Gut microbiota in neurodegenerative disorders

  • Suparna Roy Sarkar
    Affiliations
    Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
    Search for articles by this author
  • Sugato Banerjee
    Correspondence
    Corresponding author at: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, India.
    Affiliations
    Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
    Search for articles by this author

      Highlights

      • Gut Brain interactions
      • Role of gut bacteria in Alzheimer's disease and possible therapeutics
      • Role of gut bacteria in Parkinson's disease and possible therapeutics
      • Role of gut bacteria in Multiple Sclerosis and possible therapeutics
      • Role of gut bacteria in Amyloid lateral sclerosis

      Abstract

      Gut dysbiosis, a primary factor behind various gastrointestinal disorders may also augment lipopolysaccharides, pro-inflammatory cytokines, T helper cells and monocytes causing increased intestinal and BBB permeability via microbiota-gut-brain axis. Consequentially, accumulation of misfolded proteins, axonal damage and neuronal demyelination sets in, thus facilitating the pathogenesis of neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. Studies revealed that intake of probiotics may help in the integrity of intestinal and BBB thus ameliorating the above neurodegenerative disorders. This review summarizes the current understanding of the role of gut microbiota in neurodegenerative disorders and possible intervention strategies.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Neuroimmunology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Akbari E.
        • Asemi Z.
        • Daneshvar Kakhaki R.
        • Bahmani F.
        • Kouchaki E.
        • Tamtaji O.R.
        • Hamidi G.A.
        • Salami M.
        Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: a randomized, double-blind and controlled trial.
        Front. Aging Neurosci. 2016; 8: 256
        • Alzheimer's Disease Fact Sheet National Institute on Aging
        • U.S. Department of Health and Human Services
        • Arpaia N.
        • Campbell C.
        • Fan X.
        • Dikiy S.
        • van der Veeken J.
        • Liu H.
        • Cross J.R.
        • Pfeffer K.
        • Coffer P.J.
        • Rudensky A.Y.
        Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.
        Nature. 2013; 504: 451-455
        • Arumugam M.
        • Raes J.
        • Pelletier E.
        • Le Paslier D.
        • Yamada T.
        • Mende D.R.
        • Fernandes G.R.
        • Tap J.
        • Bruls T.
        • Batto J.M.
        • Bertalan M.
        • Borruel N.
        • Casellas F.
        • Fernandez L.
        • Gautier L.
        • Hansen T.
        • Hattori M.
        • Hayashi T.
        • Kleerebezem M.
        • Kurokawa K.
        • Leclerc M.
        • Levenez F.
        • Manichanh C.
        • Nielsen H.B.
        • Nielsen T.
        • Pons N.
        • Poulain J.
        • Qin J.
        • Sicheritz-Ponten T.
        • Tims S.
        • Torrents D.
        • Ugarte E.
        • Zoetendal E.G.
        • Wang J.
        • Guarner F.
        • Pedersen O.
        • de Vos W.M.
        • Brunak S.
        • Doré J.
        • Antolín M.
        • Artiguenave F.
        • Blottiere H.M.
        • Almeida M.
        • Brechot C.
        • Cara C.
        • Chervaux C.
        • Cultrone A.
        • Delorme C.
        • Denariaz G.
        • Dervyn R.
        • Foerstner K.U.
        • Friss C.
        • van de Guchte M.
        • Guedon E.
        • Haimet F.
        • Huber W.
        • van Hylckama-Vlieg J.
        • Jamet A.
        • Juste C.
        • Kaci G.
        • Knol J.
        • Lakhdari O.
        • Layec S.
        • Le Roux K.
        • Maguin E.
        • Mérieux A.
        • Melo Minardi R.
        • M'rini C.
        • Muller J.
        • Oozeer R.
        • Parkhill J.
        • Renault P.
        • Rescigno M.
        • Sanchez N.
        • Sunagawa S.
        • Torrejon A.
        • Turner K.
        • Vandemeulebrouck G.
        • Varela E.
        • Winogradsky Y.
        • Zeller G.
        • Weissenbach J.
        • Ehrlich S.D.
        • Bork P.
        Enterotypes of the human gut microbiome.
        Nature. 2011; 473: 174-180
        • Asti A.
        • Gioglio L.
        Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation?.
        J. Alzheimers Dis. 2014; 39: 169-179
        • Bäckhed F.
        Programming of host metabolism by the gut microbiota.
        Ann. Nutr. Metab. 2011; 58: 44-52
        • Belkaid Y.
        • Hand T.W.
        Role of the microbiota in immunity and inflammation.
        Cell. 2014; 157: 121-141
        • Belmaker R.H.
        • Agam G.
        Major depressive disorder.
        N. Engl. J. Med. 2008; 358: 55-68
        • Bengmark S.
        Gut microbiota, immune development and function.
        Pharmacol. Res. 2013; 69: 87-113
        • Bhargava P.
        • Mowry E.M.
        Gut Microbiome and Multiple Sclerosis.
        Curr. Neurol. Neurosci. Rep. 2014; 14: 492
        • Biagi E.
        • Nylund L.
        • Candela M.
        • Ostan R.
        • Bucci L.
        • Pini E.
        • Nikila J.
        • Monti D.
        • Satakori R.
        • Franeschi C.
        • Brigidi P.
        Through Ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians.
        PLoS One. 2010; 5e10667
        • Block M.L.
        • Zecca L.
        • Hong J.S.
        Microglia-mediated neurotoxicity uncovering the molecular mechanisms.
        Nat. Rev. Neurosci. 2007; 8: 57-69
        • Braak H.
        • Del Tredici K.
        • Rüb U.
        • de Vos R.A.
        • Jansen Steur E.N.
        • Braak E.
        Staging of brain pathology related to sporadic Parkinson's disease.
        Neurobiol. Aging. 2003; 24: 197-211
        • Braak H.
        • de Vos R.A.
        • Bohl J.
        • Del Tredici K.
        Gastric α-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology.
        Neurosci. Lett. 2006; 396: 67-72
        • Brenner S.R.
        Blue-green algae or cyanobacteria in the intestinal micro-flora may produce neurotoxins such as Beta-N-Methylamino-L-Alanine (BMAA) which may be related to development of amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson-Dementia-complex in humans and Equine Motor Neuron Disease in horses.
        Med. Hypotheses. 2013; 80: 103
        • Çamcı G.
        • Oğuz S.
        Association between Parkinson's disease and Helicobacter Pylori.
        J. Clin. Neurol. 2016; 12: 147-150
        • Cantarel B.L.
        • Waubant E.
        • Chehoud C.
        • Kuczynski J.
        • DeSantis T.Z.
        • Warrington J.
        • Venkatesan A.
        • Fraser C.M.
        • Mowry E.M.
        Gut microbiota in multiple sclerosis: possible influence of immunomodulators.
        J. Investig. Med. 2015; 63: 729-734
        • Cassani E.
        • Privitera G.
        • Pezzoli G.
        • Pusani C.
        • Madio C.
        • Iorio L.
        • Barichella M.
        Use of probiotics for the treatment of constipation in Parkinson's disease patients.
        Minerva Gastroenterol. Dietol. 2011; 57: 117-121
        • Catanzaro R.
        • Anzalone M.
        • Calabrese F.
        • Milazzo M.
        • Capuana M.
        • Italia A.
        • Occhipinti S.
        • Marotta F.
        The gut microbiota and its correlations with the central nervous system disorders.
        Panminerva Med. 2015; 57: 127-143
        • Cattaneo A.
        • Cattane N.
        • Galluzzi S.
        • Provasi S.
        • Lopizzo N.
        • Festari C.
        • Ferrari C.
        • Guerra U.P.
        • Paghera B.
        • Muscio C.
        • Bianchetti A.
        Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly.
        Neurobiol. Aging. 2017; 49: 60-68
        • Cekanaviciute E.
        • Debelius J.W.
        • Singh S.
        • Runia T.
        • Nelson C.
        • Yoo B.
        • Kanner R.
        • Crabtree-Hartman E.
        • Mazmanian S.
        • Knight R.
        • Katz Sand I.
        Gut dysbiosis is a feature of MS and it is characterized by bacteria able to regulate lymphocyte differentiation in vitro.
        Mult. Scler. J. 2016; 22: 58-59
        • Cersosimo M.G.
        • Raina G.B.
        • Pecci C.
        • Pellene A.
        • Calandra C.R.
        • Gutiérrez C.
        • Micheli F.E.
        • Benarroch E.E.
        Gastrointestinal manifestations in Parkinson's disease: prevalence and occurrence before motor symptoms.
        J. Neurol. 2013; 260: 1332-1338
        • Chen H.
        • O'Reilly E.J.
        • Schwarzschild M.A.
        • Ascherio A.
        Peripheral inflammatory biomarkers and risk of Parkinson's disease.
        Am. J. Epidemiol. 2007; 167: 90-95
        • Chen J.
        • Chia N.
        • Kalari K.R.
        • Yao J.Z.
        • Novotna M.
        • Soldan M.M.P.
        • Luckey D.H.
        • Marietta E.V.
        • Jeraldo P.R.
        • Chen X.
        • Weinshenker B.G.
        • Rodriguez M.
        • Kantarci O.H.
        • Nelson H.
        • Muray A.J.
        • Mangalam A.K.
        Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls.
        Sci. Rep. 2016; 6: 28484
        • Chung H.
        • Kasper D.L.
        Microbiota-stimulated immune mechanisms to maintain gut homeostasis.
        Curr. Opin. Immunol. 2010; 22: 455-460
        • Clairembault T.
        • Leclair-Visonneau L.
        • Coron E.
        • Bourreille A.
        • Le Dily S.
        • Vavasseur F.
        • Heymann M.F.
        • Neunlist M.
        • Derkinderen P.
        Structural alterations of the intestinal epithelial barrier in Parkinson's disease.
        Acta Neuropathol. Commun. 2015; 3: 1
        • Collins S.M.
        • Bercik P.
        The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease.
        Gastroenterology. 2009; 136: 2003-2014
        • Compston A.
        • Coles A.
        Multiple sclerosis.
        Lancet. 2008; 372: 1502-1517
        • Dickson D.W.
        • Fujishiro H.
        • Orr C.
        • DelleDonne A.
        • Josephs K.A.
        • Frigerio R.
        • Burnett M.
        • Parisi J.E.
        • Klos K.J.
        • Ahlskog J.E.
        Neuropathology of nonmotor features of Parkinson disease.
        Parkinsonism Relat. Disord. 2009; 15: S1-S5
        • Dobbs R.J.
        • Charlett A.
        • Purkiss A.G.
        • Dobbs S.M.
        • Weller C.
        • Peterson D.W.
        Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism.
        Acta Neurol. Scand. 1999; 100: 34-41
        • Doens D.
        • Fernández P.L.
        Microglia receptors and their implications in the response to amyloid β for Alzheimer's disease pathogenesis.
        J. Neuroinflammation. 2014; 11: 48
        • Dorca-Arévalo J.
        • Soler-Jover A.
        • Gibert M.
        • Popoff M.R.
        • Martín- Satué, M., Blasi, J.
        Binding of epsilon-toxin from Clostridium perfringens in the nervous system.
        Vet. Microbiol. 2008; 131: 14-25
        • Dutta G.
        • Zhang P.
        • Liu B.
        The lipopolysaccharide Parkinson's disease animal model: mechanistic studies and drug discovery.
        Fundam. Clin. Pharmacol. 2008; 22: 453-464
        • Eckburg P.B.
        • Bik E.M.
        • Bernstein C.N.
        • Purdom E.
        • Dethlefsen L.
        • Sargent M.
        • Gill S.R.
        • Nelson K.E.
        • Relman D.A.
        Diversity of the human intestinal microbial flora.
        Science. 2005; 308: 1635-1638
        • Edwards L.L.
        • Quigley E.M.
        • Pfeiffer R.F.
        Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology.
        Neurology. 1992; 42: 726-732
        • El Kaoutari A.
        • Armougom F.
        • Gordon J.I.
        • Raoult D.
        • Henrissat B.
        The abundance and variety of carbohydrate active enzymes in the human gut microbiota.
        Nat. Rev. Microbiol. 2013; 11: 497-504
        • Elahy M.
        • Jackaman C.
        • Mamo J.C.
        • Lam V.
        • Dhaliwal S.S.
        • Giles C.
        • Nelson D.
        • Takechi R.
        Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment.
        Immun. Ageing. 2015; 12: 2
        • Ezendam J.
        • De Klerk A.
        • Gremmer E.R.
        • Van Loveren H.
        Effects of Bifidobacterium animalis administered during lactation on allergic and autoimmune responses in rodents.
        Clin. Exp. Immunol. 2008; 154: 424-431
        • Fang X.
        Potential role of gut microbiota and tissue barriers in Parkinson's disease and amyotrophic lateral sclerosis.
        Int. J. Neurosci. 2015; 126: 771-776
        • Fang X.
        • Wang X.
        • Yang S.
        • Meng F.
        • Wang X.
        • Wei H.
        • Chen T.
        Evaluation of the microbial diversity in amyotrophic lateral sclerosis using high-throughput sequencing.
        Front. Microbiol. 2016; 7: 1479
        • Fasano A.
        • Bove F.
        • Gabrielli M.
        • Petracca M.
        • Zocco M.A.
        • Ragazzoni E.
        • Barbaro F.
        • Piano C.
        • Fortuna S.
        • Tortora A.
        • Di Giacopo R.
        The role of small intestinal bacterial overgrowth in Parkinson's disease.
        Mov. Disord. 2013; 28: 1241-1249
        • Finnie J.W.
        • Blumbergs P.C.
        • Manavis J.
        Neuronal damage produced in rat brains by Clostridium perfringens type D epsilon toxin.
        J. Comp. Pathol. 1999; 120: 415-420
        • Forster C.
        Tight junctions and the modulation of barrier function in disease.
        Histochem. Cell Biol. 2008; 130: 55-70
        • Forsyth C.B.
        • Shannon K.M.
        • Kordower J.H.
        • Voigt R.M.
        • Shaikh M.
        • Jaglin J.A.
        • Estes J.D.
        • Dodiya H.B.
        • Keshavarzian A.
        Increased intestinal permeability correlates with sigmoid mucosa alphasynuclein staining and endotoxin exposure markers in early Parkinson's disease.
        PLoS One. 2011; 6e28032
        • Forsythe P.
        • Sudo N.
        • Dinan T.
        • Taylor V.H.
        • Bienenstock J.
        Mood and gut feelings.
        Brain Behav. Immun. 2009; 24: 9-16
        • Forsythe P.
        • Bienenstock J.
        • Kunze W.A.
        Vagal pathways for microbiome-braingut axis communication.
        Adv. Exp. Med. Biol. 2014; 817: 115-133
        • Fouhy F.
        • Ross R.P.
        • Fitzgerald G.F.
        • Stanton C.
        • Cotter P.D.
        Composition of the early intestinal microbiota: knowledge, knowledge gaps and the use of high-throughput sequencing to address these gaps.
        Gut Microbes. 2012; 3: 203-220
        • Franceschi C.
        Inflammaging as a major characteristic of old people: can it be prevented or cured?.
        Nutr. Rev. 2007; 65: S173-S176
        • Franceschi C.
        • Bonafè M.
        • Valensin S.
        • Olivieri F.
        • De Luca M.
        • Ottaviani E.
        • De Benedictis G.
        Inflamm-aging: an evolutionary perspective on immunosenescence.
        Ann. N. Y. Acad. Sci. 2000; 908: 244-254
        • Frank D.
        • St Amand A.
        • Feldman R.
        • Boedeker E.
        • Harpaz N.
        • Pace N.
        Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases.
        Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 13780-13785
        • Freedman S.N.
        • Shahi S.K.
        • Mangalam A.K.
        The “gut feeling”: breaking down the role of gut microbiome in multiple sclerosis.
        Neurotherapeutics. 2018; : 1-7
        • Friedland R.P.
        Mechanisms of molecular mimicry involving the microbiota in neurodegeneration.
        J. Alzheimers Dis. 2015; 45: 349-362
        • Garbuzova-Davis S.
        • Sanberg P.R.
        Blood-CNS barrier impairment in ALS patients versus an animal model.
        Front. Cell. Neurosci. 2014; 8: 21
        • Gareau M.G.
        • Wine E.
        • Rodrigues D.M.
        • Cho J.H.
        • Whary M.T.
        • Philpott D.J.
        • Macqueen G.
        • Sherman P.M.
        Bacterial infection causes stress-induced memory dysfunction in mice.
        Gut. 2011; 60: 307-317
        • Girolamo F.
        • Coppola C.
        • Ribatti D.
        Immunoregulatory effect of mast cells influenced by microbes in neurodegenerative diseases.
        Brain Behav. Immun. 2017; 65: 68-89
        • Guarner F.
        • Malagelada J.R.
        Gut flora in health and disease.
        Lancet. 2003; 361: 512-519
        • Guinane C.M.
        • Cotter P.D.
        Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ.
        Ther. Adv. Gastroenterol. 2013; 6: 295-308
        • Guo S.
        • Al-Sadi R.
        • Said H.M.
        • Ma T.Y.
        Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR-4 and CD14.
        Am. J. Pathol. 2013; 182: 375-387
        • Heneka M.T.
        • Carson M.J.
        • El Khoury J.
        • Landreth G.E.
        • Brosseron F.
        • Feinstein D.L.
        • Jacobs A.H.
        • Wyss-Coray T.
        • Vitorica J.
        • Ransohoff R.M.
        • Herrup K.
        Neuroinflammation in Alzheimer's disease.
        Lancet Neurol. 2015; 14: 388-405
        • Hu X.
        • Wang T.
        • Jin F.
        Alzheimer's disease and gut microbiota.
        Sci. China Life Sci. 2016; 59: 1006-1023
        • Hughes L.E.
        • Smith P.A.
        • Bonell S.
        • Natt R.S.
        • Wilson C.
        • Rashid T.
        • Amor S.
        • Thompson E.J.
        • Croker J.
        • Ebringer A.
        Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis.
        J. Neuroimmunol. 2003; 144: 105-115
        • Itzhaki R.F.
        • Lathe R.
        • Balin B.J.
        • Ball M.J.
        • Bearer E.L.
        • Braak H.
        • Bullido M.J.
        • Carter C.
        • Clerici M.
        • Cosby S.L.
        • Del Tredici K.
        Microbes and Alzheimer's disease.
        J. Alzheimers Dis. 2016; 51: 979-984
        • Jangi S.
        • Gandhi R.
        • Cox L.M.
        • Li N.
        • Von Glehn F.
        • Yan R.
        • Patel B.
        • Mazzola M.A.
        • Liu S.
        • Glanz B.L.
        • Cook S.
        Alterations of the human gut microbiome in multiple sclerosis.
        Nat. Commun. 2016; 7: 12015
        • Jiang C.
        • Li G.
        • Huang P.
        • Liu Z.
        • Zhao B.
        The gut microbiota and Alzheimer's disease.
        J. Alzheimers Dis. 2017; 58: 1-5
        • Joshi D.
        • Roy S.
        • Banerjee S.
        Prebiotics: a functional food in health and disease.
        in: Mandal S.C. Mandal V. Konishi T. Natural Products & Drug Discovery. Elsevier, Amsterdam2018: 507-523
        • Karlsson O.
        • Roman E.
        • Berg A.L.
        • Brittebo E.B.
        Early hippocampal cell death, and late learning and memory deficits in rats exposed to the environmental toxin BMAA (β-N-methylamino-L-alanine) during the neonatal period.
        Behav. Brain Res. 2011; 219: 310-320
        • Keshavazian A.
        • Green S.J.
        • Engen P.A.
        • Voigt R.M.
        • Naqib A.
        • Forsyth C.B.
        • Mutlu E.
        • Shanon K.M.
        Colonic bacterial composition in Parkinson's Disease.
        Mov. Disord. 2015; 30: 1351-1360
        • Kieburtz K.
        • Wunderle K.B.
        Parkinson's disease: evidence for environmental risk factors.
        Mov. Disord. 2013; 28: 8-13
        • Kwon H.K.
        • Kim G.C.
        • Kim Y.
        • Hwang W.
        • Jash A.
        • Sahoo A.
        • Kim J.E.
        • Nam J.H.
        • Im S.H.
        Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response.
        Clin. Immunol. 2013; 146: 217-227
        • Lavasani S.
        • Dzhambazov B.
        • Nouri M.
        • Fåk F.
        • Buske S.
        • Molin G.
        • Thorlacius H.
        • Alenfall J.
        • Jeppsson B.
        • Weström B.
        A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells.
        PLoS One. 2010; 5e9009
        • Lei E.
        • Vacy K.
        • Boon W.C.
        Fatty acids and their therapeutic potential in neurological disorders.
        Neurochem. Int. 2016; 95: 75-84
        • Ley R.
        • Turnbaugh P.
        • Klein S.
        • Gordon J.
        Microbial ecology: human gut microbes associated with obesity.
        Nature. 2006; 444: 1022-1023
        • Liang S.
        • Wang T.
        • Hu X.
        • Luo J.
        • Li W.
        • Wu X.
        • Duan Y.
        • Jin F.
        Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress.
        Neuroscience. 2015; 310: 561-577
        • Lien E.
        • Means T.K.
        • Heine H.
        • Yoshimura A.
        • Kusumoto S.
        • Fukase K.
        • Fenton M.J.
        • Oikawa M.
        • Qureshi N.
        • Monks B.
        • Finberg R.W.
        Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide.
        J. Clin. Invest. 2000; 105: 497-504
        • Liu Y.
        • Walter S.
        • Stagi M.
        • Cherny D.
        • Letiembre M.
        • Schulz-Schaeffer W.
        • Heine H.
        • Penke B.
        • Neumann H.
        • Fassbender K.
        LPS receptor (CD14): a receptor for phagocytosis of Alzheimer's amyloid peptide.
        Brain. 2005; 128: 1778-1789
        • Lonchamp E.
        • Dupont J.L.
        • Wioland L.
        • Courjaret R.
        • Mbebi-Liegeois C.
        • Jover E.
        • Doussau F.
        • Popoff M.R.
        • Bossu J.L.
        • De Barry J.
        • Poulain B.
        Clostridium perfringens epsilon toxin targets granule cells in the mouse cerebellum and stimulates glutamate release.
        PLoS One. 2010; 5e13046
        • Lukiw W.J.
        Bacteroides fragilis lipopolysaccharide and inflammatory signaling in Alzheimer's disease.
        Front. Microbiol. 2016; 7: 1544
        • Maassen C.B.
        • Claassen E.
        Strain-dependent effects of probiotic lactobacilli on EAE autoimmunity.
        Vaccine. 2008; 26: 2056-2057
        • Marques T.M.
        • Wall R.
        • Ross R.P.
        • Fitzgerald G.F.
        • Ryan C.A.
        • Stanton C.
        Programming infant gut microbiota: influence of dietary and environmental factors.
        Curr. Opin. Biotechnol. 2010; 21: 149-156
        • Mete A.
        • Garcia J.
        • Ortega J.
        • Lane M.
        • Scholes S.
        • Uzal F.A.
        Brain lesions associated with Clostridium perfringens type D epsilon toxin in a Holstein heifer calf.
        Vet. Pathol. 2013; 50: 765-768
        • Miyake S.
        • Kim S.
        • Suda W.
        • Oshima K.
        • Nakamura M.
        • Matsuoka T.
        • Chihara N.
        • Tomita A.
        • Sato W.
        • Kim S.W.
        • Morita H.
        • Hattori M.
        • Yamamura T.
        Dysbiosis in the Gut Microbiota of patients with Multiple Sclerosis, with a striking Depletion of Species Belonging to Clostridia XIVa and IV Clusters.
        PLoS One. 2015; 10e0137429
        • Möhle L.
        • Mattei D.
        • Heimesaat M.M.
        • Bereswill S.
        • Fischer A.
        • Alutis M.
        • French T.
        • Hambardzumyan D.
        • Matzinger P.
        • Dunay I.R.
        • Wolf S.A.
        Ly6Chi monocytes provide a link between antibiotic-induced changes in gut microbiota and adult hippocampal neurogenesis.
        Cell Rep. 2016; 15: 1945-1956
        • Mowry E.M.
        • Glenn J.D.
        The dynamics of the gut microbiome in multiple sclerosis in relation to disease.
        Neurol. Clin. 2018; 36: 185-196
        • Mowry E.M.
        • Waubant E.
        • Chehoud C.
        • DeSantis T.
        • Kuczynski J.
        • Warrington J.
        Gut bacterial populations in multiple sclerosis and in health.
        Neurology. 2012; 78: P05.106
        • Mulak A.
        • Bonaz B.
        Brain-gut-microbiota axis in Parkinson's disease.
        World J. Gastroenterol. 2015; 21: 10609-10620
        • Nair A.T.
        • Ramachandran V.
        • Joghee N.M.
        • Antony S.
        • Ramalingam G.
        Gut Microbiota Dysfunction as Reliable Non-invasive early Diagnostic Biomarkers in the Pathophysiology of Parkinson's disease: a critical Review.
        J. Neurogastroenterol. Motil. 2018; 24: 30-42
        • Niehaus I.
        • Lange J.H.
        Endotoxin: is it an environmental factor in the cause of Parkinson's disease?.
        Occup. Environ. Med. 2003; 60: 378
        • Noseworthy J.H.
        • Lucchinetti C.
        • Rodriguez M.
        • Weinshenker B.G.
        Multiple sclerosis.
        N. Engl. J. Med. 2000; 343: 938-952
        • Ouwehand A.C.
        • Bergsma N.
        • Parhiala R.
        • Lahtinen S.
        • Gueimonde M.
        • Finne-Soveri H.
        • Strandberg T.
        • Pitkälä K.
        • Salminen S.
        Bifidobacterium microbiota and parameters of immune function in elderly subjects.
        FEMS Immunol. Med. Microbiol. 2008; 53: 18-25
        • Parashar A.
        • Udayabanu M.
        Gut microbiota: implications in Parkinson's disease.
        Parkinsonism Relat. Disord. 2017; 38: 1-7
        • Pistollato F.
        • Sumalla Cano S.
        • Elio I.
        • Masias Vergara M.
        • Giampieri F.
        • Battino M.
        Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease.
        Nutr. Rev. 2016; 74: 624-634
        • Pompei A.
        • Cordisco L.
        • Amaretti A.
        • Zanoni S.
        • Matteuzzi D.
        • Rossi M.
        Folate production by bifidobacteria as a potential probiotic property.
        Appl. Environ. Microbiol. 2007; 73: 179-185
        • Pryde S.E.
        • Duncan S.H.
        • Hold G.L.
        • Stewart C.S.
        • Flint H.J.
        The microbiology of butyrate formation in the human colon.
        FEMS Microbiol. Lett. 2002; 217: 133-139
        • Qin J.
        • Li R.
        • Raes J.
        • Arumugam M.
        • Burgdorf K.S.
        • Manichanh C.
        • Nielsen T.
        • Pons N.
        • Levenez F.
        • Yamada T.
        • Mende D.R.
        A human gut microbial gene catalogue established by metagenomic sequencing.
        Nature. 2010; 464: 59-65
        • Quigley E.M.
        Gut bacteria in health and disease.
        Gastroenterol. Hepatol. (NY). 2013; 9: 560-569
        • Quigley E.M.
        Microbiota-brain-gut axis and neurodegenerative diseases.
        Curr. Neurol. Neurosci. Rep. 2017; 17: 94
        • Ransohoff R.M.
        How neuroinflammation contributes to neurodegeneration.
        Science. 2016; 353: 777-783
        • Reale M.
        • Iarlori C.
        • Thomas A.
        • Gambi D.
        • Perfetti B.
        • Di Nicola M.
        • Onofrj M.
        Peripheral cytokines profile in Parkinson's disease.
        Brain Behav. Immun. 2009; 23: 55-63
        • Ríos-Covián D.
        • Ruas-Madiedo P.
        • Margolles A.
        • Gueimonde M.
        • de Los Reyes-Gavilán C.G.
        • Salazar N.
        Intestinal short chain fatty acids and their link with diet and human health.
        Front. Microbiol. 2016; 7: 185
        • Rite I.
        • Machado A.
        • Cano J.
        • Venero J.L.
        Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons.
        J. Neurochem. 2007; 101: 1567-1582
        • Rumah K.R.
        • Linden J.
        • Fischetti V.A.
        • Vartanian T.
        Isolation of Clostridium perfringens type B in an individual at first clinical presentation of multiple sclerosis provides clues for environmental triggers of the disease.
        PLoS One. 2013; 8e76359
        • Savica R.
        • Carlin J.M.
        • Grossardt B.R.
        • Bower J.H.
        • Ahlskog J.E.
        • Maraganore D.M.
        • Bharucha A.E.
        • Rocca W.A.
        Medical records documentation of constipation preceding Parkinson disease a case-control study.
        Neurology. 2009; 73: 1752-1758
        • Savignac H.M.
        • Tramullas M.
        • Kiely B.
        • Dinan T.G.
        • Cryan J.F.
        Bifidobacteria modulate cognitive processes in an anxious mouse strain.
        Behav. Brain Res. 2015; 287: 59-72
        • Scheperjans F.
        • Aho V.
        • Pereira P.A.
        • Koskinen K.
        • Paulin L.
        • Pekkonen E.
        • Haapaniemi E.
        • Kaakkola S.
        • Eerola-Rautio J.
        • Pohja M.
        • Kinnunen E.
        Gut microbiota are related to Parkinson's disease and clinical phenotype.
        Mov. Disord. 2015; 30: 350-358
        • Schirmer M.
        • Smeekens S.P.
        • Vlamakis H.
        • Jaeger M.
        • Oosting M.
        • Franzosa E.A.
        • Horst R.T.
        • Jansen T.
        • Jacobs L.
        • Bonder M.J.
        • Kurilshikov A.
        Linking the human gut microbiome to inflammatory cytokine production capacity.
        Cell. 2016; 167: 1125-1136
        • Sekirov I.
        • Russell S.L.
        • Antunes L.C.
        • Finlay B.B.
        Gut microbiota in health and disease.
        Physiol. Rev. 2010; 90: 859-904
        • Shahi S.K.
        • Freedman S.N.
        • Mangalam A.K.
        Gut microbiome in multiple sclerosis: the players involved and the roles they play.
        Gut Microbes. 2017; 8: 607-615
        • Shannon K.M.
        • Keshavarzian A.
        • Dodiya H.B.
        • Jakate S.
        • Kordower J.H.
        Is alpha-synuclein in the colon a biomarker for premotor Parkinson's disease? Evidence from 3 cases.
        Mov. Disord. 2012; 27: 716-719
        • Sivieri K.
        • Morales M.L.V.
        • Adorno M.A.T.
        • Sakamoto I.K.
        • Saad S.M.I.
        • Rossi E.A.
        Lactobacillus acidophilus CRL 1014 improved "gut health" in the SHIME® reactor.
        BMC Gastroenterol. 2013; 13: 100
        • Stilling R.M.
        • Dinan T.G.
        • Cryan J.F.
        Microbial genes, brain & behaviour–epigenetic regulation of the gut–brain axis.
        Genes Brain Behav. 2014; 13: 69-86
        • Sui Y.T.
        • Bullock K.M.
        • Eickson M.A.
        • Zhang J.
        • Banks W.A.
        Alpha synuclein is transported into and out of the brain by the blood-brain barrier.
        Peptides. 2014; 62: 197-202
        • Surwase S.N.
        • Jadhav J.P.
        Bioconversion of L-tyrosine to L-DOPA by a novel bacterium Bacillus sp. JPJ.
        Amino Acids. 2011; 41: 495-506
        • Takata K.
        • Kinoshita M.
        • Okuno T.
        • Moriya M.
        • Kohda T.
        • Honorat J.A.
        • Sugimoto T.
        • Kumanogoh A.
        • Kayama H.
        • Takeda K.
        • Sakoda S.
        The lactic acid bacterium Pediococcus acidilactici suppresses autoimmune encephalomyelitis by inducing IL-10-producing regulatory T cells.
        PLoS One. 2011; 6e27644
        • Tan A.H.
        • Mahadeva S.
        • Thalha A.M.
        • Gibson P.R.
        • Kiew C.K.
        • Yeat C.M.
        • Ng S.W.
        • Ang S.P.
        • Chow S.K.
        • Tan C.T.
        • Yong H.S.
        Small intestinal bacterial overgrowth in Parkinson's disease.
        Parkinsonism Relat. Disord. 2014; 20: 535-540
        • Toepfer M.
        • Schroeder M.
        • Klauser A.
        • Lochmüller H.
        • Hirschmann M.
        • Riepl R.L.
        • Pongratz D.
        • Müller-Felber W.
        Delayed colonic transit times in amyotrophic lateral sclerosis assessed with radio-opaque markers.
        Eur. J. Med. Res. 1997; 2: 473-476
        • Tremlett H.
        • Fadrosh D.W.
        • Faruqi A.A.
        • Hart J.
        • Roalstad S.
        • Graves J.
        • Lynch S.
        • Waubant E.
        Gut microbiota composition and relapse risk in pediatric MS: a pilot study.
        J. Neurol. Sci. 2016; 363: 153-157
        • Tsuang D.
        • Leverenz J.B.
        • Lopez O.L.
        • Hamilton R.L.
        • Bennett D.A.
        • Schneider J.A.
        • Buchman A.S.
        • Larson E.B.
        • Crane P.K.
        • Kaye J.A.
        • Kramer P.
        • Woltjer R.
        • Trojanowski J.Q.
        • Weintraub D.
        • Chen-Plotkin A.S.
        • Irwin D.J.
        • Rick J.
        • Schellenberg G.D.
        • Watson G.S.
        • Kukull W.
        • Nelson P.T.
        • Jicha G.A.
        • Neltner J.H.
        • Galasko D.
        • Masliah E.
        • Quinn J.F.
        • Chung K.A.
        • Yearout D.
        • Mata I.F.
        • Wan J.Y.
        • Edwards K.L.
        • Montine T.J.
        • Zabetian C.P.
        APOE ε4 increases risk for dementia in pure synucleinopathies.
        JAMA Neurol. 2013; 70: 223-228
        • Tufekci K.U.
        • Genc S.
        • Genc K.
        The endotoxin-induced neuroinflammation model of Parkinson's disease.
        Parkinsons Dis. 2011; : 2011
        • Ulluwishewa D.
        • Anderson R.C.
        • McNabb W.C.
        • Moughan P.J.
        • Wells J.M.
        • Roy N.C.
        Regulation of tight junction permeability by intestinal bacteria and dietary components.
        J. Nutr. 2011; 141: 769-776
        • Vital M.
        • Howe A.C.
        • Tiedje J.M.
        Revealing the bacterial butyrate synthesis pathways by analyzing (meta) genomic data.
        MBio. 2014; 5: 1-11
        • Wang T.
        • Hu X.
        • Liang S.
        • Li W.
        • Wu X.
        • Wang L.
        • Jin F.
        Lactobacillus fermentum NS9 restores the antibiotic induced physiological and psychological abnormalities in rats.
        Benef Microbes. 2015; 6: 707-717
        • Wang I.K.
        • Wu Y.Y.
        • Yang Y.F.
        • Ting I.W.
        • Lin C.C.
        • Yen T.H.
        • Chen J.H.
        • Wang C.H.
        • Huang C.C.
        • Lin H.C.
        The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: a randomised, double-blind, placebo-controlled trial.
        Benef. Microbes. 2015; 6: 423-430
        • Wright M.L.
        • Fournier C.
        • Houser M.C.
        • Tansey M.
        • Glass J.
        • Hertzberg V.S.
        Potential role of the gut microbiome in ALS: a systematic review.
        Biol. Res. Nurs. 2018; : 1-9
        • Wu S.
        • Yi J.
        • Zhang Y.G.
        • Zhou J.
        • Sun J.
        Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model.
        Physiol. Rep. 2015; 3
        • Zhang L.S.
        • Davies S.S.
        Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions.
        Genome Med. 2016; 8: 46
        • Zhang Y.G.
        • Wu S.
        • Yi J.
        • Xia Y.
        • Jin D.
        • Zhou J.
        • Sun J.
        Target intestinal microbiota to alleviate disease progression in amyotrophic lateral sclerosis.
        Clin. Ther. 2017; 39: 322-336
        • Zhao Y.
        • Dua P.
        • Lukiw W.J.
        Microbial sources of amyloid and relevance to amyloidogenesis and Alzheimer's disease (AD).
        J. Alzheimers Dis. Parkinsonism. 2015; 5: 177-190
        • Zhou Y.
        • Lu Y.
        • Fang X.
        • Zhang J.
        • Li J.
        • Li S.
        • Deng X.
        • Yu Y.
        • Xu R.
        An astrocyte regenerative response from vimentin-containing cells in the spinal cord of amyotrophic lateral sclerosis's disease-like transgenic (G93A SOD1) mice.
        Neurodegener. Dis. 2015; 15: 1-12