;49:151–7. source

      Not checked in the free run.

    • cites [8] Wiedermann CJ, Kiechl S, Dunzendorfer S, et al. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol. 1999;34:1975–81. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most endotoxin enters the body via the gut and hepatic portal vein, and most of this endotoxin is cleared by the liver.

    “Most endotoxin enters the body via the gut and hepatic portal vein, and most of this endotoxin is cleared by the liver [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Lumsden AB, Henderson JM, Kutner MH. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology. 1988;8:232–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiome affects motor symptoms in an α-synuclein mouse model of Parkinson's disease, such that eliminating gut bacteria prevents motor deficits, while introducing the gut microbiome from PD patients exacerbates pathology.

    “And the gut microbiome affects motor symptoms in an α-synuclein mouse model of PD, such that eliminating gut bacteria prevents motor deficits, while introducing the gut microbiome from PD patients exacerbates pathology [95].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [95] Sampson TR, Debelius JW, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167:1469–80. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endotoxin may promote the production or aggregation of amyloid β, tau and α-synuclein.

    “Endotoxin may also promote the production or aggregation of amyloid β [66–68], tau [68, 69] and α-synuclein [70, 71].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [66] Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, Hong JT. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation. 2008;5:37. source

      Not checked in the free run.

    • cites [67] Asti A, Gioglio L. Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation? J Alzheimers Dis. 2014;39:169–79. source

      Not checked in the free run.

    • cites [68] Gardner LE, White JD, Eimerbrink MJ, et al. Imatinib methanesulfonate reduces hyperphosphorylation of tau following repeated peripheral exposure to lipopolysaccharide. Neuroscience. 2016;331:72–7. source

      Not checked in the free run.

    • cites [69] Bhaskar K, Konerth M, Kokiko-Cochran ON, et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68:19–31. source

      Not checked in the free run.

    • cites [70] Kim C, Lv G, Lee JS, et al. Exposure to bacterial endotoxin generates a distinct strain of α- synuclein fibril. Sci Rep. 2016;6:30891. source

      Not checked in the free run.

    • cites [71] Wang W, Nguyen LTT, Burlak C, et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc Natl Acad Sci. 2016;113:9587–92. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic endotoxin precipitates brain pathology in mice expressing prions, APP variants or TAU variants or mice with α-synuclein injected in the brain.

    “and systemic endotoxin precipitates brain pathology in mice expressing prions [74], APP variants [33] or TAU variants [69] or mice with α-synuclein injected in the brain [46].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [74] Cunningham C, Campion S, Lunnon K, Murray CL, Woods JF, Deacon RM, Rawlins JN, Perry VH. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol Psychiatry. 2009;65:304–12. source

      Not checked in the free run.

    • cites [33] Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, Wagner J, Häsler LM, Wild K, Skodras A, Blank T, Staszewski O, Datta M, Centeno TP, Capece V, Islam MR, Kerimoglu C, Staufenbiel M, Schultze JL, Beyer M, Prinz M, Jucker M, Fischer A, Neher JJ. Innate immune memory in the brain shapes neurological disease hallmarks. Nature. 2018;556:332–8. source

      Not checked in the free run.

    • cites [69] Bhaskar K, Konerth M, Kokiko-Cochran ON, et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68:19–31. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment of glial-neuronal cultures with LPS alone results in little or no neuronal apoptosis or necrosis, but rather progressive loss of neurons over several days due to microglial phagocytosis of stressed-but-viable neurons, and blocking the phagocytosis saves the neurons.

    “However, treatment of glial-neuronal cultures with LPS alone results in little or no neuronal apoptosis or necrosis, but rather progressive loss of neurons over several days due to microglial phagocytosis of stressed-but-viable neurons and blocking the phagocytosis saves the neurons [59].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Neher JJ, Neniskyte U, Zhao JW, Bal-Price A, Tolkovsky AM, Brown GC. Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J Immunol. 2011;186:4973–83. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blood endotoxin levels are elevated in amyotrophic lateral sclerosis patients, possibly as a result of gut inflammation and microbiome changes.

    “Blood endotoxin levels are elevated in ALS patients [10], possibly as a result of gut inflammation and microbiome changes [102].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Zhang R, Miller RG, Gascon R, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2009;206:121–4. source

      Not checked in the free run.

    • cites [102] Rowin J, Xia Y, Jung B, Sun J. Gut inflammation and dysbiosis in human motor neuron disease. Physiol Rep. 2017;5:e13443. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endotoxin increases α-synuclein production by macrophages and drives α-synuclein fibrillization.

    “Endotoxin increases α-synuclein production by macrophages [100] and drives α-synuclein fibrillization [70, 71].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [100] Tanji K, Mori F, Imaizumi T, et al. Upregulation of alpha-synuclein by lipopolysaccharide and interleukin-1 in human macrophages. Pathol Int. 2002;52:572–7. source

      Not checked in the free run.

    • cites [70] Kim C, Lv G, Lee JS, et al. Exposure to bacterial endotoxin generates a distinct strain of α- synuclein fibril. Sci Rep. 2016;6:30891. source

      Not checked in the free run.

    • cites [71] Wang W, Nguyen LTT, Burlak C, et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc Natl Acad Sci. 2016;113:9587–92. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Humans with the APOE4 variant are more sensitive to injected LPS than those with APOE3, and mice with endogenous ApoE replaced with APOE4 are more sensitive to LPS than those replaced with APOE3.

    “Humans with the APOE4 variant are more sensitive to injected LPS than those with APOE3, and similarly, mice with endogenous ApoE replaced with APOE4 are more sensitive to LPS than those replaced with APOE3 [83].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Gale SC, Gao L, Mikacenic C, Coyle SM, Rafaels N, Murray Dudenkov T, Madenspacher JH, Draper DW, Ge W, Aloor JJ, Azzam KM, Lai L, Blackshear PJ, Calvano SE, Barnes KC, Lowry SF, Corbett S, Wurfel MM, Fessler MB. APOε4 is associated with enhanced in vivo innate immune responses in human subjects. J Allergy Clin Immunol. 2014;134:127–34. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Peripheral endotoxin can activate the classical complement system in the brain, resulting in neuronal loss that can be prevented in complement C3-deficient mice.

    “Peripheral endotoxin can activate the classical complement system in the brain, resulting in neuronal loss that can be prevented in complement C3-deficient mice [63].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Bodea LG, Wang Y, Linnartz-Gerlach B, Kopatz J, Sinkkonen L, Musgrove R, Kaoma T, Muller A, Vallar L, Di Monte DA, Balling R, Neumann H. Neurodegeneration by activation of the microglial complement-phagosome pathway. J Neurosci. 2014;34:8546–56. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During Parkinson's disease, α-synuclein aggregation starts in the gut, and one of the earliest symptoms of PD is gut dysfunction.

    “During PD, α-synuclein aggregation starts in the gut, and one of the earliest symptoms of PD is gut dysfunction [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Curr Treat Options Neurol. 2018;20:54. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is a large increase in bacterial load and bacterial species in Alzheimer's disease brains, including Porphyromonas gingivalis, which can live intracellularly in glia and neurons.

    “There is a large increase in bacterial load and bacterial species in AD brains [79, 90], including P. gingivalis, which can live intracellularly in glia and neurons [91].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [79] Zhan X, Stamova B, Jin L-W, et al. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology. 2016;87:2324–32. source

      Not checked in the free run.

    • cites [90] Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, Davies M, West NX, Allen SJ. 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front Aging Neurosci. 2017;9:195. source

      Not checked in the free run.

    • cites [91] Ilievski V, Zuchowska PK, Green SJ, Toth PT, Ragozzino ME, Le K, Aljewari HW, O'Brien-Simpson NM, Reynolds EC, Watanabe K. Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice. PLoS One. 2018;13:e0204941. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic oral application of Porphyromonas gingivalis or injection of P. gingivalis LPS results in brain inflammation and neurodegeneration in wild-type mice.

    “Chronic oral application of P. gingivalis or injection of P. gingivalis LPS results in brain inflammation and neurodegeneration in wild-type mice [70, 89].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Kim C, Lv G, Lee JS, et al. Exposure to bacterial endotoxin generates a distinct strain of α- synuclein fibril. Sci Rep. 2016;6:30891. source

      Not checked in the free run.

    • cites [89] Zhang J, Yu C, Zhang X, Chen H, Dong J, Lu W, Song Z, Zhou W. Porphyromonas gingivalis lipopolysaccharide induces cognitive dysfunction, mediated by neuronal inflammation via activation of the TLR4 signaling pathway in C57BL/6 mice. J Neuroinflammation. 2018;15:37. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single injection of peripheral endotoxin into wild-type mice and transgenic mice expressing human A53T mutant α-synuclein resulted in indistinguishable acute neuroinflammation, but only the transgenic mice treated with endotoxin developed persistent neuroinflammation, aggregated α-synuclein, progressive degeneration of dopamine neurons and Lewy body-like inclusions in nigral neurons.

    “A single injection of peripheral endotoxin into wild-type mice and transgenic mice (expressing human A53T mutant α-synuclein) resulted in indistinguishable acute neuroinflammation, but only the transgenic mice treated with endotoxin developed persistent neuroinflammation, aggregated α-synuclein, progressive degeneration of dopamine neurons and Lewy body-like inclusions in nigral neurons [101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS. Neuroinflammation and α-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson’s disease. Environ Health Perspect. 2011;119:807–14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sequence variants of the LPS-receptor TLR4 and the LPS-binding receptor TREM2 are associated with an increased risk of Alzheimer's disease.

    “Sequence variants of the LPS-receptor TLR4 [84] and the LPS-binding receptor TREM2 [22] are also associated with an increased risk of AD, indicating additional genetic links between AD and endotoxin.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Chen YC, Yip PK, Huang YL, Sun Y, Wen LL, Chu YM, Chen TF. Sequence variants of toll like receptor 4 and late-onset Alzheimer’s disease. PLoS One. 2012;7:e50771. source

      Not checked in the free run.

    • cites [22] Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NK, Seaman WE. Pattern recognition by TREM-2: binding of anionic ligands. J Immunol. 2003;171:594–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Peripheral endotoxin can cause microglial activation and loss of brain synapses, and the endotoxin-binding protein APOE2 can protect against this synaptic loss.

    “Peripheral endotoxin can also cause microglial activation and loss of brain synapses, and the endotoxin-binding protein APOE2 can protect against this synaptic loss [64].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Zhu Y, Nwabuisi-Heath E, Dumanis SB, Tai LM, Yu C, Rebeck GW, LaDu MJ. APOE genotype alters glial activation and loss of synaptic markers in mice. Glia. 2012;60:559–69. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single dose of peripheral endotoxin in mice caused increased expression of α-synuclein in neurons of the large intestine, followed by an increase in large intestinal permeability, in a manner similar to that observed in patients with Parkinson's disease.

    “A single dose of peripheral endotoxin in mice caused increased expression of α-synuclein in neurons of the large intestine, followed by an increase in large intestinal permeability, in a manner similar to that observed in patients with PD [99].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Kelly LP, Carvey PM, Keshavarzian A, Shannon KM, Shaikh M, Bakay RA, Kordower JH. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson’s disease. Mov Disord. 2014;29:999–1009. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The longer-term effect of blood endotoxin on the brain is not mediated by blood cytokines, but may be mediated in part by endotoxin activating brain cells to produce cytokines within the brain.

    “This implies that the longer-term effect of blood endotoxin on the brain is not mediated by blood cytokines, but may be mediated in part by endotoxin activating the above cells to produce cytokines within the brain (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Chakravarty S, Herkenham M. Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci. 2005;25:1788–96. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This supports a dual-hit hypothesis for Parkinson's disease: elevated endotoxin plus aggregable α-synuclein results in neurodegeneration.

    “This supports a dual-hit hypothesis for PD: elevated endotoxin plus aggregable α-synuclein results in neurodegeneration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Gao HM, Zhang F, Zhou H, Kam W, Wilson B, Hong JS. Neuroinflammation and α-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson’s disease. Environ Health Perspect. 2011;119:807–14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Parkinson's disease patients have increased gastrointestinal permeability and LPS binding protein (LBP), and a proportion have elevated blood endotoxin.

    “PD patients have increased gastrointestinal permeability [92] and LPS binding protein (LBP) [92], and a proportion of PD patients have elevated blood endotoxin [93].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Forsyth CB, Shannon KM, Kordower JH, et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson’s disease. PLoS One. 2011;6:e28032. source

      Not checked in the free run.

    • cites [93] Wijeyekoon RS. The biological basis of heterogeneity in Parkinson’s disease - insights from an innate immune perspective. Doctoral thesis, University of Cambridge, 2018, doi: https://doi.org/10.17863/CAM.30569 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    People with chronic gum disease (periodontitis) have elevated blood endotoxin, a higher risk of Alzheimer's disease and a faster rate of cognitive decline.

    “People with chronic gum disease (periodontitis) have elevated blood endotoxin [85, 86], a higher risk of Alzheimer’s disease and a faster rate of cognitive decline [87].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [85] Wahaidi VY, Kowolik MJ, Eckert GJ, Galli DM. Endotoxemia and the host systemic response during experimental gingivitis. J Clin Periodontol. 2011;38:412–7. source

      Not checked in the free run.

    • cites [86] Shaddox LM, Wiedey J, Calderon NL, Magnusson I, Bimstein E, Bidwell JA, Zapert EF, Aukhil I, Wallet SM. Local inflammatory markers and systemic endotoxin in aggressive periodontitis. J Dent Res. 2011;90:1140–4. source

      Not checked in the free run.

    • cites [87] Ide M, Harris M, Stevens A, Sussams R, Hopkins V, Culliford D, Fuller J, Ibbett P, Raybould R, Thomas R, Puenter U, Teeling J, Perry VH, Holmes C. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One. 2016;11:e0151081. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gut colonisation with endotoxin-producing Helicobacter pylori is associated with Parkinson's disease, and eradication of H. pylori improved PD symptoms.

    “Gut colonisation with endotoxin-producing Helicobacter pylori is associated with PD [96], and eradication of H. pylori improved PD symptoms [97, 98].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [96] Shen X, Yang H, Wu Y, et al. Meta-analysis: association of Helicobacter pylori infection with Parkinson’s diseases. Helicobacter. 2017;22. https://doi.org/10.1111/hel.12398 . source

      Not checked in the free run.

    • cites [97] Rees K, Stowe R, Patel S, Ives N, Breen K, Clarke CE, Ben‐Shlomo Y. Helicobacter pylori eradication for Parkinson's disease. Cochrane Database Syst Rev. 2011;11:CD008453. source

      Not checked in the free run.

    • cites [98] Liu H, Su W, Li S, et al. Eradication of Helicobacter pylori infection might improve clinical status of patients with Parkinson’s disease, especially on bradykinesia. Clin Neurol Neurosurg. 2017;160:101–4. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Brain endotoxin levels are increased two- or threefold in Alzheimer's disease patients, and endotoxin is also found in AD amyloid plaques.

    “Brain endotoxin levels are increased two- or threefold in AD patients [78, 79], and endotoxin is also found in AD amyloid plaques [79].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] Zhao Y, Jaber V, Lukiw WJ. Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): detection of lipopolysaccharide (LPS) in AD hippocampus. Front Cell Infect Microbiol. 2017;7:318. source

      Not checked in the free run.

    • cites [79] Zhan X, Stamova B, Jin L-W, et al. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology. 2016;87:2324–32. source

      Not checked in the free run.

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

    Interpretationreasoning

    It is still unclear that the cognitive deficits in sepsis are caused by endotoxin.

    “However, it is still unclear that the cognitive deficits are caused by the endotoxin”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Serious infections increase the risk of subsequently developing schizophrenia, and genetic risk factors for schizophrenia increase microglial phagocytosis of synapses, leading to the idea that schizophrenia is triggered by excessive microglial phagocytosis of synapses during adolescence, and one potential cause of this is increased endotoxin.

    “Serious infections increase the risk of subsequently developing schizophrenia [110], and genetic risk factors for schizophrenia increase microglial phagocytosis of synapses [111], leading to the idea that schizophrenia is triggered by excessive microglial phagocytosis of synapses during adolescence [111], and one potential cause of this is increased endotoxin.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [110] Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am J Psychiatry. 2011;168:1303–10. source

      Not checked in the free run.

    • cites [111] Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Daly MJ, Carroll MC, Stevens B, McCarroll SA. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530:177–83. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Whether neurodegenerative disease is caused by increased endotoxin is not known.

    “whether neurodegenerative disease is caused by increased endotoxin is not known”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Increased endotoxin can cause neurodegeneration.

    “increased endotoxin can cause neurodegeneration”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Testing the causal link between endotoxin and neurodegenerative disease depends on determining whether reducing endotoxin levels or endotoxin actions reduces neurodegenerative disease pathology.

    “Testing this causal link depends on determining whether reducing endotoxin levels or endotoxin actions reduces neurodegenerative disease pathology.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Blood ammonia levels correlate with hepatic encephalopathy.

    “although blood endotoxin levels correlate with hepatic encephalopathy, so to do blood ammonia and cytokine levels, which are also potentially causal for the encephalopathy”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Jain L, Sharma BC, Sharma P, Srivastava S, Agrawal A, Sarin SK. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012;44:1027–31. source

      Not checked in the free run.

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

    Premisecitation

    Bacterial meningitis can be caused by gram-negative bacteria, such as Neisseria meningitidis, often resulting in long-term cognitive problems, and much of the pathology has been attributed to endotoxin.

    “Bacterial meningitis can be caused by gram-negative bacteria, such as Neisseria meningitidis, infecting the brain meninges, often resulting in long-term cognitive problems, and much of the pathology has been attributed to endotoxin [107].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Brandtzaeg P, van Deuren M. Classification and pathogenesis of meningococcal infections. Methods Mol Biol. 2012;799:21–35. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Addition of LPS to microglia or astrocytes in culture resulted in TDP-43 mislocalization and aggregation, and addition of peripheral LPS to TDP-43(A315T) transgenic mice resulted in TDP-43 aggregation in vivo.

    “Addition of LPS to microglia or astrocytes in culture resulted in TDP-43 mislocalization and aggregation, and addition of peripheral LPS to TDP-43(A315T) transgenic mice resulted in TDP-43 aggregation in vivo [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Correia AS, Patel P, Dutta K, Julien JP. Inflammation induces TDP-43 mislocalization and aggregation. PLoS One. 2015;10:e0140248. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic alcohol consumption and binge drinking increase serum endotoxin and cytokine levels, which might contribute to long-term cognitive deficits.

    “Chronic alcohol consumption and binge drinking increase serum endotoxin and cytokine levels [106], which might contribute to long-term cognitive deficits.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Bala S, Marcos M, Gattu A, Catalano D, Szabo G. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PLoS One. 2014;9:e96864. source

      Not checked in the free run.

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

    Interpretationreasoning

    It is still not known whether endotoxin causes hepatic encephalopathy.

    “so we still do not know whether endotoxin causes hepatic encephalopathy [114]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Jain L, Sharma BC, Sharma P, Srivastava S, Agrawal A, Sarin SK. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012;44:1027–31. source

      Not checked in the free run.

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

    Interpretationreasoning

    The key tests of the plasma endotoxin theory of neurodegeneration are (a) whether plasma endotoxin levels correlate with and/or precede neurodegeneration in relevant diseases, and (b) whether lowering plasma endotoxin levels in patients reduces subsequent neurodegeneration.

    “The key tests of the plasma endotoxin theory of neurodegeneration are the following: (a) do plasma endotoxin levels correlate with and/or precede neurodegeneration in relevant diseases, and (b) does lowering plasma endotoxin levels in patients reduce subsequent neurodegeneration.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Sepsis is most often caused by bacteria such as E. coli or Pseudomonas aeruginosa.

    “sepsis is most often caused by bacteria such as E. coli or Pseudomonas aeruginosa [113]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Widmann CN, Heneka MT. Long-term cerebral consequences of sepsis. Lancet Neurol. 2014;13:630–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIV infection can progress to HIV-associated dementia, and this correlates with plasma endotoxin levels, which may drive monocyte activation and trafficking into the brain.

    “HIV infection can progress to HIV-associated dementia, and this correlates with plasma endotoxin levels, which may drive monocyte activation and trafficking into the brain [105].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Ancuta P, Kamat A, Kunstman KJ, Kim EY, Autissier P, Wurcel A, Zaman T, Stone D, Mefford M, Morgello S, Singer EJ, Wolinsky SM, Gabuzda D. Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS One. 2008;3:e2516. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single pre-natal exposure to LPS or early post-natal exposure can result in long-term activation of brain microglia, lasting into adulthood, and behavioural deficits reminiscent of autism or schizophrenia.

    “A single pre-natal exposure to LPS (of embryos, for example as a result of maternal infection) or early post-natal exposure can result in long-term activation of brain microglia, lasting into adulthood [108], and behavioural deficits reminiscent of autism or schizophrenia [109].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [108] O'Loughlin E, Pakan JMP, Yilmazer-Hanke D, McDermott KW. Acute in utero exposure to lipopolysaccharide induces inflammation in the pre- and postnatal brain and alters the glial cytoarchitecture in the developing amygdala. J Neuroinflammation. 2017;14:212. source

      Not checked in the free run.

    • cites [109] Custódio CS, Mello BSF, Filho AJMC, de Carvalho Lima CN, Cordeiro RC, Miyajima F, Réus GZ, Vasconcelos SMM, Barichello T, Quevedo J, de Oliveira AC, de Lucena DF, Macedo DS. Neonatal immune challenge with lipopolysaccharide triggers long-lasting sex- and age-related behavioral and immune/neurotrophic alterations in mice: relevance to autism spectrum disorders. Mol Neurobiol. 2018;55:3775–88.

      Not checked in the free run.

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

    Premisecitation

    Perinatal infections are associated with autism, potentially due to dysfunctional microglial phagocytosis of synapses, which could in principle be driven by endotoxin.

    “Perinatal infections are also associated with autism [109], potentially due to dysfunctional microglial phagocytosis of synapses [112], which could in principle be driven by endotoxin.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [109] Custódio CS, Mello BSF, Filho AJMC, de Carvalho Lima CN, Cordeiro RC, Miyajima F, Réus GZ, Vasconcelos SMM, Barichello T, Quevedo J, de Oliveira AC, de Lucena DF, Macedo DS. Neonatal immune challenge with lipopolysaccharide triggers long-lasting sex- and age-related behavioral and immune/neurotrophic alterations in mice: relevance to autism spectrum disorders. Mol Neurobiol. 2018;55:3775–88.

      Not checked in the free run.

    • cites [112] Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A, Gozzi A, Ragozzino D, Gross CT. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci. 2014;17:400–6. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This suggests a dual-hit hypothesis for ALS and FTD: increased endotoxin levels plus aggregable TDP-43 results in neurodegeneration.

    “This suggests a dual-hit hypothesis for ALS and FTD: increased endotoxin levels plus aggregable TDP-43 results in neurodegeneration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Correia AS, Patel P, Dutta K, Julien JP. Inflammation induces TDP-43 mislocalization and aggregation. PLoS One. 2015;10:e0140248. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    About half of patients with cirrhosis will develop long-term cognitive deficits, called hepatic encephalopathy, progressing from forgetfulness and confusion to coma.

    “About half of patients with cirrhosis will develop long-term cognitive deficits (called hepatic encephalopathy), progressing from forgetfulness and confusion to coma.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Jain L, Sharma BC, Sharma P, Srivastava S, Agrawal A, Sarin SK. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012;44:1027–31. source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationreasoning

    It is difficult to extrapolate from sepsis to other diseases because the causative bacteria have highly inflammatory LPS lipid A structures.

    “making it difficult to extrapolate to other diseases”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Blood ammonia and cytokine levels are also potentially causal for hepatic encephalopathy.

    “which are also potentially causal for the encephalopathy”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Jain L, Sharma BC, Sharma P, Srivastava S, Agrawal A, Sarin SK. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012;44:1027–31. source

      Not checked in the free run.

66 of 66

  • The paper relies on this without support.

    Animal models of endotoxin-induced neurodegeneration are informative about human neurodegeneration.

    “It is not ethical to test this directly in humans, but this question has been tested in animals.”
    “Note, however, that (i) these levels of endotoxin would be lethal in humans; (ii) E. coli LPS is normally used in these studies, partly because it is the most inflammatory; and (iii) peripheral endotoxin can dramatically increase (‘priming’) or decrease (‘tolerance’) subsequent responses to inflammatory stimuli, including endotoxin, depending on the dose and timing [33, 47].”

  • The paper relies on this without support.

    Blood endotoxin levels reflect pathologically relevant exposure in the brain.

    “Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease.”
    “Blood and brain endotoxin levels are elevated in Alzheimer’s disease, which is accelerated by systemic infections, including gum disease.”

  • The paper relies on this without support.

    The liver is the main organ for clearing blood endotoxin.

    “The liver is the main organ for clearing blood endotoxin”
3 of 3

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?

  • Elevated blood LPS levels have been found in ALS patients, which may be attributable to gut inflammation and microbiota changes.

    “Elevated blood LPS levels have been found in ALS patients (51), which may be attributable to gut inflammation and microbiota changes (64).”

    From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [64]

  • The gut microbiota releases byproducts from the cell wall, such as endotoxins like LPS, which can act locally and may be present in the gut, gingiva, and skin, as well as other tissues, causing dysregulation of GBA signaling, or can cross the intestinal barrier to enter the circulatory system (metabolic endotoxemia).

    “The gut microbiota releases byproducts from the cell wall, such as endotoxins like LPS, which can act locally and may be present in the gut, gingiva, and skin, as well as other tissues, causing dysregulation of GBA signaling (64), or can cross the intestinal barrier to enter the circulatory system; this is called metabolic endotoxemia (65).”

    From Modulation of the gut–brain axis via the gut microbiota: a new era in treatment of amyotrophic lateral sclerosis (2023) · cites this paper as [64]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Van Oosten M, Rensen PC, Van Amersfoort ES, Van Eck M, Van Dam AM, Breve JJ, Vogel T, Panet A, Van Berkel TJ, Kuiper J. Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality. A new therapeutic approach to treat gram-negative sepsis. J Biol Chem. 2001;276:8820–4. · DOI · Paper page

Cited by

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Related

Authors
Brown, G. C.
Affiliations
University of Cambridge (GB)
Corresponding author
Brown, Guy C.
ORCID
Brown, Guy C.
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2019-09-13
Volume
16
Issue
1
Pages
180-180
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-019-1564-7
PMC
PMC6744684
OpenAlex
W2971383976
Cited by
457
References
116
Citations by year
2026: 31 · 2025: 65 · 2024: 99 · 2023: 77 · 2022: 71 · 2021: 74 · 2020: 37 · 2019: 2
FWCI
4.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
  • Apollo (cc-by)
Funders
  • Wellcome Trust (RG50995)
  • Innovative Medicines Initiative (115976)
  • Medical Research Council (MR/L010593)
  • Alzheimer’s Research UK (RG91100)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
lipopolysaccharide, neurodegeneration, neuroinflammation, microglial activation, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, gut microbiota, intestinal permeability, APOE ε4, amyloid-beta, tau aggregation, alpha-synuclein, TDP-43, synaptic loss, dopaminergic neurons, systemic infection, sepsis, AIDS, liver failure
MeSH terms
Animals, Endotoxins, Humans, Nerve Degeneration, Neurodegenerative Diseases

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

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

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