The Role of the Gut Microbiota and Microbial Metabolites in the Pathogenesis
of Alzheimer’s Disease

Yi      Wang
Abstract

Alzheimer’s disease is a neurodegenerative disease that causes memory loss, cognitive dysfunction and dementia. It is a multifactorial disease involving a wide range of pathological factors that have yet to be fully understood. As proposed by scientists and supported by a growing amount of evidence in recent years, the gut microbiota plays an important role in the pathogenesis of Alzheimer’s disease via a constant bidirectional communication through the brain-gut-microbiota axis, which is a multifunctional network involving the nervous system and the peripheral circulatory system. This communication pathway facilitates the exchange of information and signals between the brain and the gut, such as microbe-derived metabolites and neurotransmitters, which allows gut microbes to influence the central nervous system. This review summarizes recent research findings on the pathological risk factors of Alzheimer’s disease, the brain-gut-microbiota axis, the role of gut microbe-derived products in neurological disorders, and clinical/preclinical studies investigating the role of the gut microbiota in Alzheimer’s disease. In addition, some suggestions for future research are proposed.
Keywords: Alzheimer’s disease, gut microbiota, central nervous system, brain-gut-microbiota axis, β-amyloid, prion.
Graphical Abstract

[1]
Reitz C, Mayeux R. Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers. Biochem Pharmacol  2014; 88(4): 640-51.
 [http://dx.doi.org/10.1016/j.bcp.2013.12.024] [PMID: 24398425]

[2]
Doulberis M, Kotronis G, Gialamprinou D, et al. Alzheimer’s disease and gastrointestinal microbiota; impact of Helicobacter pylori infection involvement. Int J Neurosci  2021; 131(3): 289-301.
 [PMID: 32125206]

[3]
Obrenovich M, Tabrez S, Siddiqui B, McCloskey B, Perry G. The microbiota-gut-brain axis-heart shunt part II: Prosaic foods and the brain-heart connection in Alzheimer disease. Microorganisms  2020; 8(4): 493.
 [http://dx.doi.org/10.3390/microorganisms8040493] [PMID: 32244373]

[4]
Sochocka M, Donskow-Łysoniewska K, Diniz BS, Kurpas D, Brzozowska E, Leszek J. The gut microbiome alterations and inflammation-driven pathogenesis of Alzheimer’s disease-a critical review. Mol Neurobiol  2019; 56(3): 1841-51.
 [http://dx.doi.org/10.1007/s12035-018-1188-4] [PMID: 29936690]

[5]
Ooms S, Overeem S, Besse K, Rikkert MO, Verbeek M, Claassen JA. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: A randomized clinical trial. JAMA Neurol  2014; 71(8): 971-7.
 [http://dx.doi.org/10.1001/jamaneurol.2014.1173] [PMID: 24887018]

[6]
Jouanne M, Rault S, Voisin-Chiret A-S. Tau protein aggregation in Alzheimer’s disease: An attractive target for the development of novel therapeutic agents. Eur J Med Chem  2017; 139: 153-67.
 [http://dx.doi.org/10.1016/j.ejmech.2017.07.070] [PMID: 28800454]

[7]
Köhler CA, Maes M, Slyepchenko A, et al. The gut-brain axis, including the microbiome, leaky gut and bacterial translocation: Mechanisms and pathophysiological role in Alzheimer’s disease. Curr Pharm Des  2016; 22(40): 6152-66.
 [http://dx.doi.org/10.2174/1381612822666160907093807] [PMID: 27604604]

[8]
Lee C D, Daggett A, Gu X, et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron  2018; 97(5): 1032-48.
 [http://dx.doi.org/10.1016/j.neuron.2018.02.002]

[9]
Kowalski K, Mulak A. Brain-gut-microbiota axis in Alzheimer’s disease. J Neurogastroenterol Motil  2019; 25(1): 48-60.
 [http://dx.doi.org/10.5056/jnm18087] [PMID: 30646475]

[10]
Pluta R, Ułamek-Kozioł M, Januszewski S, Czuczwar SJ. Gut microbiota and pro/prebiotics in Alzheimer’s disease. Aging (Albany NY)  2020; 12(6): 5539-50.
 [http://dx.doi.org/10.18632/aging.102930] [PMID: 32191919]

[11]
Khan MS, Ikram M, Park JS, Park TJ, Kim MO. Gut microbiota, its role in induction of Alzheimer’s disease pathology, and possible therapeutic interventions: Special focus on anthocyanins. Cells  2020; 9(4): 853.
 [http://dx.doi.org/10.3390/cells9040853] [PMID: 32244729]

[12]
Arriagada PV, Growdon JH, Hedley-Whyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer’s disease. Neurology  1992; 42(3 Pt 1): 631-9.
 [http://dx.doi.org/10.1212/WNL.42.3.631] [PMID: 1549228]

[13]
Johnson GV, Hartigan JA. Tau protein in normal and Alzheimer’s disease brain: An update. J Alzheimers Dis  1999; 1(4-5): 329-51.
 [http://dx.doi.org/10.3233/JAD-1999-14-512] [PMID: 12214129]

[14]
Zempel H, Thies E, Mandelkow E, Mandelkow E-M. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci  2010; 30(36): 11938-50.
 [http://dx.doi.org/10.1523/JNEUROSCI.2357-10.2010] [PMID: 20826658]

[15]
Hoover BR, Reed MN, Su J, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron  2010; 68(6): 1067-81.
 [http://dx.doi.org/10.1016/j.neuron.2010.11.030] [PMID: 21172610]

[16]
Wang X-L, Zeng J, Yang Y, et al. Helicobacter pylori filtrate induces Alzheimer-like tau hyperphosphorylation by activating glycogen synthase kinase-3β. J Alzheimers Dis  2015; 43(1): 153-65.
 [http://dx.doi.org/10.3233/JAD-140198] [PMID: 25079798]

[17]
Petra AI, Panagiotidou S, Hatziagelaki E, Stewart JM, Conti P, Theoharides TC. Gut-microbiota-brain axis and its effect on neuropsychiatric disorders with suspected immune dysregulation. Clin Ther  2015; 37(5): 984-95.
 [http://dx.doi.org/10.1016/j.clinthera.2015.04.002] [PMID: 26046241]

[18]
Dinan TG, Cryan JF. Gut instincts: Microbiota as a key regulator of brain development, ageing and neurodegeneration. J Physiol  2017; 595(2): 489-503.
 [http://dx.doi.org/10.1113/JP273106] [PMID: 27641441]

[19]
Askarova S, Umbayev B, Masoud A-R, et al. The links between the gut microbiome, aging, modern lifestyle and Alzheimer’s disease. Front Cell Infect Microbiol  2020; 10: 104.
 [http://dx.doi.org/10.3389/fcimb.2020.00104] [PMID: 32257964]

[20]
Quigley EMM. Microbiota-brain-gut axis and neurodegenerative diseases. Curr Neurol Neurosci Rep  2017; 17(12): 94.
 [http://dx.doi.org/10.1007/s11910-017-0802-6] [PMID: 29039142]

[21]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science  2002; 297(5580): 353-6.
 [http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]

[22]
De Strooper B. Proteases and proteolysis in Alzheimer disease: A multifactorial view on the disease process. Physiol Rev  2010; 90(2): 465-94.
 [http://dx.doi.org/10.1152/physrev.00023.2009] [PMID: 20393191]

[23]
Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci  2006; 26(27): 7212-21.
 [http://dx.doi.org/10.1523/JNEUROSCI.1450-06.2006] [PMID: 16822978]

[24]
Allen HB. Alzheimer’s disease: Assessing the role of spirochetes, biofilms, the immune system, and amyloid-β with regard to potential treatment and prevention. J Alzheimers Dis  2016; 53(4): 1271-6.
 [http://dx.doi.org/10.3233/JAD-160388] [PMID: 27372648]

[25]
Lim J-E, Kou J, Song M, et al. MyD88 deficiency ameliorates β-amyloidosis in an animal model of Alzheimer’s disease. Am J Pathol  2011; 179(3): 1095-103.
 [http://dx.doi.org/10.1016/j.ajpath.2011.05.045] [PMID: 21763676]

[26]
Chen GF, Xu TH, Yan Y, et al. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol Sin  2017; 38(9): 1205-35.
 [http://dx.doi.org/10.1038/aps.2017.28] [PMID: 28713158]

[27]
Zhao Y, Lukiw WJ. Microbiome-generated amyloid and potential impact on amyloidogenesis in Alzheimer’s disease (AD). J Nat Sci  2015; 1(7): e138.
 [PMID: 26097896]

[28]
Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature  2013; 501(7465): 45-51.
 [http://dx.doi.org/10.1038/nature12481] [PMID: 24005412]

[29]
Eisele YS. From soluble aβ to progressive aβ aggregation: Could prion-like templated misfolding play a role? Brain Pathol  2013; 23(3): 333-41.
 [http://dx.doi.org/10.1111/bpa.12049] [PMID: 23587139]

[30]
Karch CM, Cruchaga C, Goate AM. Alzheimer’s disease genetics: From the bench to the clinic. Neuron  2014; 83(1): 11-26.
 [http://dx.doi.org/10.1016/j.neuron.2014.05.041] [PMID: 24991952]

[31]
Liu C-C, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy. Nat Rev Neurol  2013; 9(2): 106-18.
 [http://dx.doi.org/10.1038/nrneurol.2012.263] [PMID: 23296339]

[32]
Efthymiou AG, Goate AM. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol Neurodegener  2017; 12(1): 43.
 [http://dx.doi.org/10.1186/s13024-017-0184-x] [PMID: 28549481]

[33]
Gandy S, Heppner FL. Microglia as dynamic and essential components of the amyloid hypothesis. Neuron  2013; 78(4): 575-7.
 [http://dx.doi.org/10.1016/j.neuron.2013.05.007] [PMID: 23719156]

[34]
Schellenberg GD, Montine TJ. The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol  2012; 124(3): 305-23.
 [http://dx.doi.org/10.1007/s00401-012-0996-2] [PMID: 22618995]

[35]
Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med  2013; 368(2): 117-27.
 [http://dx.doi.org/10.1056/NEJMoa1211851] [PMID: 23150934]

[36]
Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med  2013; 368(2): 107-16.
 [http://dx.doi.org/10.1056/NEJMoa1211103] [PMID: 23150908]

[37]
Sims R, Van der Lee SJ, Naj AC, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet  2017; 49(9): 1373-84.
 [http://dx.doi.org/10.1038/ng.3916] [PMID: 28714976]

[38]
Prusiner SB. Biology and genetics of prions causing neurodegeneration. Annu Rev Genet  2013; 47(1): 601-23.
 [http://dx.doi.org/10.1146/annurev-genet-110711-155524] [PMID: 24274755]

[39]
Lal R, Lin H, Quist AP. Amyloid beta ion channel: 3D structure and relevance to amyloid channel paradigm. Biochim Biophys Acta  2007; 1768(8): 1966-75.
 [http://dx.doi.org/10.1016/j.bbamem.2007.04.021] [PMID: 17553456]

[40]
Catalano SM, Dodson EC, Henze DA, Joyce JG, Krafft GA, Kinney GG. The role of Amyloid-beta Derived Diffusible Ligands (ADDLs) in Alzheimer’s disease. Curr Top Med Chem  2006; 6(6): 597-608.
 [http://dx.doi.org/10.2174/156802606776743066] [PMID: 16712494]

[41]
Haigh C. Doubling-down on prion protein function in Alzheimer’s disease. Sci Transl Med  2019; 11(499): eaay3567.
 [http://dx.doi.org/10.1126/scitranslmed.aay3567]

[42]
Walker LC. Prion-like mechanisms in Alzheimer disease. Handb Clin Neurol  2018; 153: 303-19.

[43]
Holtzman D M, Morris J C, Goate A M. Alzheimer’s disease: The challenge of the second century. Sci Transl Med  2011; 3(77): 77sr1.
 [http://dx.doi.org/10.1126/scitranslmed.3002369]

[44]
Aoyagi A, Condello C, Stöhr J, et al. Aβ and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain. Sci Transl Med  2019; 11(490): eaat8462.
 [http://dx.doi.org/10.1126/scitranslmed.aat8462] [PMID: 31043574]

[45]
Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology  2016; 17(1): 7-19.
 [http://dx.doi.org/10.1007/s10522-015-9578-8] [PMID: 25921609]

[46]
Cattaneo A, Cattane N, Galluzzi S, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging  2017; 49: 60-8.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2016.08.019] [PMID: 27776263]

[47]
Li C-Q, Zheng Q, Wang Q, Zeng Q-P. Biotic/abiotic stress-driven Alzheimer’s disease. Front Cell Neurosci  2016; 10: 269.
 [http://dx.doi.org/10.3389/fncel.2016.00269] [PMID: 27932953]

[48]
Perry VH, Teeling J. In Microglia and macrophages of the central nervous system: The contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol  2013; 35(5): 601-12.

[49]
Merezhko M, Muggalla P, Nykänen N-P, Yan X, Sakha P, Huttunen HJ. Multiplex assay for live-cell monitoring of cellular fates of Amyloid-β Precursor Protein (APP). PLoS One  2014; 9(6): e98619.
 [http://dx.doi.org/10.1371/journal.pone.0098619] [PMID: 24932508]

[50]
McIntee FL, Giannoni P, Blais S, et al. In vivo differential brain clearance and catabolism of monomeric and oligomeric Alzheimer’s Aβ protein. Front Aging Neurosci  2016; 8: 223.
 [http://dx.doi.org/10.3389/fnagi.2016.00223] [PMID: 27729857]

[51]
Zhao Y, Wu X, Li X, et al. TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron  2018; 97(5): 1023-31.
 [http://dx.doi.org/10.1016/j.neuron.2018.01.031]

[52]
Savage JC, Jay T, Goduni E, et al. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci  2015; 35(16): 6532-43.
 [http://dx.doi.org/10.1523/JNEUROSCI.4586-14.2015] [PMID: 25904803]

[53]
Zhao Y, Bhattacharjee S, Jones BM, et al. Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a. Neuroreport  2013; 24(6): 318-23.
 [http://dx.doi.org/10.1097/WNR.0b013e32835fb6b0] [PMID: 23462268]

[54]
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(10): 624-34.
 [http://dx.doi.org/10.1093/nutrit/nuw023] [PMID: 27634977]

[55]
Wang C, Yue H, Hu Z, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science  2020; 367(6478): 688-94.
 [http://dx.doi.org/10.1126/science.aaz2288] [PMID: 32029629]

[56]
Cecarini V, Bonfili L, Cuccioloni M, et al. Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer’s disease. Biochim Biophys Acta  2012; 1822(11): 1741-51.
 [http://dx.doi.org/10.1016/j.bbadis.2012.07.015] [PMID: 22867901]

[57]
Martins IJ, Fernando WM. High fibre diets and Alzheimer's disease. Food Nutr Sci  2014; 5(4): 410-24.
 [http://dx.doi.org/10.4236/fns.2014.54049]

[58]
Gräff J, Rei D, Guan J-S, et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature  2012; 483(7388): 222-6.
 [http://dx.doi.org/10.1038/nature10849] [PMID: 22388814]

[59]
Gomes S, Martins I, Fonseca AC, Oliveira CR, Resende R, Pereira CM. Protective effect of leptin and ghrelin against toxicity induced by amyloid-β oligomers in a hypothalamic cell line. J Neuroendocrinol  2014; 26(3): 176-85.
 [http://dx.doi.org/10.1111/jne.12138] [PMID: 24528254]

[60]
Niedowicz DM, Studzinski CM, Weidner AM, et al. Leptin regulates amyloid β production via the γ-secretase complex. Biochim Biophys Acta  2013; 1832(3): 439-44.
 [http://dx.doi.org/10.1016/j.bbadis.2012.12.009] [PMID: 23274884]

[61]
Stoyanova II. Ghrelin: A link between ageing, metabolism and neurodegenerative disorders. Neurobiol Dis  2014; 72(Pt A): 72-83.
 [http://dx.doi.org/10.1016/j.nbd.2014.08.026] [PMID: 25173805]

[62]
Gault VA, Hölscher C. Protease-resistant glucose-dependent insulinotropic polypeptide agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. J Neurophysiol  2008; 99(4): 1590-5.
 [http://dx.doi.org/10.1152/jn.01161.2007] [PMID: 18234983]

[63]
Bonfili L, Cecarini V, Berardi S, et al. Microbiota modulation counteracts Alzheimer’s disease progression influencing neuronal proteolysis and gut hormones plasma levels. Sci Rep  2017; 7(1): 2426.
 [http://dx.doi.org/10.1038/s41598-017-02587-2] [PMID: 28546539]

[64]
Sun Z-Z, Li X-Y, Wang S, Shen L, Ji H-F. Bidirectional interactions between curcumin and gut microbiota in transgenic mice with Alzheimer’s disease. Appl Microbiol Biotechnol  2020; 104(8): 3507-15.
 [http://dx.doi.org/10.1007/s00253-020-10461-x] [PMID: 32095862]

[65]
Johnson KV-A, Foster KR. Why does the microbiome affect behaviour? Nat Rev Microbiol  2018; 16(10): 647-55.
 [http://dx.doi.org/10.1038/s41579-018-0014-3] [PMID: 29691482]

[66]
Patrick KL, Bell SL, Weindel CG, Watson RO. Exploring the “multiple-hit hypothesis” of neurodegenerative disease: Bacterial infection comes up to bat. Front Cell Infect Microbiol  2019; 9: 138.
 [http://dx.doi.org/10.3389/fcimb.2019.00138] [PMID: 31192157]

[67]
Lukiw WJ. Gastrointestinal (GI) tract microbiome-derived neurotoxins-potent neuro-inflammatory signals from the GI tract via the systemic circulation into the brain. Front Cell Infect Microbiol  2020; 10: 22.
 [http://dx.doi.org/10.3389/fcimb.2020.00022] [PMID: 32117799]

[68]
Lloyd-Price J, Abu-Ali G, Huttenhower C. The healthy human microbiome. Genome Med  2016; 8(1): 51.
 [http://dx.doi.org/10.1186/s13073-016-0307-y] [PMID: 27122046]

[69]
Westfall S, Lomis N, Kahouli I, Dia SY, Singh SP, Prakash S. Microbiome, probiotics and neurodegenerative diseases: Deciphering the gut brain axis. Cell Mol Life Sci  2017; 74(20): 3769-87.
 [http://dx.doi.org/10.1007/s00018-017-2550-9] [PMID: 28643167]

[70]
Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol  2016; 14(8): e1002533.
 [http://dx.doi.org/10.1371/journal.pbio.1002533] [PMID: 27541692]

[71]
Zhao Y, Lukiw WJ. Microbiome-mediated upregulation of microRNA-146a in sporadic Alzheimer’s disease. Front Neurol  2018; 9: 145.
 [http://dx.doi.org/10.3389/fneur.2018.00145] [PMID: 29615954]

[72]
Rinninella E, Raoul P, Cintoni M, et al. What is the healthy gut microbiota composition? a changing ecosystem across age, environment, diet, and diseases. Microorganisms  2019; 7(1): 14.
 [http://dx.doi.org/10.3390/microorganisms7010014] [PMID: 30634578]

[73]
Sharon G, Cruz N J, Kang D-W, et al. Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice. Cell  2019; 177(6): 1600-18.
 [http://dx.doi.org/10.1016/j.cell.2019.05.004]

[74]
Harach T, Marungruang N, Duthilleul N, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep  2017; 7(1): 41802.
 [http://dx.doi.org/10.1038/srep41802] [PMID: 28176819]

[75]
Vendrik KEW, Ooijevaar RE, De Jong PRC, et al. Fecal microbiota transplantation in neurological disorders. Front Cell Infect Microbiol  2020; 10: 98.
 [http://dx.doi.org/10.3389/fcimb.2020.00098] [PMID: 32266160]

[76]
Zhao Y, Sharfman NM, Jaber VR, Lukiw WJ. Down-regulation of essential synaptic components by GI-tract microbiome-derived lipopolysaccharide (LPS) in LPS-treated Human Neuronal-Glial (HNG) cells in primary culture; relevance to Alzheimer’s Disease (AD). Front Cell Neurosci  2019; 13: 314.
 [http://dx.doi.org/10.3389/fncel.2019.00314] [PMID: 31354434]

[77]
Vogt NM, Kerby RL, Dill-McFarland KA, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep  2017; 7(1): 13537.
 [http://dx.doi.org/10.1038/s41598-017-13601-y] [PMID: 29051531]

[78]
Saji N, Niida S, Murotani K, et al. Analysis of the relationship between the gut microbiome and dementia: A cross-sectional study conducted in Japan. Sci Rep  2019; 9(1): 1008.
 [http://dx.doi.org/10.1038/s41598-018-38218-7] [PMID: 30700769]

[79]
Nguyen TTT, Fujimura Y, Mimura I, et al. Cultivable butyrate-producing bacteria of elderly Japanese diagnosed with Alzheimer’s disease. J Microbiol  2018; 56(10): 760-71.
 [http://dx.doi.org/10.1007/s12275-018-8297-7] [PMID: 30136260]

[80]
Liu P, Wu L, Peng G, et al. Altered microbiomes distinguish Alzheimer’s disease from amnestic mild cognitive impairment and health in a Chinese cohort. Brain Behav Immun  2019; 80: 633-43.
 [http://dx.doi.org/10.1016/j.bbi.2019.05.008] [PMID: 31063846]

[81]
Pisa D, Alonso R, Fernández-Fernández AM, Rábano A, Carrasco L. Polymicrobial infections in brain tissue from Alzheimer’s disease patients. Sci Rep  2017; 7(1): 5559.
 [http://dx.doi.org/10.1038/s41598-017-05903-y] [PMID: 28717130]

[82]
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.
 [http://dx.doi.org/10.3389/fcimb.2017.00318] [PMID: 28744452]

[83]
Maqsood R, Stone TW. The gut-brain axis, BDNF, NMDA and CNS disorders. Neurochem Res  2016; 41(11): 2819-35.
 [http://dx.doi.org/10.1007/s11064-016-2039-1] [PMID: 27553784]

[84]
Li H, Sun J, Du J, et al. Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut-brain axis. Neurogastroenterol Motil  2018; 30(5): e13260.
 [http://dx.doi.org/10.1111/nmo.13260] [PMID: 29193450]

[85]
Roubaud-Baudron C, Krolak-Salmon P, Quadrio I, Mégraud F, Salles N. Impact of chronic Helicobacter pylori infection on Alzheimer's disease: Preliminary results. Neurobiol Aging  2012; 33(5): 1009.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2011.10.021]

[86]
Bu XL, Yao XQ, Jiao SS, et al. A study on the association between infectious burden and Alzheimer’s disease. Eur J Neurol  2015; 22(12): 1519-25.
 [http://dx.doi.org/10.1111/ene.12477] [PMID: 24910016]

[87]
Wang H-X, Wang Y-P. Gut microbiota-brain axis. Chin Med J (Engl)  2016; 129(19): 2373-80.
 [http://dx.doi.org/10.4103/0366-6999.190667] [PMID: 27647198]

[88]
Links between gut microbes and depression strengthened. Nature  2019; 566(7742): 7.
 [http://dx.doi.org/10.1038/d41586-019-00483-5] [PMID: 30718890]

[89]
Jiang C, Li G, Huang P, Liu Z, Zhao B. The gut microbiota and Alzheimer’s disease. J Alzheimers Dis  2017; 58(1): 1-15.
 [http://dx.doi.org/10.3233/JAD-161141] [PMID: 28372330]

[90]
Bonaz B, Bazin T, Pellissier S. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci  2018; 12: 49.
 [http://dx.doi.org/10.3389/fnins.2018.00049] [PMID: 29467611]

[91]
Briguglio M, Dell’Osso B, Panzica G, et al. Dietary neurotransmitters: A narrative review on current knowledge. Nutrients  2018; 10(5): 591.
 [http://dx.doi.org/10.3390/nu10050591] [PMID: 29748506]

[92]
Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement  2016; 12(6): 719-32.
 [http://dx.doi.org/10.1016/j.jalz.2016.02.010] [PMID: 27179961]

[93]
Semar S, Klotz M, Letiembre M, et al. Changes of the enteric nervous system in amyloid-β protein precursor transgenic mice correlate with disease progression. J Alzheimers Dis  2013; 36(1): 7-20.
 [http://dx.doi.org/10.3233/JAD-120511] [PMID: 23531500]

[94]
Chalazonitis A, Rao M. Enteric nervous system manifestations of neurodegenerative disease. Brain Res  2018; 1693(Pt B): 207-13.
 [http://dx.doi.org/10.1016/j.brainres.2018.01.011] [PMID: 29360466]

[95]
Dinan TG, Cryan JF. The microbiome-gut-brain axis in health and disease. Gastroenterology Clinics  2017; 46(1): 77-89.
 [http://dx.doi.org/10.1016/j.gtc.2016.09.007] [PMID: 28164854]

[96]
Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell  2015; 161(2): 264-76.
 [http://dx.doi.org/10.1016/j.cell.2015.02.047] [PMID: 25860609]

[97]
Bhattacharjee S, Lukiw WJ. Alzheimer’s disease and the microbiome. Front Cell Neurosci  2013; 7: 153.
 [http://dx.doi.org/10.3389/fncel.2013.00153] [PMID: 24062644]

[98]
Wekerle H. The gut-brain connection: Triggering of brain autoimmune disease by commensal gut bacteria. Rheumatology (Oxford)  2016; 55 (Suppl. 2): ii68-75.
 [http://dx.doi.org/10.1093/rheumatology/kew353] [PMID: 27856664]

[99]
Logsdon AF, Erickson MA, Rhea EM, Salameh TS, Banks WA. Gut reactions: How the blood-brain barrier connects the microbiome and the brain. Exp Biol Med (Maywood)  2018; 243(2): 159-65.
 [http://dx.doi.org/10.1177/1535370217743766] [PMID: 29169241]

[100]
Zac-Varghese S, Tan T, Bloom SR. Hormonal interactions between gut and brain. Discov Med  2010; 10(55): 543-52.
 [PMID: 21189225]

[101]
Potgieter M, Bester J, Kell DB, Pretorius E. The dormant blood microbiome in chronic, inflammatory diseases. FEMS Microbiol Rev  2015; 39(4): 567-91.
 [http://dx.doi.org/10.1093/femsre/fuv013] [PMID: 25940667]

[102]
König J, Wells J, Cani PD, et al. Human intestinal barrier function in health and disease. Clin Transl Gastroenterol  2016; 7(10): e196.
 [http://dx.doi.org/10.1038/ctg.2016.54] [PMID: 27763627]

[103]
Bischoff SC, Barbara G, Buurman W, et al. Intestinal permeability--a new target for disease prevention and therapy. BMC Gastroenterol  2014; 14(1): 189.
 [http://dx.doi.org/10.1186/s12876-014-0189-7] [PMID: 25407511]

[104]
Montagne A, Barnes SR, Sweeney MD, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron  2015; 85(2): 296-302.
 [http://dx.doi.org/10.1016/j.neuron.2014.12.032] [PMID: 25611508]

[105]
Borre YE, Moloney RD, Clarke G, Dinan TG, Cryan JF. The impact of microbiota on brain and behavior: Mechanisms & therapeutic potential. In: Lyte M, Cryan J, Eds. Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease Advances in Experimental Medicine and Biology.  New York, NY: Springer 2014; pp. 373-403.
 [http://dx.doi.org/10.1007/978-1-4939-0897-4_17]

[106]
Bostanciklioğlu M. The role of gut microbiota in pathogenesis of Alzheimer’s disease. J Appl Microbiol  2019; 127(4): 954-67.
 [http://dx.doi.org/10.1111/jam.14264] [PMID: 30920075]

[107]
Xu R, Wang Q. Towards understanding brain-gut-microbiome connections in Alzheimer’s disease. BMC Syst Biol  2016; 10(3) (Suppl. 3): 63.
 [http://dx.doi.org/10.1186/s12918-016-0307-y] [PMID: 27585440]

[108]
Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med  2013; 19(5): 576-85.
 [http://dx.doi.org/10.1038/nm.3145] [PMID: 23563705]

[109]
Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature  2011; 472(7341): 57-63.
 [http://dx.doi.org/10.1038/nature09922] [PMID: 21475195]

[110]
Zhu W, Gregory JC, Org E, et al. Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell  2016; 165(1): 111-24.
 [http://dx.doi.org/10.1016/j.cell.2016.02.011] [PMID: 26972052]

[111]
Gao X, Liu X, Xu J, Xue C, Xue Y, Wang Y. Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. J Biosci Bioeng  2014; 118(4): 476-81.
 [http://dx.doi.org/10.1016/j.jbiosc.2014.03.001] [PMID: 24721123]

[112]
Rath S, Rud T, Pieper DH, Vital M. Potential TMA-producing bacteria are ubiquitously found in mammalia. Front Microbiol  2020; 10: 2966.
 [http://dx.doi.org/10.3389/fmicb.2019.02966] [PMID: 31998260]

[113]
Craciun S, Balskus EP. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci USA  2012; 109(52): 21307-12.
 [http://dx.doi.org/10.1073/pnas.1215689109] [PMID: 23151509]

[114]
Tilg H. A gut feeling about thrombosis. N Engl J Med  2016; 374(25): 2494-6.
 [http://dx.doi.org/10.1056/NEJMcibr1604458] [PMID: 27332910]

[115]
Del Rio D, Zimetti F, Caffarra P, et al. The gut microbial metabolite trimethylamine-N-oxide is present in human cerebrospinal fluid. Nutrients  2017; 9(10): 1053.
 [http://dx.doi.org/10.3390/nu9101053] [PMID: 28937600]

[116]
Vogt NM, Romano KA, Darst BF, et al. The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease. Alzheimers Res Ther  2018; 10(1): 124.
 [http://dx.doi.org/10.1186/s13195-018-0451-2] [PMID: 30579367]

[117]
Wang Q-J, Shen Y-E, Wang X, et al. Concomitant memantine and Lactobacillus plantarum treatment attenuates cognitive impairments in APP/PS1 mice. Aging (Albany NY)  2020; 12(1): 628-49.
 [http://dx.doi.org/10.18632/aging.102645] [PMID: 31907339]

[118]
Li D, Ke Y, Zhan R, et al. Trimethylamine-N-oxide promotes brain aging and cognitive impairment in mice. Aging Cell  2018; 17(4): e12768.
 [http://dx.doi.org/10.1111/acel.12768] [PMID: 29749694]

[119]
Rowland I, Gibson G, Heinken A, et al. Gut microbiota functions: Metabolism of nutrients and other food components. Eur J Nutr  2018; 57(1): 1-24.
 [http://dx.doi.org/10.1007/s00394-017-1445-8] [PMID: 28393285]

[120]
Oliphant K, Allen-Vercoe E. Macronutrient metabolism by the human gut microbiome: Major fermentation by-products and their impact on host health. Microbiome  2019; 7(1): 91.
 [http://dx.doi.org/10.1186/s40168-019-0704-8] [PMID: 31196177]

[121]
Macfabe DF. Short-chain fatty acid fermentation products of the gut microbiome: Implications in autism spectrum disorders. Microb Ecol Health Dis  2012; 23(1): 19260.
 [PMID: 23990817]

[122]
Erny D, Hrabě de Angelis AL, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci  2015; 18(7): 965-77.
 [http://dx.doi.org/10.1038/nn.4030] [PMID: 26030851]

[123]
Ho L, Ono K, Tsuji M, Mazzola P, Singh R, Pasinetti GM. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer’s disease-type beta-amyloid neuropathological mechanisms. Expert Rev Neurother  2018; 18(1): 83-90.
 [http://dx.doi.org/10.1080/14737175.2018.1400909] [PMID: 29095058]

[124]
Liu J, Sun J, Wang F, et al. Neuroprotective effects of Clostridium butyricum against vascular dementia in mice via metabolic butyrate. BioMed research international  2015; 2015

[125]
Bindels LB, Dewulf EM, Delzenne NM. GPR43/FFA2: Physiopathological relevance and therapeutic prospects. Trends Pharmacol Sci  2013; 34(4): 226-32.
 [http://dx.doi.org/10.1016/j.tips.2013.02.002] [PMID: 23489932]

[126]
Kobayashi Y, Sugahara H, Shimada K, et al. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer’s disease. Sci Rep  2017; 7(1): 13510.
 [http://dx.doi.org/10.1038/s41598-017-13368-2] [PMID: 29044140]

[127]
Yuille S, Reichardt N, Panda S, Dunbar H, Mulder IE. Human gut bacteria as potent class I histone deacetylase inhibitors in vitro through production of butyric acid and valeric acid. PLoS One  2018; 13(7): e0201073.
 [http://dx.doi.org/10.1371/journal.pone.0201073] [PMID: 30052654]

[128]
Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol  2010; 28(10): 1057-68.
 [http://dx.doi.org/10.1038/nbt.1685] [PMID: 20944598]

[129]
Wang C, Schroeder FA, Wey H-Y, et al. In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs. J Med Chem  2014; 57(19): 7999-8009.
 [http://dx.doi.org/10.1021/jm500872p] [PMID: 25203558]

[130]
Wey H-Y, Wang C, Schroeder FA, Logan J, Price JC, Hooker JM. Kinetic analysis and quantification of [11C] Martinostat for in vivo HDAC imaging of the brain. ACS Chem Neurosci  2015; 6(5): 708-15.
 [http://dx.doi.org/10.1021/acschemneuro.5b00066] [PMID: 25768025]

[131]
Wang MJ, Yi S, Han JY, et al. Oligomeric forms of amyloid-β protein in plasma as a potential blood-based biomarker for Alzheimer’s disease. Alzheimers Res Ther  2017; 9(1): 98.
 [http://dx.doi.org/10.1186/s13195-017-0324-0] [PMID: 29246249]

[132]
Welling MM, Nabuurs RJ, van der Weerd L. Potential role of antimicrobial peptides in the early onset of Alzheimer’s disease. Alzheimers Dement  2015; 11(1): 51-7.
 [http://dx.doi.org/10.1016/j.jalz.2013.12.020] [PMID: 24637300]

[133]
Den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res  2013; 54(9): 2325-40.
 [http://dx.doi.org/10.1194/jlr.R036012] [PMID: 23821742]

[134]
Zilberter Y, Zilberter M. The vicious circle of hypometabolism in neurodegenerative diseases: Ways and mechanisms of metabolic correction. J Neurosci Res  2017; 95(11): 2217-35.
 [http://dx.doi.org/10.1002/jnr.24064] [PMID: 28463438]

[135]
Jacobson AN, Choudhury BP, Fischbach MA. The biosynthesis of Lipooligosaccharide from Bacteroides thetaiotaomicron. MBio  2018; 9(2): e02289-17.
 [http://dx.doi.org/10.1128/mBio.02289-17] [PMID: 29535205]

[136]
Zhang R, Miller RG, Gascon R, et al. Circulating endotoxin and systemic immune activation in sporadic Amyotrophic Lateral Sclerosis (sALS). J Neuroimmunol  2009; 206(1-2): 121-4.
 [http://dx.doi.org/10.1016/j.jneuroim.2008.09.017] [PMID: 19013651]

[137]
Zhao Y, Cong L, Lukiw WJ. Lipopolysaccharide (LPS) accumulates in neocortical neurons of Alzheimer’s Disease (AD) brain and impairs transcription in human neuronal-glial primary cocultures. Front Aging Neurosci  2017; 9: 407.
 [http://dx.doi.org/10.3389/fnagi.2017.00407] [PMID: 29311897]

[138]
Hauss-Wegrzyniak B, Lynch MA, Vraniak PD, Wenk GL. Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. Exp Neurol  2002; 176(2): 336-41.
 [http://dx.doi.org/10.1006/exnr.2002.7966] [PMID: 12359175]

[139]
Hauss-Wegrzyniak B, Vraniak PD, Wenk GL. LPS-induced neuroinflammatory effects do not recover with time. Neuroreport  2000; 11(8): 1759-63.
 [http://dx.doi.org/10.1097/00001756-200006050-00032] [PMID: 10852239]

[140]
Asti A, Gioglio L. Can a bacterial endotoxin be a key factor in the kinetics of amyloid fibril formation? J Alzheimers Dis  2014; 39(1): 169-79.
 [http://dx.doi.org/10.3233/JAD-131394] [PMID: 24150108]

[141]
Lee JW, Lee YK, Yuk DY, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation  2008; 5(1): 37.
 [http://dx.doi.org/10.1186/1742-2094-5-37] [PMID: 18759972]

[142]
Kahn MS, Kranjac D, Alonzo CA, et al. Prolonged elevation in hippocampal Aβ and cognitive deficits following repeated endotoxin exposure in the mouse. Behav Brain Res  2012; 229(1): 176-84.
 [http://dx.doi.org/10.1016/j.bbr.2012.01.010] [PMID: 22249135]

[143]
Zhan X, Stamova B, Jin L-W, DeCarli C, Phinney B, Sharp FR. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology  2016; 87(22): 2324-32.
 [http://dx.doi.org/10.1212/WNL.0000000000003391] [PMID: 27784770]

[144]
Zhao Y, Dua P, Lukiw WJ. Microbial sources of amyloid and relevance to amyloidogenesis and Alzheimer’s Disease (AD). J Alzheimers Dis Parkinsonism  2015; 5(1): 177.
 [PMID: 25977840]

[145]
Chen SG, Stribinskis V, Rane MJ, et al. Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans. Sci Rep  2016; 6(1): 34477.
 [http://dx.doi.org/10.1038/srep34477] [PMID: 27708338]

[146]
Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog  2017; 13(12): e1006654.
 [http://dx.doi.org/10.1371/journal.ppat.1006654] [PMID: 29267402]

[147]
Jang SE, Lim SM, Jeong JJ, et al. Gastrointestinal inflammation by gut microbiota disturbance induces memory impairment in mice. Mucosal Immunol  2018; 11(2): 369-79.
 [http://dx.doi.org/10.1038/mi.2017.49] [PMID: 28612842]

[148]
Zhou Y, Smith D, Leong BJ, Brännström K, Almqvist F, Chapman MR. Promiscuous cross-seeding between bacterial amyloids promotes interspecies biofilms. J Biol Chem  2012; 287(42): 35092-103.
 [http://dx.doi.org/10.1074/jbc.M112.383737] [PMID: 22891247]

[149]
Lundmark K, Westermark GT, Olsén A, Westermark P. Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism. Proc Natl Acad Sci USA  2005; 102(17): 6098-102.
 [http://dx.doi.org/10.1073/pnas.0501814102] [PMID: 15829582]

[150]
Nelson PT, Braak H, Markesbery WR. Neuropathology and cognitive impairment in Alzheimer disease: A complex but coherent relationship. J Neuropathol Exp Neurol  2009; 68(1): 1-14.
 [http://dx.doi.org/10.1097/NEN.0b013e3181919a48] [PMID: 19104448]

[151]
Li Y, Sun H, Chen Z, Xu H, Bu G, Zheng H. Implications of GABAergic neurotransmission in Alzheimer’s disease. Front Aging Neurosci  2016; 8: 31.
 [http://dx.doi.org/10.3389/fnagi.2016.00031] [PMID: 26941642]

[152]
Lanctôt KL, Herrmann N, Mazzotta P, Khan LR, Ingber N. GABAergic function in Alzheimer’s disease: Evidence for dysfunction and potential as a therapeutic target for the treatment of behavioural and psychological symptoms of dementia. Can J Psychiatry  2004; 49(7): 439-53.
 [http://dx.doi.org/10.1177/070674370404900705] [PMID: 15362248]

[153]
Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxietylike behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil  2011; 23(3): 255-264, e119.
 [http://dx.doi.org/10.1111/j.1365-2982.2010.01620.x] [PMID: 21054680]

[154]
Bailey MT, Cryan JF. The microbiome as a key regulator of brain, behavior and immunity: Commentary on the 2017 named series. Brain Behav Immun  2017; 66: 18-22.
 [http://dx.doi.org/10.1016/j.bbi.2017.08.017] [PMID: 28843452]

[155]
Bhandage AK, Jin Z, Korol SV, et al. GABA regulates release of inflammatory cytokines from peripheral blood mononuclear cells and CD4+ T cells and is immunosuppressive in type 1 diabetes. EBioMedicine  2018; 30: 283-94.
 [http://dx.doi.org/10.1016/j.ebiom.2018.03.019] [PMID: 29627388]

[156]
Jo S, Yarishkin O, Hwang YJ, et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat Med  2014; 20(8): 886-96.
 [http://dx.doi.org/10.1038/nm.3639] [PMID: 24973918]

[157]
de J R De-Paula V, Forlenza AS, Forlenza OV. Relevance of gutmicrobiota in cognition, behaviour and Alzheimer’s disease. Pharmacol Res  2018; 136: 29-34.
 [http://dx.doi.org/10.1016/j.phrs.2018.07.007] [PMID: 30138667]

[158]
Ramirez MJ, Lai MK, Tordera RM, Francis PT. Serotonergic therapies for cognitive symptoms in Alzheimer’s disease: Rationale and current status. Drugs  2014; 74(7): 729-36.
 [http://dx.doi.org/10.1007/s40265-014-0217-5] [PMID: 24802806]

[159]
Trillo L, Das D, Hsieh W, et al. Ascending monoaminergic systems alterations in Alzheimer’s disease. translating basic science into clinical care. Neurosci Biobehav Rev  2013; 37(8): 1363-79.
 [http://dx.doi.org/10.1016/j.neubiorev.2013.05.008] [PMID: 23707776]

[160]
Yun H-M, Park K-R, Kim E-C, Kim S, Hong JT. Serotonin 6 receptor controls Alzheimer’s disease and depression. Oncotarget  2015; 6(29): 26716-28.
 [http://dx.doi.org/10.18632/oncotarget.5777] [PMID: 26449188]

[161]
Zhu C-B, Blakely RD, Hewlett WA. The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology  2006; 31(10): 2121-31.
 [http://dx.doi.org/10.1038/sj.npp.1301029] [PMID: 16452991]

[162]
Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat Rev Neurosci  2008; 9(1): 46-56.
 [http://dx.doi.org/10.1038/nrn2297] [PMID: 18073775]

[163]
Ledo JH, Azevedo EP, Beckman D, et al. Cross talk between brain innate immunity and serotonin signaling underlies depressive-like behavior induced by Alzheimer’s amyloid-β oligomers in mice. J Neurosci  2016; 36(48): 12106-16.
 [http://dx.doi.org/10.1523/JNEUROSCI.1269-16.2016] [PMID: 27903721]

[164]
Liu Y-W, Liong MT, Chung YE, et al. Effects of Lactobacillus plantarum PS128 on children with autism spectrum disorder in Taiwan: A randomized, double-blind, placebo-controlled trial. Nutrients  2019; 11(4): 820.
 [http://dx.doi.org/10.3390/nu11040820] [PMID: 30979038]

[165]
Smirnovas V, Baron GS, Offerdahl DK, Raymond GJ, Caughey B, Surewicz WK. Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange. Nat Struct Mol Biol  2011; 18(4): 504-6.
 [http://dx.doi.org/10.1038/nsmb.2035] [PMID: 21441913]

[166]
Saleem F, Bjorndahl TC, Ladner CL, Perez-Pineiro R, Ametaj BN, Wishart DS. Lipopolysaccharide induced conversion of recombinant prion protein. Prion  2014; 8(2): 221-32.
 [http://dx.doi.org/10.4161/pri.28939] [PMID: 24819168]

[167]
Cherny I, Rockah L, Levy-Nissenbaum O, Gophna U, Ron EZ, Gazit E. The formation of Escherichia coli curli amyloid fibrils is mediated by prion-like peptide repeats. J Mol Biol  2005; 352(2): 245-52.
 [http://dx.doi.org/10.1016/j.jmb.2005.07.028] [PMID: 16083908]

[168]
Rothhammer V, Mascanfroni ID, Bunse L, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med  2016; 22(6): 586-97.
 [http://dx.doi.org/10.1038/nm.4106] [PMID: 27158906]

[169]
Saksida T, Koprivica I, Vujičić M, et al. Impaired IL-17 production in gut-residing immune cells of 5xFAD mice with Alzheimer’s disease pathology. J Alzheimers Dis  2018; 61(2): 619-30.
 [http://dx.doi.org/10.3233/JAD-170538] [PMID: 29254086]

[170]
Wang C, Klechikov AG, Gharibyan AL, et al. The role of proinflammatory S100A9 in Alzheimer’s disease amyloidneuroinflammatory cascade. Acta Neuropathol  2014; 127(4): 507-22.
 [http://dx.doi.org/10.1007/s00401-013-1208-4] [PMID: 24240735]

[171]
Leblhuber F, Geisler S, Steiner K, Fuchs D, Schütz B. Elevated fecal calprotectin in patients with Alzheimer’s dementia indicates leaky gut. J Neural Transm (Vienna)  2015; 122(9): 1319-22.
 [http://dx.doi.org/10.1007/s00702-015-1381-9] [PMID: 25680441]

[172]
Zhao Y, Lukiw WJ. Bacteroidetes neurotoxins and inflammatory neurodegeneration. Mol Neurobiol  2018; 55(12): 9100-7.
 [http://dx.doi.org/10.1007/s12035-018-1015-y] [PMID: 29637444]

[173]
Sheppard O, Coleman MP, Durrant CS. Lipopolysaccharideinduced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta. J Neuroinflammation  2019; 16(1): 106.
 [http://dx.doi.org/10.1186/s12974-019-1490-8] [PMID: 31103036]

[174]
Sweeney MD, Zhao Z, Montagne A, Nelson AR, Zlokovic BV. Blood-brain barrier: From physiology to disease and back. Physiol Rev  2019; 99(1): 21-78.
 [http://dx.doi.org/10.1152/physrev.00050.2017] [PMID: 30280653]

[175]
Tulkens J, Vergauwen G, Van Deun J, et al. Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction. Gut  2020; 69(1): 191-3.
 [http://dx.doi.org/10.1136/gutjnl-2018-317726] [PMID: 30518529]

[176]
Jaeger LB, Dohgu S, Sultana R, et al. Lipopolysaccharide alters the blood-brain barrier transport of amyloid β protein: A mechanism for inflammation in the progression of Alzheimer’s disease. Brain Behav Immun  2009; 23(4): 507-17.
 [http://dx.doi.org/10.1016/j.bbi.2009.01.017] [PMID: 19486646]

[177]
Rapsinski GJ, Wynosky-Dolfi MA, Oppong GO, et al. Toll-like receptor 2 and NLRP3 cooperate to recognize a functional bacterial amyloid, curli. Infect Immun  2015; 83(2): 693-701.
 [http://dx.doi.org/10.1128/IAI.02370-14] [PMID: 25422268]

[178]
Nishimori JH, Newman TN, Oppong GO, et al. Microbial amyloids induce interleukin 17A (IL-17A) and IL-22 responses via Toll-like receptor 2 activation in the intestinal mucosa. Infect Immun  2012; 80(12): 4398-408.
 [http://dx.doi.org/10.1128/IAI.00911-12] [PMID: 23027540]

[179]
Venegas DP, Marjorie K, Landskron G, et al. Short Chain Fatty Acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol  2019; 10.

[180]
Thangaraju M, Cresci GA, Liu K, et al. GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon. Cancer Res  2009; 69(7): 2826-32.
 [http://dx.doi.org/10.1158/0008-5472.CAN-08-4466] [PMID: 19276343]

[181]
Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci USA  2014; 111(6): 2247-52.
 [http://dx.doi.org/10.1073/pnas.1322269111] [PMID: 24390544]

[182]
Cox TM. Substrate reduction therapy for lysosomal storage diseases. Acta Paediatr Suppl  2005; 94(447): 69-75.
 [http://dx.doi.org/10.1080/08035320510028157] [PMID: 15895716]

[183]
Yan H, Ajuwon KM. Butyrate modifies intestinal barrier function in IPEC-J2 cells through a selective upregulation of tight junction proteins and activation of the Akt signaling pathway. PLoS One  2017; 12(6): e0179586.
 [http://dx.doi.org/10.1371/journal.pone.0179586] [PMID: 28654658]

[184]
Kim S, Kwon S-H, Kam T-I, et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron  2019; 103(4): 627-41.
 [http://dx.doi.org/10.1016/j.neuron.2019.05.035]

[185]
Bravo JA, Forsythe P, Chew MV, et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci USA  2011; 108(38): 16050-5.
 [http://dx.doi.org/10.1073/pnas.1102999108] [PMID: 21876150]

[186]
Perez-Burgos A, Wang L, McVey Neufeld KA, et al. The TRPV1 channel in rodents is a major target for antinociceptive effect of the probiotic Lactobacillus reuteri DSM 17938. J Physiol  2015; 593(17): 3943-57.
 [http://dx.doi.org/10.1113/JP270229] [PMID: 26084409]

[187]
Pizarro TT, Pastorelli L, Bamias G, et al. SAMP1/YitFc mouse strain: A spontaneous model of Crohn’s disease-like ileitis. Inflamm Bowel Dis  2011; 17(12): 2566-84.
 [http://dx.doi.org/10.1002/ibd.21638] [PMID: 21557393]

[188]
Kong S-Z, Li J-C, Li S-D, et al. Anti-aging effect of chitosan oligosaccharide on d-galactose-induced subacute aging in mice. Mar Drugs  2018; 16(6): 181.
 [http://dx.doi.org/10.3390/md16060181] [PMID: 29794973]

[189]
Contestabile A, Fila T, Bartesaghi R, Contestabile A, Ciani E. Choline acetyltransferase activity at different ages in brain of Ts65Dn mice, an animal model for Down’s syndrome and related neurodegenerative diseases. J Neurochem  2006; 97(2): 515-26.
 [http://dx.doi.org/10.1111/j.1471-4159.2006.03769.x] [PMID: 16539660]

[190]
McGowan E, Eriksen J, Hutton M. A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet  2006; 22(5): 281-9.
 [http://dx.doi.org/10.1016/j.tig.2006.03.007] [PMID: 16567017]

[191]
Pu X-a, Young AP, Kubisch HM. Production of transgenic mice by pronuclear microinjection. Method Mol Biol  2019; 1874: 17-41.
 [http://dx.doi.org/10.1007/978-1-4939-8831-0_2]

[192]
Brandscheid C, Schuck F, Reinhardt S, et al. Altered gut microbiome composition and tryptic activity of the 5xFAD Alzheimer’s mouse model. J Alzheimers Dis  2017; 56(2): 775-88.
 [http://dx.doi.org/10.3233/JAD-160926] [PMID: 28035935]

[193]
Poole S, Singhrao SK, Chukkapalli S, et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. J Alzheimers Dis  2015; 43(1): 67-80.
 [http://dx.doi.org/10.3233/JAD-140315] [PMID: 25061055]

[194]
Akbari E, Asemi Z, Daneshvar Kakhaki R, et al. 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.
 [http://dx.doi.org/10.3389/fnagi.2016.00256] [PMID: 27891089]

[195]
Araos R, Andreatos N, Ugalde J, Mitchell S, Mylonakis E, D’Agata EMC. Fecal microbiome among nursing home residents with advanced dementia and Clostridium difficile. Dig Dis Sci  2018; 63(6): 1525-31.
 [http://dx.doi.org/10.1007/s10620-018-5030-7] [PMID: 29594967]

[196]
Katan M, Moon YP, Paik MC, Sacco RL, Wright CB, Elkind MS. Infectious burden and cognitive function: The Northern Manhattan Study. Neurology  2013; 80(13): 1209-15.
 [http://dx.doi.org/10.1212/WNL.0b013e3182896e79] [PMID: 23530151]

[197]
Beydoun MA, Beydoun HA, Shroff MR, Kitner-Triolo MH, Zonderman AB. Helicobacter pylori seropositivity and cognitive performance among US adults: Evidence from a large national survey. Psychosom Med  2013; 75(5): 486-96.
 [http://dx.doi.org/10.1097/PSY.0b013e31829108c3] [PMID: 23697465]

[198]
Ide M, Harris M, Stevens A, et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One  2016; 11(3): e0151081.
 [http://dx.doi.org/10.1371/journal.pone.0151081] [PMID: 26963387]

[199]
Zhuang Z-Q, Shen L-L, Li W-W, et al. Gut microbiota is altered in patients with Alzheimer’s disease. J Alzheimers Dis  2018; 63(4): 1337-46.
 [http://dx.doi.org/10.3233/JAD-180176] [PMID: 29758946]

[200]
Syed AK, Boles BR. Fold modulating function: Bacterial toxins to functional amyloids. Front Microbiol  2014; 5: 401.
 [http://dx.doi.org/10.3389/fmicb.2014.00401] [PMID: 25136340]

[201]
Li S, Konstantinov SR, Smits R, Peppelenbosch MP. Bacterial biofilms in colorectal cancer initiation and progression. Trends Mol Med  2017; 23(1): 18-30.
 [http://dx.doi.org/10.1016/j.molmed.2016.11.004] [PMID: 27986421]

[202]
Schindler SE, Bollinger JG, Ovod V, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology  2019; 93(17): e1647-59.
 [http://dx.doi.org/10.1212/WNL.0000000000008081] [PMID: 31371569]

[203]
Cammarota G, Masucci L, Ianiro G, et al. Randomised clinical trial: Faecal microbiota transplantation by colonoscopy vs. vancomycin for the treatment of recurrent Clostridium difficile infection. Aliment Pharmacol Ther  2015; 41(9): 835-43.
 [http://dx.doi.org/10.1111/apt.13144] [PMID: 25728808]

[204]
Bharadwaj P. Animal models of Alzheimer’s disease. In: Martins RN, Brennan CS, Fernando B, Brenana MA, Fuller SJ, Eds. Neuro-degeneration and Alzheimer’s Disease: The Role of Diabetes Genetics, Hormones, and Lifestyle.  Hoboken, New Jersey: Wiley Online Library 2019; pp. 291-310.
 [http://dx.doi.org/10.1002/9781119356752.ch10]

[205]
Saito T, Matsuba Y, Mihira N, et al. Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci  2014; 17(5): 661-3.
 [http://dx.doi.org/10.1038/nn.3697] [PMID: 24728269]

[206]
Willuweit A, Velden J, Godemann R, et al. Early-onset and robust amyloid pathology in a new homozygous mouse model of Alzheimer’s disease. PLoS One  2009; 4(11): e7931.
 [http://dx.doi.org/10.1371/journal.pone.0007931] [PMID: 19936202]

[207]
Allen B, Ingram E, Takao M, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci  2002; 22(21): 9340-51.
 [http://dx.doi.org/10.1523/JNEUROSCI.22-21-09340.2002] [PMID: 12417659]

[208]
Terwel D, Lasrado R, Snauwaert J, et al. Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice. J Biol Chem  2005; 280(5): 3963-73.
 [http://dx.doi.org/10.1074/jbc.M409876200] [PMID: 15509565]

[209]
Nimgampalle M, Kuna Y. Anti-Alzheimer properties of probiotic, Lactobacillus plantarum MTCC 1325 in Alzheimer’s disease induced albino rats. J Clin Diagn Res  2017; 11(8): KC01-5.
 [http://dx.doi.org/10.7860/JCDR/2017/26106.10428] [PMID: 28969160]

[210]
Nägga K, Rajani R, Mårdh E, Borch K, Mårdh S, Marcusson J. Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia. Dement Geriatr Cogn Disord  2003; 16(4): 269-75.
 [http://dx.doi.org/10.1159/000072812] [PMID: 14512723]

[211]
Malaguarnera M, Bella R, Alagona G, Ferri R, Carnemolla A, Pennisi G. Helicobacter pylori and Alzheimer’s disease: A possible link. Eur J Intern Med  2004; 15(6): 381-6.
 [http://dx.doi.org/10.1016/j.ejim.2004.05.008] [PMID: 15522573]

[212]
Meer-Scherrer L, Chang Loa C, Adelson ME, et al. Lyme disease associated with Alzheimer’s disease. Curr Microbiol  2006; 52(4): 330-2.
 [http://dx.doi.org/10.1007/s00284-005-0454-7] [PMID: 16528463]

[213]
Kountouras J, Tsolaki M, Gavalas E, et al. Relationship between Helicobacter pylori infection and Alzheimer disease. Neurology  2006; 66(6): 938-40.
 [http://dx.doi.org/10.1212/01.wnl.0000203644.68059.5f] [PMID: 16567719]

[214]
Kountouras J, Tsolaki M, Boziki M, et al. Association between Helicobacter pylori infection and mild cognitive impairment. Eur J Neurol  2007; 14(9): 976-82.
 [http://dx.doi.org/10.1111/j.1468-1331.2007.01827.x] [PMID: 17718688]

[215]
Kountouras J, Boziki M, Gavalas E, et al. Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer’s disease. Int J Neurosci  2009; 119(6): 765-77.
 [http://dx.doi.org/10.1080/00207450902782083] [PMID: 19326283]

[216]
Kountouras J, Boziki M, Gavalas E, et al. Eradication of Helicobacter pylori may be beneficial in the management of Alzheimer’s disease. J Neurol  2009; 256(5): 758-67.
 [http://dx.doi.org/10.1007/s00415-009-5011-z] [PMID: 19240960]

[217]
Kountouras J, Boziki M, Gavalas E, et al. Five-year survival after Helicobacter pylori eradication in Alzheimer disease patients. Cogn Behav Neurol  2010; 23(3): 199-204.
 [http://dx.doi.org/10.1097/WNN.0b013e3181df3034] [PMID: 20829670]

[218]
Shiota S, Murakami K, Yoshiiwa A, et al. The relationship between Helicobacter pylori infection and Alzheimer’s disease in Japan. J Neurol  2011; 258(8): 1460-3.
 [http://dx.doi.org/10.1007/s00415-011-5957-5] [PMID: 21336779]

[219]
Sparks Stein P, Steffen MJ, Smith C, et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease. Alzheimers Dement  2012; 8(3): 196-203.
 [http://dx.doi.org/10.1016/j.jalz.2011.04.006] [PMID: 22546352]

[220]
Roubaud-Baudron C, Panhard X, Krolak-Salmon P, Quadrio I, Mégraud F, Salles N. Change of the dependent variable. Neurobiol Aging  2013; 34(6): e1.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2012.12.022] [PMID: 23380420]

[221]
Farhad SZ, Amini S, Khalilian A, et al. The effect of chronic periodontitis on serum levels of tumor necrosis factor-alpha in Alzheimer disease. Dent Res J (Isfahan)  2014; 11(5): 549-52.
 [PMID: 25426144]

[222]
Noble JM, Scarmeas N, Celenti RS, et al. Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease. PLoS One  2014; 9(12): e114959.
 [http://dx.doi.org/10.1371/journal.pone.0114959] [PMID: 25522313]

[223]
Kamer AR, Pirraglia E, Tsui W, et al. Periodontal disease associates with higher brain amyloid load in normal elderly. Neurobiol Aging  2015; 36(2): 627-33.
 [http://dx.doi.org/10.1016/j.neurobiolaging.2014.10.038] [PMID: 25491073]

[224]
Mahami-Oskouei M, Hamidi F, Talebi M, et al. Toxoplasmosis and Alzheimer: Can Toxoplasma gondii really be introduced as a risk factor in etiology of Alzheimer? Parasitol Res  2016; 115(8): 3169-74.
 [http://dx.doi.org/10.1007/s00436-016-5075-5] [PMID: 27106237]

[225]
Andreadou E, Pantazaki AA, Daniilidou M, Tsolaki M. Rhamnolipids, microbial virulence factors, in Alzheimer’s disease. J Alzheimers Dis  2017; 59(1): 209-22.
 [http://dx.doi.org/10.3233/JAD-161020] [PMID: 28598837]
Cite As
CNS & Neurological Disorders - Drug Targets

The Role of the Gut Microbiota and Microbial Metabolites in the Pathogenesis of Alzheimer’s Disease

Abstract

Graphical Abstract
